Date: 2023.1.12

Name: Fan Zaixi

Journal: Journal of Virology

Title:  Establishment of a Cynomolgus Macaque Model of Human T-Cell Leukemia Virus Type 1 (HTLV-1) Infection by Direct Inoculation of Adult T-Cell Leukemia Patient-Derived Cell Lines for HTLV-1 Infection

Authors: Emiko Urano, Kayoko Ueda, Mahoko Higuchi, Mugi Furukawa, Tomotaka, Okamura, Yuetsu Tanaka, Yasuhiro Yasutomi

URL: Establishment of a Cynomolgus Macaque Model of Human T-Cell Leukemia Virus Type 1 (HTLV-1) Infection by Direct Inoculation of Adult T-Cell Leukemia Patient-Derived Cell Lines for HTLV-1 Infection | Journal of Virology (asm.org)

 

Abstracts: Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, the precise mechanisms leading to HTLV-1 chronic infection and the onset of the diseases have remained unclear, and effective vaccines for inhibiting the infection and the progression of pathogenesis have therefore not been developed. The use of a nonhuman primate (NHP) model is thought to be important for revealing the mechanisms of the progressive status and for the development of prevention procedures. In this study, we developed a cynomolgus macaque (CM) model of HTLV-1 infection by direct intravenous inoculation of HTLV-1-producing cells derived from ATL patients. The cell line used for infection, ATL-040, was selected as the most infectious one in our cell line library. CMs inoculated intravenously with 1x108 ATL-040 cells per animal became persistently infected with HTLV-1, as shown by the HTLV-1 provirus load (PVL) in peripheral blood mononuclear cells and HTLV-1-specifific antibodies (2/2 animals). One CM inoculated intravenously with 1x107 ATL-040 cells did not have detectable PVLs despite the fact that anti-HTLV-1 antibodies were maintained for more than 2 years. Furthermore, immunological approaches, including CD8+ T cell depletion prior to infection (3/3 animals) and intrathecal inoculation (3/3 animals), led to increased proviral loads in the cynomolgus monkeys. The present method and the cynomolgus monkey model of HTLV-1 infection will be benefificial for immunological and virological studies on HTLV-1 aiming at the development of anti-HTLV-1 prophylactic vaccines and therapy drugs.

 

Date: 2022.12.8

Name: Jintian Gao

Journal: PLoS Pathog 18(9): e1010845

Title: Measuring the latent reservoir for HIV-1: Quantification bias in near full-length genome sequencing methods 

Authors: Jennifer A. White1, Joshua T. Kufera1, Niklas Bachmann1, Weiwei Dai1, Francesco R. Simonetti1, Ciara Armstrong1, Jun Lai1, Subul Beg1, Janet D. Siliciano1, Robert

URL: https://doi.org/10.1371/journal.ppat.1010845

 

Abstracts: Antiretroviral therapy (ART) effectively inhibits HIV-1 replication but is not curative due to the persistence of a latent viral reservoir in resting CD4+ T cells. This reservoir is a major

 

barrier to cure. Sequencing studies have revealed that the population of proviruses persisting in ART-treated individuals is dominated by defective proviruses that cannot give rise to viral rebound due to fatal defects including large deletions and APOBEC3-mediated hypermutation. Near full genome sequencing (nFGS) of individual proviruses is used in reservoir assays to provide an estimate of the fraction of proviruses that are intact. nFGS methods rely on a long-distance outer PCR capturing most (~9 kb) of the genome, followed by nested inner PCRs. The outer PCR is carried out at limit dilution, and interpretation of the results is based on the assumption that all proviruses are quantitatively captured. Here, we evaluate nFGS methods using the intact proviral DNA assay (IPDA), a multiplex digital droplet PCR assay that quantitates intact and defective proviruses with single molecule sensitivity using only short, highly efficient amplicons. We analyzed proviral templates of known sequence to avoid the additional complication of sequence polymorphism. With the IPDA, we quantitated molecular yields at each step of nFGS methods. We demonstrate that nFGS methods are inefficient and miss ~70% of full-length proviruses due to amplification failure at the initial outer PCR step. In contrast, proviruses with large internal deletions encompassing 70% of the genome can be quantitatively amplified under the same conditions. Accurate measurement of the latent reservoir of HIV-1 is essential for evaluating the efficacy of cure strategies, and the bias against full length proviruses in nFGS methods must be considered.

 

 

Date: 2022.11.10

Name: Jumpei Maki

Journal: J. Virol. 2022, 96, e01953-21

Title: Bryostatin-1 Decreases HIV-1 Infection and Viral Production in Human Primary Macrophages

Authors: Laurent Hany, Marc-Olivier Turmel, Corinne Barat, Michel Ouellet, Michel J Tremblay

URL: DOI: https://doi.org/10.1128/jvi.01953-21

 

Abstracts: While combination antiretroviral therapy maintains undetectable viremia in people living with HIV (PLWH), a lifelong treatment is necessary to prevent viremic rebound after therapy cessation. This rebound seemed mainly caused by long-lived HIV-1 latently infected cells reverting to a viral productive status. Reversing latency and elimination of these cells by the so-called shock-and-kill strategy is one of the main investigated leads to achieve an HIV-1 cure. Small molecules referred to as latency reversal agents (LRAs) proved to efficiently reactivate latent CD4+ T cells. However, the LRA impact on de novo infection or HIV-1 production in productively infected macrophages remains elusive. Nontoxic doses of bryostatin-1, JQ1, and romidepsin were investigated in human monocyte-derived macrophages (MDMs). Treatment with bryostatin-1 or romidepsin resulted in a downregulation of CD4 and CCR5 receptors, respectively, accompanied by a reduction of R5 tropic virus infection. HIV-1 replication was mainly regulated by receptor modulation for bryostatin-1, while romidepsin effects rely on upregulation of SAMHD1 activity. LRA stimulation of chronically infected cells did not enhance HIV-1 production or gene expression. Surprisingly, bryostatin-1 caused a major decrease in viral production. This effect was not viral strain specific but appears to occur only in myeloid cells. Bryostatin-1 treatment of infected MDMs led to decreased amounts of capsid and matrix mature proteins with little to no modulation of precursors. Our observations revealed that bryostatin-1-treated myeloid and CD4+ T cells respond differently upon HIV-1 infection. Therefore, additional studies are warranted to more fully assess the efficiency of HIV-1 eradicating strategies.

 

 

Date: 2022.10.13

Name: Sakura Hayashi

Journal: Journal of Virology

Title: Establishment of a Monoclonal Antibody against Human NTCP That Blocks Hepatitis B Virus Infection

Authors: Toshitada Takemori, Akiko Sugimoto-Ishige, Hironori Nishitsuji. et al.

URL: DOI: https://doi.org/10.1128/jvi.01686-21

 

Abstracts: A number of entry inhibitors are being developed to enhance the treatment of HBV patients with oral nucleoside/nucleotide analogues (NA). To amplify the effectiveness of NA therapy, several efforts have been made to develop therapeutic MAbs with neutralizing activity against HBs antigens. Hepatitis B virus (HBV) infects 240 million people worldwide. Current therapy profoundly suppresses HBV replication but requires long-term maintenance therapy. Therefore, there is still a medical need for an efficient HBV cure. HBV enters host cells by binding via the preS1 domain of the viral L protein to the Na+/taurocholate cotransporting polypeptide (NTCP). Thus, NTCP should be a key target for the development of anti-HBV therapeutics. Indeed, myrcludex B, a synthetic form of the myristoylated preS1 peptide, effectively reduces HBV/hepatitis D virus (HDV) infection and has been approved as Hepcludex in Europe for the treatment of patients with chronic HDV infection. We established a monoclonal antibody (MAb), N6HB426-20, that recognizes the extracellular domain of human NTCP and blocks HBV entry in vitro into human liver cells but has much less of an inhibitory effect on bile acid uptake. In vivo, administration of the N6HB426-20 MAb prevented HBV viremia for an extended period of time after HBV inoculation in a mouse model system without strongly inhibiting bile acid absorption. Among the extracellular loops (ECLs) of NTCP, regions of amino acids (aa) 84 to 87 in ECL1 and aa 157 to 165 near ECL2 of transmembrane domain 5 are critically important for HBV/HDV infection. Epitope mapping and the three-dimensional (3D) model of the NTCP structure suggested that the N6HB426-20 MAb may recognize aa 276/277 at the tip of ECL4 and interfere with binding of HBV to the region from aa 84 to 87. In summary, we identified an in vivo neutralizing NTCP-targeting antibody capable of preventing HBV infection. Further improvements in efficacy of this drug will pave the way for its clinical applications.

 

 

Date: 2020.9.17

Name: Shiro Aso

Journal: Nucleic Acids Research

Title: The chromatin landscape at the HIV-1 provirusintegration site determines viral expression

Authors: Gerlinde Vansant, Heng-Chang Chen, Eduard Zorita, Katerina Trejbalova,

Dalibor Mikl ́ık, Guillaume Filion and Zeger Debyser

URL: DOI: 10.1093/nar/gkaa536

 

Abstracts: HIV-1 persists lifelong in memory cells of the immune system as latent provirus that rebounds upon treatment interruption. Therefore, the latent reservoir is the main target for an HIV cure. Here, we studied the direct link between integration site and transcription using LEDGINs and Barcoded HIV-ensembles (B- HIVE). LEDGINs are antivirals that inhibit the interaction between HIV-1 integrase and the chromatin- tethering factor LEDGF/p75. They were used as a tool to retarget integration, while the effect on HIV expression was measured with B-HIVE. B-HIVE tracks insert-specific HIV expression by tagging a unique barcode in the HIV genome. We confirmed that LEDGINs retarget integration out of gene-dense and actively transcribed regions. The distance to H3K36me3, the marker recognized by LEDGF/p75, clearly increased. LEDGIN treatment reduced viral RNA expression and increased the proportion of silent provirus. Finally, silent proviruses obtained after LEDGIN treatment were located further away from epigenetic marks associated with active transcription. Interestingly, proximity to enhancers stimulated transcription irrespective of LEDGIN treatment, while the distance to H3K36me3 only changed after treatment with LEDGINs. The fact that proximity to these markers are associated with RNA expression support the direct link between provirus integration site and viral expression.

 

 

Date: 2020.9.3

Name: Ayaka Washizaki

Journal: PNAS

Title: Prodrugs of PKC modulators show enhanced HIV latency reversal and an expanded therapeutic window.

URL: https://doi.org/10.1073/pnas.1919408117

Background: HIV-1感染症は抗HIV療法(ART)の発展により慢性疾患の一つとなったが、ARTでは体内の潜伏感染細胞を完全に除くことはできない。現在HIV-1感染症の完治を目指してShock and kill療法の開発が進んでいる。Shock and killはLatency reversing agents (LRAs)を用いて潜伏感染細胞を再活性化して、ウイルスによる細胞毒性または宿主の免疫により排除しようという治療法である。現在、Shock and kill実現のためにLRAの研究が盛んに行われており、様々なクラスのLRAが報告されているが、その中でもPKC activatorは強くHIVを再活性化できることがすでに知られている。

しかしながら、過去の癌患者への臨床試験においてPKC activatorは静脈への短時間投与で副作用が起こることが報告されており、投与には長時間にわたる点滴を必要とする。このような長時間投与は患者と施術者両者への大きな負担となる。

したがって今回筆者らはprodrugの手法に着目した。Prodrugは実際の薬剤に何らかの側鎖をつけたもので投与後体内において代謝され、側鎖が外れることにより、薬剤としての効果を発揮するというものである。LRAのprodrug(pro-LRA)の場合は、体内で代謝されることによりpro-drugに変化することで投与後の急激な血中濃度の上昇を防ぐという狙いがある。

実際に、筆者らが合成したPro-LRAについてHIV-1再活性化能を見てみると、parent LRAに比べ遅れてHIV-1の再活性化が見られた。そして、最終的にはparent LRAと同等のHIV再活性化能を示した。またマウスへの投与実験ではparent LRAが毒性を示した濃度においても、pro-LRAを投与したマウスでは毒性を示さなかった。このことから、pro-drugによりHIV-1再活性化能はそのままに毒性のみを抑えてTherapeutic windowを広げられることが明らかとなった。

 

これらの結果より、prodrugはLRAにおいても有用であることが示唆され、今後ますますの研究の推進が期待される。

 

 

Date: 2020.7.9

Name: Satyajit Biswas

Journal: Nature Medicine

Title: CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption

Authors: Justin Harper. et al

URL: https:// doi.org/10.1038/s41591-020-0782-y

 

Abstract: Inhibitory immune checkpoint receptors expressed on T cell and over expressed inhibitory checkpoint receptors can disrupts T cell mediated immunological function. Blockade of inhibitory checkpoint receptors may activate the T cell proliferation. On HIV/SIV infected individuals, continuous antigen stimulation is sustained expression of inhibitory receptors, thus cardinal feature of T cell impaired. Long term ART treated SIV/HIV infected patients can able to persists replication competent SIV/HIV on resting memory CD4+ T cells which often express immune checkpoint receptors PD-1 and CTLA-4. Blockade of PD-1 and CTLA-4 which highly expressed on CD4+ T cell may activate the T cell mediated immune response and trigger the immunity against active or latent HIV/SIV reservoir. During this study, Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4⁺ T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8⁺ T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.

 

 

Date: 2020.5.28

Name: Hisatoshi Shida

Journal: Nature Medicine

Title: Tcell-inducing vaccine durably prevents mucosal SHIV infection even with lower neutralizing antibody titers

Authors: Prabhu S. Arunachalam, Tysheena P. Charles, et al

URL: https:// doi.org/10.1038/s41591-020-0858-8

 

Abstract: Recent efforts toward an HIV vaccine focus on inducing broadly neutralizing antibodies, but eliciting both neutralizing antibodies (nAbs) and cellular responses may be superior. Here, we immunized macaques with an HIV envelope trimer, either alone to induce nAbs, or together with a heterologous viral vector regimen to elicit nAbs and cellular immunity, including CD8+ tissue-resident memory T cells. After ten vaginal challenges with autologous virus, protection was observed in both vaccine groups at 53.3% and 66.7%, respectively. A nAb titer >300 was generally associated with protection but in the heterologous viral vector"+"nAb group, titers <300 were sufficient. In this group, protection was durable as the animals resisted six more challenges 5 months later. Antigen stimulation of T cells in ex vivo vaginal tissue cultures triggered antiviral responses in myeloid and CD4+ T cells. We propose that cellular immune responses reduce the threshold of nAbs required to confer superior and durable protection.

 

 

Date: 2020.5.21

Name: Tomoyuki Miura

Journal: Nature Medicine

Title: Structural basis for potent neutralization of betacoronaviruses by single-domain camelid antibodies

Authors: Daniel Wrapp, et al

URL: https://doi.org/10.1016/j.cell.2020.04.031

Abstract: Coronaviruses make use of a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. Because of the vital role that these S proteins play, they represent a vulnerable target for the development of therapeutics. Here, we describe the isolation of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs neutralize MERS-CoV or SARS-CoV-1 S pseudotyped viruses, respectively. Crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs interfere with receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S and demonstrate that this cross-reactive VHH neutralizes SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion. These data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that these molecules may serve as useful therapeutics during coronavirus outbreaks.

 

 

 

Date: 2020.4.30

Name: Satyajit Biswas

Journal: Retrovirlogy

Title: Role of HTLV-1 orf-I encoded proteins in viral transmission and persistence

Authors: Sarkis Sarkis, Veronica Galli, Ramona Moles, David Yurick, Georges Khour, Damian F. J. Purcell, Genovefa Franchini* and Cynthia A. Pise‐Masison*

URL: https://doi.org/10.1186/s12977-019-0502-1

 

Abstract: The human T cell leukemia virus type 1 (HTVL-1), first reported in 1980 by Robert Gallo’s group, is the etiologic agent of both cancer and inflammatory diseases. Despite approximately 40 years of investigation, the prognosis for afflicted patients remains poor with no effective treatments. The virus persists in the infected host by evading the host immune response and inducing proliferation of infected CD4⁺ T-cells. Here, we will review the role that viral orf-I protein products play in altering intracellular signaling, protein expression and cell–cell communication in order to escape immune recognition and promote T-cell proliferation. We will also review studies of orf-I mutations found in infected patients and their potential impact on viral load, transmission and persistence. Finally, we will compare the orf-I gene in HTLV-1 subtypes as well as related STLV-1.

 

 

Date: 2020.4.16

Name: Yalcin Pisil

Journal: Pathogens

Title: Specific Substitutions in Region V2 of gp120 env confer SHIV Neutralisation Resistance

Authors: Yalcin Pisil, Zafer Yazici, Hisatoshi Shida, Shuzo Matsushita, Tomoyuki Miura

Background/Objective: A tier 2 SHIV-MK38 strain was obtained after two in vivo passages of tier 1 SHIV-MK1. SHIV-MK38#818, cloned from the MK38 strain, was neutralisation-resistant, like the parental MK38 strain, to SHIV-infected monkey plasma (MP), HIV-1-infected human pooled plasma (HPP), and KD247 monoclonal antibody (mAb) (anti-V3 gp120 env). We investigated the mechanisms underlying the resistance of #818, specifically the amino acid substitutions that confer resistance to MK1.

 

Results: The neutralisation resistance of the mutant MK1s with 7 of 11 substitutions in the V1, C2, C4, and V5 regions did not change significantly. These substitutions did not alter any negative charges or N-glycans. The substitutions N169D and K187E, which added negative charges, and S190N in the V2 region of gp120 and A389T in V4, which created sites for N-glycan, conferred high neutralisation resistance. The combinations N169D+K187E, N169D+S190N, and N169D+A389T resulted in MK1 neutralisation resistance close to that of #818. The combinations without 169D were neutralisation-sensitive. Therefore, N169D is the most important substitution for neutralisation resistance.
Discussion: This study demonstrated that although the V3 region sequences of #818 and MK1 are the same, V3 binding antibodies cannot neutralise #818 pseudovirus. Instead, mutations in the V2 and V4 regions inhibit the neutralisation of anti-V3 antibodies. We hypothesised that 169D and 190N altered the MK1 Env conformation so that the V3 region is buried. Therefore, the V2 region may block KD247 from binding to the tip of the V3 region.

 

 

Date:2020.4.3

Name: Anastasiia Kovba

Journal: Nature Communications

Title: Sensing of HIV-1 by TLR8 activates human T cells and reverses latency

Authors: Hany Zekaria Meås, Markus Haug, Marianne Sandvold Beckwith, Claire Louet, Liv Ryan, Zhenyi Hu, Johannes Landsron, Svein Arne Nordbø, Kjetil Taskén, Hang Yin, Jan Kristian Damås, Trude Helen Flo

URL: https://doi.org/10.1038/s41467-019-13837-4

Background: During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood.

Conclusion: Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, further promoted T helper cell differentiation towards Th1 and Th17. In addition, we found that endosomal HIV induced cytokine secretion from CD4+ T cells in a TLR8-specific manner. TLR8 engagement also enhanced HIV-1 replication and potentiated the reversal of latency in patient-derived T cells. The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. In addition, it can potentially be exploited for therapeutic targeting and vaccine development.

 

 

Date: 2020.3.19

Name: Hisatoshi shida

Journal: Cell (2020)

Title: SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Authors: Markus Hoffmann et al.

URL: https://doi.org/10.1016/j.cell.2020.02.052

Background: The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to

cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets.

Conclusion: Authors demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Their results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

 

 

Date: 2020.2.27

Name: Ayaka Washizaki

Journal : Nature

Title: Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo. 

Authors: Christopher C. Nixon, Maud Mavigner, Gavin C. Sampey, Alyssa D. Brooks, Rae Ann Spagnuolo, David M. Irlbeck, Cameron Mattingly, Phong T. Ho, Nils Schoof, Corinne G. Cammon, Greg K. Tharp, Matthew Kanke, Zhang Wang, Rachel A. Cleary, Amit A. Upadhyay, Chandrav De, Saintedym R. Wills, Shane D. Falcinelli, Cristin Galardi, Hasse Walum, Nathaniel J. Schramm, Jennifer Deutsch, Jeffrey D. Lifson, Christine M. Fennessey, Brandon F. Keele, Sherrie Jean, Sean Maguire, Baolin Liao, Edward P. Browne, Robert G. Ferris, Jessica H. Brehm, David Favre, Thomas H. Vanderford, Steven E. Bosinger, Corbin D. Jones, Jean-Pierre Routy, Nancie M. Archin, David M. Margolis, Angela Wahl, Richard M. Dunham, Guido Silvestri, Ann Chahroudi & J. Victor Garcia

URL: https://doi.org/10.1038/s41586-020-1951-3

Background: HIV-1感染症は抗HIV療法(ART)の発展により慢性疾患の一つとなったが、ARTでは体内の潜伏感染細胞を完全に除くことはできない。現在HIV-1感染症の完治を目指してShock and kill療法の開発が進んでいる。Shock and killはLatency reversing agents (LRAs)を用いて潜伏感染細胞を再活性化して、ウイルスによる細胞毒性または宿主の免疫により排除しようという治療法である。現在、Shock and killのClinical trialが精力的に進められている。しかしながら、ヒトでは血液以外の組織(例えばHIVの主要なリザーバーとして知られているリンパ節など)の入手が困難なため、shock and killの有効性の評価を正しく行うことは難しい。そこで筆者はマウスとサルという二種類の動物モデルを用いてnon-canonical NF-kB pathwayを活性化するAZD5582によるウイルスの再活性化を測定した。その結果AZDはどちらの動物モデルにおいてもviremiaを引き起こすことが明らかになった。またこの時に組織でもウイルスRNAの上昇が見られ、AZDは全身の組織からのウイルスの再活性化が可能であることが明らかになった。今回の試験では、ウイルスの再活性化は見られたもののリザーバーサイズの縮小は見られなかった。このことからShockだけでリザーバーサイズを縮小することは難しく、therapeutic vaccineなどのkillの導入の必要性が示唆された。

 

 

Date: 2020.2.6

Name: Satyajit Biswas

Journal: PLOS Pathogen

Title: Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling

Authors: Michi Miura, Supravat Dey, Saumya Ramanayake, Abhyudai Singh, David S. Rueda, Charles R. M. Bangham

Abstract: The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-strand transcription is usually silent at a given time in each cell. However, cellular stress responses trigger the reactivation of HTLV-1, enabling the virus to transmit to a new host cell. Using single-molecule RNA FISH, we measured the kinetics of the HTLV-1 transcriptional reactivation in peripheral blood mononuclear cells (PBMCs) isolated from HTLV-1+ individuals. The abundance of the HTLV-1 sense and antisense transcripts was quantified hourly during incubation of the HTLV-1-infected PBMCs ex vivo. We found that, in each cell, the sense-strand transcription occurs in two distinct phases: the initial low-rate transcription is followed by a phase of rapid transcription. The onset of transcription peaked between 1 and 3 hours after the start of in vitro incubation. The variance in the transcription intensity was similar in polyclonal HTLV-1+ PBMCs (with tens of thousands of distinct provirus insertion sites), and in samples with a single dominant HTLV-1+ clone. A stochastic simulation model was developed to estimate the parameters of HTLV-1 proviral transcription kinetics. In PBMCs from a leukemic subject with one dominant T-cell clone, the model indicated that the average duration of HTLV-1 sense-strand activation by Tax (i.e. the rapid transcription) was less than one hour. HTLV-1 antisense transcription was stable during reactivation of the sense-strand. The antisense transcript HBZ was produced at an average rate of ~0.1 molecules per hour per HTLV-1+ cell; however, between 20% and 70% of HTLV-1-infected cells were HBZ-negative at a given time, the percentage depending on the individual subject. HTLV-1-infected cells are exposed to a range of stresses when they are drawn from the host, which initiate the viral reactivation. We conclude that whereas anti-sense-strand transcription is stable throughout the stress response, the HTLV-1 sense-strand reactivation is highly heterogeneous and occurs in short, self-terminating bursts.

 

 

Date: 2019.12.18

Name: Anastasiia Kovba

Journal: Science translational medicine

Title: The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation

Authors: Melissa-Rose Abrahams, Sarah B. Joseph, Nigel Garrett, Lynn Tyers, Matthew Moeser, Nancie Archin, Olivia D. Council, David Matten, Shuntai Zhou, Deelan Doolabh, Colin Anthony, Nilu Goonetilleke, Salim Abdool Karim, David M. Margolis, Sergei Kosakovsky Pond, Carolyn Williamson, Ronald Swanstrom

Abstract: Although antiretroviral therapy (ART) is highly effective at suppressing HIV-1 replication, the virus persists as a latent reservoir in resting CD4+T cells during therapy. This reservoir forms even when ART is initiated early after infection, but the dynamics of its formation are largely unknown. The viral reservoirs of individuals who initiate ART during chronic infection are generally larger and genetically more diverse than those of individuals who initiate therapy during acute infection, consistent with the hypothesis that the reservoir is formed continuously throughout untreated infection. To determine when viruses enter the latent reservoir, we compared sequences of replication-competent viruses from resting peripheral CD4+ T cells from nine HIV-positive women on therapy to viral sequences circulating in blood collected longitudinally before therapy. We found that, on average, 71% of the unique viruses induced from the post-therapy latent reservoir were most genetically similar to viruses replicating just before ART initiation. This proportion is far greater than would be expected if the reservoir formed continuously and was always long lived. We conclude that ART alters the host environment in a way that allows the formation or stabilization of most of the long-lived latent HIV-1 reservoir, which points to new strategies targeted at limiting the formation of the reservoir around the time of therapy initiation.

 

 

Date: 2019.12.4

Name: Satyajit Biswas

Journal: Frontiers in Microbiology

Title: Inhibition of HTLV-1 Infection by HIV-1 First- and Second-Generation Integrase Strand Transfer Inhibitors

Authors: Michał S. Barski, Jordan J. Minnell and Goedele N. Maertens

Abstract: The Human T Cell Leukemia Virus types-1 (HTLV-1) belong to the retroviridae family like Human Immunodeficiency Virus type-1 (HIV-1) which identified as the first human oncogenic retrovirus about 30-year ago but it is not ubiquitous virus. In recent time it is estimated that more than 10 million people around the world are infected with this oncogenic delta-type retrovirus but exact the exact number still not determined due to lack of information and data. Cell to cell transmission of HTLV-1 is occur mainly by three routes: Mother to infant transmission, transmission of infected T-lymphocytes through blood transfusion and by sexual; transmission. From them around to ten percent of asymptomatic HTLV-1 carriers develop a severe HTLV-1 associated diseases: Adult T cell leukemia/ lymphoma (ATLL), or a neurological disorder named Tropical Spastic Paraparesis/ HTLV-1 Associated Myelopathy (TSP/ HAM). HTLV-1 is a blood borne pathogen like HIV-1 and viral infection happens in a similar fashion, with the major route of transmission is breastfeeding. HTLV-1 retrovirus has the ability to develop latency/ silence state in the asymptomatic carriers but the latent site in carriers still unknown. Besides, there is no successful therapeutic or preventive regimen for HTLV-1. Therefore, it is essential to develop a better therapy to inhibit transmission or block the onset/ development of HTLV-1 associated diseases. At present, we have seen the overwhelmed success of integrase strand transfer inhibitors (INSTIs) on the treatment of HIV-1 and reduction of proviral load into the HTLV-1 infected carriers. In this article, they tested FDA- approved and two-phase HIV-1 INSTIs in-vitro and in a cell to cell infection model and found that they are highly active in blocking HTLV-1 infection with bictegravir (EC50= 0.30 ± 0.17 nM) performed best overall. They revealed that, INSTIs, in particular bictegravir, are more potent in blocking HTLV-1 transmission than tenofovir disoproxil fumarate (TDF) on RT inhibition. This research data also suggests that HIV-1 INSTIs could reveal or present a good clinical strategy in HTLV-1 management and justifies the inclusion of INSTIs in clinical trials.

 

 

Date: 2019.11.21

Name: Tomoyuki Miura

Journal: Nature

Title: Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET

Authors: Maolin Lu, Xiaochu Ma, Luis R. Castillo-Menendez, Jason Gorman, Nirmin Alsahafi, Utz Ermel, Daniel S. Terry, Michael Chambers, Dongjun Peng, Baoshan Zhang, Tongqing Zhou, Nick Reichard, Kevin Wang, Jonathan R. Grover, Brennan P. Carman, Matthew R. Gardner, Ivana Nikić-Spiegel, Akihiro Sugawara, James Arthos, Edward A. Lemke, Amos B. Smith III, Michael Farzan, Cameron Abrams, James B. Munro, Adrian B. McDermott, Andrés Finzi, Peter D. Kwong, Scott C. Blanchard, Joseph G. Sodroski, Walther Mothes

Abstract: The HIV-1 envelope glycoprotein (Env) trimer mediates cell entry and is conformationally dynamic. Imaging by single-molecule fluorescence resonance energy transfer (smFRET) has revealed that, on the surface of intact virions, mature pre-fusion Env transitions from a pre-triggered conformation (state 1) through a default intermediate conformation (state 2) to a conformation in which it is bound to three CD4 receptor molecules (state 3). It is currently unclear how these states relate to known structures. Breakthroughs in the structural characterization of the HIV-1 Env trimer have previously been achieved by generating soluble and proteolytically cleaved trimers of gp140 Env that are stabilized by a disulfide bond, an isoleucine-to-proline substitution at residue 559 and a truncation at residue 664 (SOSIP.664 trimers). Cryo-electron microscopy studies have been performed with C-terminally truncated Env of the HIV-1JR-FL strain in complex with the antibody PGT151. Both approaches have revealed similar structures for Env. Although these structures have been presumed to represent the pre-triggered state 1 of HIV-1 Env, this hypothesis has never directly been tested. Here we use smFRET to compare the conformational states of Env trimers used for structural studies with native Env on intact virus. We find that the constructs upon which extant high-resolution structures are based predominantly occupy downstream conformations that represent states 2 and 3. Therefore, the structure of the pretriggered state-1 conformation of viral Env that has been identified by smFRET and that is preferentially stabilized by many broadly neutralizing antibodies—and thus of interest for the design of immunogens—remains unknown.

 

 

Date: 2019.9.26

Name: Megumi Murata

Journal: PLOS Pathogens

Authors: Sonia Assil1, Nicolas Futsch, Elodie De ́cembre, Sandrine Alais, Antoine Gessain, Francois-Loïc Cosset, Renaud Mahieux, Marlène DreuxID, He ́lène DutartreID

Title: Sensing of cell-associated HTLV by plasmacytoid dendritic cells is regulated by dense β-galactoside glycosylation

Abstract: Human T Lymphotropic virus (HTLV) infection can persist in individuals resulting, at least in part, from viral escape of the innate immunity, including inhibition of type I interferon response in infected T-cells. Plasmacytoid dendritic cells (pDCs) are known to bypass viral escape by their robust type I interferon production. Here, we demonstrated that pDCs produce type I interferons upon physical cell contact with HTLV-infected cells, yet pDC activation inversely correlates with the ability of the HTLV-producing cells to transmit infection. We show that pDCs sense surface associated-HTLV present with glycan-rich structure referred to as biofilm-
like structure, which thus represents a newly described viral structure triggering the antiviral response by pDCs. Consistently, heparan sulfate proteoglycans and especially the cell surface pattern of terminal β-galactoside glycosylation, modulate the transmission of the immunostimulatory RNA to pDCs. Altogether, our results uncover a function of virus-containing cell surface-associated glycosylated structures in the activation of innate immunity.

 

 

Date: 2019.8.9

Name: Yovita Hendra

Journal: PLOS Pathogens

Title: FOXO1 transcription factor plays a key role in T cell—HIV-1 interaction

Authors: Arthur Roux, He´loise Leroy, Be´ne´dicte De Muylder, Lucie Bracq,

Samia Oussous,  Isabelle Dusanter-Fourt, Ghina Chougui, Rachida Tacine, Clotilde Randriamampita, Delphine Desjardins, Roger Le Grand, Frederic Bouillaud, Serge Benichou, Florence Margottin-Goguet, Remi Cheynier, Georges Bismutt, Marianne Mangeney

Abstract: HIV-1 is dependent on the host cell for providing the metabolic resources for completion of its viral replication cycle. Thus, HIV-1 replicates efficiently only in activated CD4+ T cells. Barriers preventing HIV-1 replication in resting CD4+ T cells include a block that limits reverse transcription and also the lack of activity of several inducible transcription factors, such as NF-κB and NFAT. Because FOXO1 is a master regulator of T cell functions, we studied the effect of its inhibition on T cell/HIV-1 interactions. By using AS1842856, a FOXO1 pharmacologic inhibitor, we observe that FOXO1 inhibition induces a metabolic activation of T cells with a G0/G1 transition in the absence of any stimulatory signal. One parallel outcome of this change is the inhibition of the activity of the HIV restriction factor SAMHD1 and the activation of the NFAT pathway. FOXO1 inhibition by AS1842856 makes resting T cells permissive to HIV-1 infection. In addition, we found that FOXO1 inhibition by either AS1842856 treatment or upon FOXO1 knockdown induces the reactivation of HIV-1 latent proviruses in T cells. We conclude that FOXO1 has a central role in the HIV-1/T cell interaction and that inhibiting FOXO1 with drugs such as AS1842856 may be a new therapeutic shock-and-kill strategy to eliminate the HIV-1 reservoir in human T cells.

 

 

Date: 2019.8.9

Name: Samantha Raina Satrya

Journal: Cell

Title: Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance. 

Authors: Kimberly M. Cirelli, Diane G. Carnathan, Bartek Nogal, Jacob T. Martin, Oscar L. Rodriguez, Amit A. Upadhyay, Chiamaka A. Enemuo, Etse H. Gebru, Yury Choe, Federico Viviano, Catherine Nakao, Matthias G. Pauthner, Samantha Reiss, Christopher A. Cottrell, Melissa L. Smith, Raiza Bastidas, William Gibson, Amber N. Wolabaugh, Mariane B. Melo, Benjamin Cossette, Venkatesh Kumar, Nirav B. Patel,

Talar Tokatlian, Sergey Menis, Daniel W. Kulp, Dennis R. Burton, Ben Murrell, William R. Schief, Steven E. Bosinger, Andrew B. Ward, Corey T. Watson, Guido Silvestri, Darrell J. Irvine, and Shane Crotty

Abstract: Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (TFH) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identi- fied differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization stra- tegies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes.

 

 

Date: 2019.7.18

Name: Anna Hu

Journal : Science Translational Medicine

Title: Heterogeneous antiretroviral drug distribution and HIV/SHIV detection in the gut of three species

Authors: Corbin G. Thompson, Elias P. Rosen, Heather M. A. Prince, Nicole White, Craig Sykes, Gabriela de la Cruz, Michelle Mathews, Claire Deleage, Jacob D. Estes, Paige Charlins, Leila R. Mulder, Martina Kovarova, Lourdes Adamson, Shifali Arora, Evan S. Dellon, Anne F. Peery, Nicholas J. Shaheen, Cynthia Gay, David C. Muddiman, Ramesh Akkina, J. Victor Garcia, Paul Luciw and Angela D. M. Kashuba

URL: https://stm.sciencemag.org/content/11/499/eaap8758/tab-pdf

Background: One of the major obstacles to combating the eradication of HIV is the persistence of HIV in reservoirs. Currently, several major reservoir locations are known, including the peripheral blood, lymph nodes, GALT, and central nervous system. While antiretroviral drug therapy (ART) can help prevent HIV replication and suppress viral activity to undetectable levels, it is unable to completely eradicate HIV in these latent reservoirs, possibly due to suboptimal antiretroviral (ARV) drug penetration into tissues. In this report, a more sophisticated view into the distribution of ARV drugs in git (ileum and rectal) tissue is accomplished using mass spectrometry imaging (MSI).

Conclusion: One objective of this report is to assess the colocalization of ARV drugs with HIV target cells (CD3+ T cells). They found that there was a low penetration and heterogeneous ARV drug distribution overall, as 40-60% of CD3+ T cells remained unexposed in gut samples from all three species (human, rhesus macaque, humanized mice (hu-HSC-Raga and BLT strains). Secondly, they aimed to determine the extent to which ARV drug distributions are associated with potential sites of viral replication based on viral RNA expression. Compared to colocalization with CD3+ T cells, there was a high ARV drug distribution colocalization with viral RNA expression, but with high variability. Lastly, they aimed to evaluate ARV drug distributions in the context of MDR1 drug efflux transporter expression. Depending on whether the ARV drugs are substrates of the transporters., it seems that MDR1 transporters may play a role in the difference in ARV drug distribution. Overall, this report enriches our previous understanding of the heterogenous distribution of ARVs in tissues as a possible explanation for the insuffuciences of ART and shed light on the great potential MSI technology holds for understanding ART efficacy in the future. 

 

 

Date: 2019.6.13

Name: Hisatoshi shida

Journal: Nature Com. 10:2257 (2019)

Title: CTL-mediated immunotherapy can suppress SHIV rebound in ART-free macaques Authors: Jin Fan et al.

URL: https://doi.org/10.1038/s41467-019-09725-6

Background: A major barrier to human immunodeficiency virus (HIV) cure is the existence of viral reservoirs that lead to viral rebound following discontinuation of antiretroviral therapy (ART). They postulated that enhancing cytotoxic T lymphocytes (CTL) targeting conserved envelope (Env) regions can eliminate HIV infected cells in latency. In this paper, they evaluated the use of adoptively transferred HIV vaccine-induced subtype C Env-specific CTLs in a macaque subtype B simian-human immunodeficiency virus (SHIV) model to determine whether plasma viremia can be controlled after ART interruption.

Conclusion: Adoptive cellular therapy (ACT) using autologous Env-specific T cells augmented by therapeutic vaccination can suppress ART-free viral rebound in the SHIV model. Furthermore, phenotypic and functional characterization of adoptively transferred cells in ACT-responsive and nonresponsive animals support a critical role for cross-reactive central memory T cells in viremia control. This study offers an approach to potentiate immunological suppression of HIV in the absence of antiviral drugs.

 

 

Date: 2019.6.6

Name: Ayaka Washizaki

Journal: Frontiers in immunology

Title: Antigen production after latency reversal and expression of inhibitory receptors in CD8+ T cells limit the killing of HIV-1 reactivated cells

Authors: Alba Ruiz, Oscar Blanch-Lombarte, Esther Jimenez-Moyano, Dan Ouchi, Beatriz Mothe, Ruth Peña, Cristina Galvez, Meritxell Genescà, Javier Martinez-Picado, Philip Goulder, Richard Barnard, Bonnie Howell, Bonaventura Clotet and Julia G. Prado

URL:  https://doi.org/10.3389/fimmu.2018.03162

Background: HIV感染症は抗レトロウイルス療法(ART)の発展により不治の病から慢性疾患の一つとなった。しかしながら、ART下でも潜伏感染した細胞を体内から完全に除くことはできずARTを中断するとウイルスのリバウンドが観察されることが明らかとなっている。したがって、HIV患者は終生のART療法を強いられている。この状況を打破するためHIV治癒のための戦略が模索されているそのひとつがShock and kill療法である。Shock and kill療法では潜伏感染細胞をLatency Reversing Agent(LRA)を用いて再活性化し、再活性化した細胞を宿主免疫系により排除するという方法である。現在までに160以上のLRAが報告されている。その一方で、免疫のexhaustionが起こることが知られているHIV患者において、再活性化した細胞が宿主免疫系により本当に排除されるのかについては深く研究されていない。そこで、筆者らはLRAでの刺激後の抗原提示およびCD8+ T 細胞による細胞障害性について検討を行った。

Conclusion: CD8+ T 細胞による感染細胞の排除には個人差があり、感染細胞の排除の能力はCD8+ T 細胞が発現しているinhibitory receptorの発現パターンに相関があることが明らかとなった。このことはShock and kill療法の効果には個人差による限界があることを示している。さらにCD8+ T 細胞におけるinhibitory receptorの発現パターンがshock and killの効果を事前に予測するためのマーカーの一つとなることを示唆している。

 

 

Date:2019.5.23

Name:山浦　瑞樹

Journal: Virology

Title: The ability of SAMHD1 to block HIV-1 but not SIV requires expression of MxB

Authors: CindyBuffone^aJulianeKutzner^bSilvanaOpp^aAliciaMartinez-Lopez^aAnastasiaSelyutina^aSi AnaCoggings^cLydia R.Studdard^cLingmeiDing^dBaekKim^cPaulSpearman^dTorstenSchaller^bFelipeDiaz-Griffero^a

URL: https://doi.org/10.1016/j.virol.2019.03.018

Background: SAMHD1 is a human restriction factor known to prevent infection of macrophages, resting CD4⁺ T cells, and dendritic cells by HIV-1. To test the contribution of MxB to the ability of SAMHD1 to block HIV-1 infection, they created human THP-1 cell lines that were knocked out for expression of MxB, SAMHD1, or both.To understand how MxB assists SAMHD1 restriction of HIV-1, they examined direct interaction between SAMHD1 and MxB in pull-down experiments. In addition, we investigated several properties of SAMHD1 in the absence of MxB expression, including subcellular localization, phosphorylation of the SAMHD1 residue T592, and dNTPs levels.

Conclusion: interestingly, MxB depletion renders SAMHD1 ineffective against HIV-1 but not SIVmac. They observed similar results in human primary macrophages that were knockdown for the expression of MxB. These experiments showed that SAMHD1 restriction of HIV-1 requires expression of MxB. It is expected to reveal the rerationship between SMAHD1 and MxB next time.

 

 

Date: 2019.4.18

Name: WeiKeat TAN

Journal: Cell; Volume 27, Issue 1, Pages 142-153

Published date: 2019 Apr 2

Title: HIV Controllers Exhibit Effective CD8+ T Cell Recognition of HIV-1-Infected Non-activated CD4+ T Cells

Authors: Blandine Monel, Annmarie McKeon, Pedro Lamothe-Molina, Priya Jani, Julie Boucau, Yovana Pacheco, R. Brad Jones, Sylvie Le Gall, and Bruce D. Walker

URL: https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30323-7

Background: HIV can establish a latent reservoir in a small pool of resting CD4 T cells by direct infection. and those HIV infected resting CD4 T cells remain a persistent reservoir of HIV infection, representing a critical barrier to curing HIV. Thus, there remained the question of whether resting CD4 T cells infected by HIV can be targeted by HIV specific CD8 T cells for elimination. In the current study, they, therefore, evaluated whether HIV specific CD8 T cells could recognize and kill non-activated, infected CD4 T cells due to the recognition of processed viral proteins following viral entry, without requiring productive infection.

Conclusion: In brief, this paper reported that HIV-specific CD8 T cell responses have the potential to reduce the establishment of an HIV reservoir in non-activated CD4 T cells, hence contributing to HIV control. In detailed, incoming viral proteins are degraded in the cytosol of non-productively infected resting CD4 T cells to produce antigenic peptides for presentation by HLA class I. CD8 T cells then directly recognize and kill HIV-infected non-activated CD4 T cells through the formation of immunologic synapses and class I restricted recognition of processed viral peptides. Notably, CD8 T cells from HIV controllers are more efficient in recognizing resting infected cells that doesn’t undergo viral protein production, leading to HLA class I-restricted degranulation, cytokine production, and target cell death. This study indicates that resting HIV-infected CD4 T cells can be targeted by CD8 T cells directly after HIV entry, before reverse transcription, and thus before the establishment of latency, and suggest a mechanism whereby the immune response may reduce the size of the HIV reservoir before the establishment of the reservoir.

 

 

Date:2019.4.11

Name:明里　宏文

Journal: Nature

Title: HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell　transplantation.

Authors: Gupta RK, Abdul-Jawad S, McCoy LE, Mok HP, Peppa D, Salgado M, Martinez-Picado J, Nijhuis M, Wensing AMJ, Lee H, Grant P, Nastouli E, Lambert J, Pace M, Salasc F, Monit C, Innes AJ, Muir L, Waters L, Frater J, Lever AML, Edwards SG, Gabriel IH, Olavarria E.

URL: https://www.nature.com/articles/s41586-019-0898-8

Background: A cure for HIV-1 remains unattainable as only one case has been reported, a decade ago1,2. The individual-who is known as the 'Berlin patient'-underwent two allogeneic haematopoietic stem-cell transplantation (HSCT) procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5 (CCR5Δ32/Δ32) to treat his acute myeloid leukaemia. Total body irradiation was given with each HSCT. Notably, it is unclear which treatment or patient parameters contributed to this case of long-term HIV remission. Here the authors show that HIV-1 remission may be possible with a less aggressive and toxic approach.

Conclusion: An adult infected with HIV-1 underwent allogeneic HSCT for Hodgkin's lymphoma using cells from a CCR5Δ32/Δ32 donor. He experienced mild gut graft-versus-host disease. Antiretroviral therapy was interrupted 16 months after transplantation. HIV-1 remission has been maintained over a further 18 months. Plasma HIV-1 RNA has been undetectable at less than one copy per millilitre along with undetectable HIV-1 DNA in peripheral CD4 T lymphocytes. Quantitative viral outgrowth assays from peripheral CD4 T lymphocytes show no reactivatable virus using a total of 24 million resting CD4 T cells. CCR5-tropic, but not CXCR4-tropic, viruses were identified in HIV-1 DNA from CD4 T cells of the patient before the transplant. CD4 T cells isolated from peripheral blood after transplantation did not express CCR5 and were susceptible only to CXCR4-tropic virus ex vivo. HIV-1 Gag-specific CD4 and CD8 T cell responses were lost after transplantation, whereas cytomegalovirus-specific responses were detectable. Similarly, HIV-1-specific antibodies and avidities fell to levels comparable to those in the Berlin patient following transplantation. Although at 18 months after the interruption of treatment it is premature to concludethat this patient has been cured, these data suggest that a single allogeneic HSCT with homozygous CCR5Δ32 donor cells may be sufficient to achieve HIV-1 remission with reduced intensity conditioning and no irradiation, and the findings provide further support for thedevelopment of HIV-1 remission strategies based on preventing CCR5 expression.The impact of the news of a second case of HIV remission might be overlooked by some in the scientific community because the report simply confirms previous results and shows a lack of obvious scalability for treatment. However, this case has certainly generated interest, and might have instilled a sense of hope in some individuals. Such cases also provide motivation to continue working on and refining research endeavours, even if scalable approaches to achieve long-term HIV remission might be many years away. Optimism does not need to be in conflict with rationalism.

 

 

Date: 2019.3.7

Name: 村田　めぐみ

Journal: Nature Microbiology

Title: HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy

Authors: Yonatan Ganor, Fernando Real, Alexis Sennepin, Charles-Antoine Dutertre, Lisa Prevedel, Lin Xu, Daniela Tudor, Bénédicte Charmeteau, Anne Couedel-Courteille, Sabrina Marion, Ali-Redha Zenak, Jean-Pierre Jourdain, Zhicheng Zhou, Alain Schmitt, Claude Capron, Eliseo A Eugenin, Rémi Cheynier, Marc Revol, Sarra Cristofari, Anne Hosmalin and Morgane Bomsel

URL: https://www.nature.com/articles/s41586-019-0898-8

Background: A major obstacle preventing HIV-1 eradication is the presence of a latent inducible viral reservoir that is best characterized in peripheral blood resting memory cluster of CD4+ T cells. Yet, HIV-1 infection characteristics in macrophages and accumulating evidence suggest that tissue macrophages might also constitute HIV-1 reservoirs. Sexual transmission is the main acquisition mode of HIV-1 and men can both transmit and be infected by HIV-1 sexually, with penile infection accounting for approximately one-third of HIV-1 transmission cases in men who have sex with men. Authors’ own recent studies identified the inner foreskin and urethra as penile HIV-1 entry sites, in which HIV-1 selectively targets different types of immune cells—namely, foreskin Langerhans cells and urethral macrophages. However, to date, no studies have determined whether macrophages derived from the human male genital tract and/or other genital mucosa of HIV-1/cART patients produce infectious virus following reactivation.

Conclusion: The authors show, using penile tissues from HIV-1-infected individuals under suppressive combination antiretroviral therapy, that urethral macrophages contain integrated HIV-1 DNA, RNA, proteins and intact virions in virus-containing compartment-like structures, whereas viral components remain undetectable in urethral T cells. Moreover, urethral cells specifically release replication-competent infectious HIV-1 following reactivation with the macrophage activator lipopolysaccharide, while the T-cellactivator phytohaemagglutinin is ineffective. HIV-1 urethral reservoirs localize preferentially in a subset of polarized macrophages that highly expresses the interleukin-1 receptor, CD206 and interleukin-4 receptor, but not CD163. To our knowledge, these results are the first evidence that human urethral tissue macrophages constitute a principal HIV-1 reservoir. Such findings are determinant for therapeutic strategies aimed at HIV-1 eradication.

 

 

Date: 2019.2.21

Name: Tomoyuki Miura

Journal: Nature Communicasions, 9: 2363, 2018.

Title: A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge.

Authors: Madani, N. et al.

DOI: 10.1038/s41467-018-04758-9

Background: The Env trimer mediates HIV-1 entry into cells. The “closed,” antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies.

Conclusion: CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous SHIV. The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.

 

 

Date: 2019.2.14 

Name: 関　洋平

Journal: Nature

Title: A quantitative approach for measuring the reservoir of latent HIV-1 proviruses

Authors: Bruner KM, Wang Z, Simonetti FR, Bender AM, Kwon KJ, Sengupta S, Fray EJ, Beg SA, Antar AAR, Jenike KM, Bertagnolli LN, Capoferri AA, Kufera JT, Timmons A, Nobles C, Gregg J, Wada N, Ho YC, Zhang H, Margolick JB, Blankson JN, Deeks SG, Bushman FD, Siliciano JD, Laird GM, Siliciano RF.

URL: https://www.nature.com/articles/s41586-019-0898-8 

Background: HIV感染症の根治療法を開発するためには、排除の対象となる潜伏感染下におけるリザーバー細胞を正確かつ高感度に検出することが必要となる。現在、PCR法に基づくproviral DNAの検出が広く行われているが、多くのものはdefective provirusであるためリザーバー細胞数を正しく評価できているとは言えず、intact provirusとdefective provirusを分けて検出することが求められている。

Conclusion: Defective provirusは、intact provirus においてlarge deletionやhypermutationが生じ、感染性ウイルス粒子を産生できなくなったものである。著者らは、ddPCRを用いてパッケージングシグナル領域とenv遺伝子領域を同時に検出することで、9割以上のdeleted provirusが検出可能であることを見出した。加えて、env内のrev-response element (RRE) にAPOBEC3Gの標的となりかつ保存された配列が存在することを見出し、envに対するプローブを当該配列を認識するように設計することでhypermutated provirusも同時に検出することが可能であることを示した。この検出方法は、全長ゲノム配列解析を必要とせずにintact provirusとdefective provirusを分けて測定できる世界初の方法であり、今後のHIV cureへ向けた研究において非常に有用なものであると考えられる。

 

 

Date: 2019.1.17

Name: 山浦　瑞樹

Journal: Journal of Virology

Title: Central Nervous System Inflammation and Infection during Early, Nonaccelerated Simian-Human Immunodeficiency Virus Infection in Rhesus Macaques

Authors: Denise C. Hsu, Piyanate Sunyakumthorn, Matthew Wegner, Alexandra Schuetz, Decha Silsorn, Jacob D. Estes, Claire Deleage, Khamis Tomusange, Samir K. Lakhashe, Ruth M. Ruprecht,Eric Lombardini, Rawiwan Im-Erbsin, Yanin Kuncharin, Yuwadee Phuang-Ngern, Dutsadee Inthawong, Weerawan Chuenarom, Robin Burke, Merlin L. Robb, Lishomwa C. Ndhlovu,Jintanat Ananworanich, Victor Valcour, Robert J. O'Connell, Serena Spudich, Nelson L. Michael, Sandhya Vasan

URL: https://jvi.asm.org/content/92/11/e00222-18

Background: 中枢神経系（CNS）に対するヒト免疫不全ウイルス（HIV）の影響に関する初期の研究では、末期のHIV感染症でしばしば起こるHIV関連痴呆（HAD）に焦点が当てられていた．残念なことに、認知障害、運動障害、およびニューロパチーは、有効なARTにもかかわらず持続する可能性があるが、HIV感染の過程のより早い時期の治療はそれらの頻度と重症度を減らす可能性がある．先行研究で、ハービソン等は中枢神経系に対するSHIV-SF162p3の効果を報告しているが、AIDSモデルにおいて末期脳炎に焦点を当てている．一方で、臨床研究によると、感染初期におけるCNSの関与は病理学的に異なる過程であることが示されている．そこで、本研究では、非急性に発症するSHIV-1157ipd3N4を用い、感染初期の神経学的炎症の機序についてアカゲザルで観察した．

Conclusion: 本研究によって、SHIV-1157ipd3N4が人間の初期の臨床経過を模倣していること、そして初期の神経学的炎症が脳および髄膜においてT細胞媒介性であることを証明した．本研究によってもたらされた知見は、今後HIV感染者の神経学的炎症に対する有効なアプローチを検討する際に活用されるだろう．

 

 

Date: 2019.1.10

Name: Yalcin Pisil

Journal: Antiviral Research 162 (2019) 101–109

Title: Discovery of 4-oxoquinolines, a new chemical class of anti-HIV-1 Compounds

Authors: Tomomi Shiroishi-Wakatsukia,b,c, Masami Maejima-Kitagawab, Akiko Hamanob, Daigo Muratac, Sayaka Sukegawab, Kazuhiro Matsuokab, Hirotaka Odeb, Atsuko Hachiyab, Mayumi Imahashib, Yoshiyuki Yokomakub, Nobuhiko Nomurac, Wataru Sugiurab,1, Yasumasa Iwatania,

URL: https://www.journals.elsevier.com/antiviral-research

https://www.sciencedirect.com/science/article/pii/S0166354218304261?via%3Dihub

Backround: Anti-HIV drugs have expanded immensely in the last three decades to more than 40 approved drugs belonging to five classes: nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inhibitors, and integrase (IN) strand transfer inhibitors (INSTIs). The INSTIs, such as raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG), are currently used as a highly potent “key drug” with a favorable safety profile in the management of HIV-1. INSTIs inhibit HIV-1 IN-catalyzed integration of proviral DNA into the host chromosome through a mechanism in which the ßdiketo acid moiety of the INSTI binds to two metals at the IN catalytic center. DTG is a second-generation INSTI that represents a potent genetic barrier to HIV-1 resistance. Improvements in the efficacy and toxicity of ART offers the promise of controlling disease progression and prolonging the survival of HIV-1-infected patients. Consequently, longterm ART is still required, and we must anticipate drug-resistance and side effects caused by the currently used drugs. In addition, it is necessary to continue providing novel drug development pipelines for HIV-1/AIDS therapy. They performed random screening of a diverse library of 12,000 small-molecule compounds using our in vitro HIV-1 integrase mediated strand-transfer (INST) assay and our additional cell-based assay, and identified a novel chemical compound, calbazole, and its derivatives, which possess potent inhibitory effects on HIV-1 INST.

Conclusion: The compounds displayed inhibitory effects against various subtypes. In addition, PI-resistant, INSTI-resistant, NRTI-resistant, or NNRTI resistant HIV-1 displayed no cross resistance to these compounds, suggesting new chemical class of anti-HIV-1 compunds. 4-oxoquinoline moiety is a common moiety for novel compounds. R1 and R7 positions were required for their anti-HIV-1 activity. Novel 4-oxoquinoline derivatives discovered in this study exhibited potent anti-HIV activity (EC50 < 0.1 μM) despite the lack of a 3-carboxylate moiety in their chemical structures. The compounds displayed inhibitory effects against various subtypes, and no cross resistance to these compounds was shown by PI-resistant, INSTI-resistant, NRTI-resistant, or NNRTIresistant HIV-1. 4-oxoquinoline-3-carboxylic acid derivatives display antibacterial activities , anti-HIV activity such as EVG (INSTI); K-12, K-37 and 6- desfluoroquinolone (Tat-mediated transactivation inh.), 1-diisopropylphosphonate-4-oxoquinoline (RTI). Interestingly, novel 4-oxoquinolines lack a 3-carboxylate group. 4-oxoquinolines significantly reduce the p24 antigen production in HIV-1 latently infected cells, suggesting the inhibitory effect on viral gene expression. These findings may be important for the further development of a novel chemical class of anti-HIV-1 drugs.

 

 

Date: 2018.12.27

Name: Hisatoshi shida

Journal: Science Doi.10.1126/Science.aat9120 (2018)

Title: Innate immune recognition of glycans targets HIV nanoparticle immunogens to germinal centers

Authors: Talar Tokatlian et al.

URL: http://science.sciencemag.org/content/early/2018/12/19/science.aat9120.long

Background: In vaccine design, arraying antigens in a multivalent nanoparticle form is often employed, but in vivo mechanisms underlying the enhanced immunity elicited by such vaccines remain poorly understood. They compared the fate of two different heavily glycosylated HIV antigens, a gp120-derived mini-protein and a large, stabilized envelope trimer, in protein nanoparticle or “free” forms following primary immunization.

Conclusion: Unlike monomeric antigens, nanoparticles were rapidly shuttled to the follicular dendritic cell (FDC) network and then concentrated in germinal centers in a complement-, mannose-binding lectin (MBL)–, and immunogen glycan–dependent manner. Loss of FDC localization in MBL-deficient mice or via immunogen deglycosylation significantly impacted antibody responses. These findings identify an innate immune-mediated recognition pathway promoting antibody responses to particulate antigens, with broad implications for humoral immunity and vaccine design.

 

 

Date: 2018.12.14

Name: 村田めぐみ

Journal: Nature communications

Title: Ultra-long-acting removable drug delivery system for HIV treatment and prevention

Authors: Martina Kovarova, S. Rahima Benhabbour, Ivana Massud, Rae Ann Spagnuolo, Brianna Skinner, Caroline E. Baker, Craig Sykes, Katie R. Mollan, Angela D. M. Kashuba, J. Gerardo García-Lerma, Russell J. Mumper & J. Victor Garcia

URL: https://www.nature.com/articles/s41467-018-06490-w

Background: HIVの特に慢性感染期における処方されたレジメンの順守は非常に重要である。Injectable long-acting formulations of antiretrovirals (LA-ARVs)はHIV治療・予防に対する薬の順守を向上させる方法として注目されている。しかし、LA-ARV は服用後は緊急時であっても体内より薬を取り出せないというデメリットがある。これに対して、今回著者らはultra-LA removable systemという方法を使用した。これは体温でゲルを形成する生分解性ポリマーにドルテグラビルを溶解し、皮下に接種するという方法である。

Conclusion: 著者らはマウスモデルと霊長類モデルを用いて、LA-ARVs単回投与ののち、９ヶ月のフォローアップを行った。その結果、９ヶ月にわたり血中の薬剤濃度が維持されることを示した。次にマウスを用いてHIV感染実験を行なった。この実験により、１）感染後のLA-ARVs投与により、血中のウイルス量を抑えること、また、２）感染前のLA-ARVs投与により、その後の複数回の経膣感染を防御できたこと、を示し、このLA-ARVsはHIVの治療・予防の両面において有効であることを示した。このLA-ARVsは今後、複数の薬剤のレジメンにも十分効果が見込める有効な方法であると期待される。

 

 

Date: 2018.11.8

Name: Tomoyuki Miura

Journal: Nature, 563(7731): 360-364, 2018.

Title: Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys.

Authors: Borducchi, E. N. et al.

URL: https://www.ncbi.nlm.nih.gov/pubmed/30283138

Background: The latent viral reservoir is the critical barrier for the development of a cure for HIV-1 infection. Previous studies have shown direct antiviral activity of potent HIV-1 Env-specific broadly neutralizing antibodies (bNAbs) administered when antiretroviral therapy (ART) was discontinued, but it remains unclear whether bNAbs can target the viral reservoir during ART. Here they showed that administration of the V3 glycan-dependent bNAb PGT121 together with the Toll-like receptor 7 (TLR7) agonist vesatolimod (GS-9620) during ART delayed viral rebound following discontinuation of ART in simian–human immunodeficiency virus (SHIV)-SF162P3-infected rhesus monkeys in which ART was initiated during early acute infection.

Conclusion: Administration of the PGT121 together with the TLR7 agonist during ART delayed viral rebound following discontinuation of ART in SHIV-SF162P3-infected rhesus monkeys. The data demonstrate the potential of bNAb administration together with innate immune stimulation as a possible strategy for targeting the viral reservoir.

 

 

Date: 2018.9.27

Name: Li Jialin

Journal: AIDS 2018, 32:555–563

Title: Development of broad neutralization activity in simian/human immunodeficiency virus-infected rhesus macaques after long-term infection

Authors: Nan Gao, Wei Wang, Chu Wang, Tiejun Gu, Rui Guo, Bin Yu, Wei Kong, Chuan Qin, Elena E. Giorgi, Zhiwei Chen, Samantha Townsley, Shiu-Lok Hu, Xianghui Yu, and Feng Gao

URL: https://insights.ovid.com/pubmed?pmid=29239895

Background: Nonhuman primates (NHPs) are the only animal model that can be used to evaluate protection efficacy of HIV-1 envelope vaccines. However, whether broadly neutralizing antibodies (bnAbs) can be elicited in NHPs infected with SHIV has not been fully understood. This study is to investigate whether broad neutralization activities were developed in SHIV- infected macaques after long-term infection as in humans.

Conclusion: With their results, which demonstrate that bnAbs targeting common HIV-1 epitopes can be elicited in SHIV1157ipd3N4-infected macaques as in humans after 4–6 years of infection, and SHIV/NHP can serve as an ideal model to study bnAb maturation.

 

 

Date: 2018.9.13

Name: 山浦　瑞樹

Journal: PLOS ONE　July.2018

Title: Brain is a potential sanctuary for subtype C HIV-1 irrespective of ART treatment outcome

Authors: For Yue Tso,Guobin Kang,Eun Hee Kwon,Peter Julius,Qingsheng Li,John T. West,Charles Wood

URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201325

Background: HIV根治を目指すうえで、HIVウイルスのリザーバーの存在は重要な因子になる。Koenig Sらが1986年にScience誌で「脳は数あるHIVのリザーバーの一つである」と報告して以来、複数のラボで数多くの研究が為されてきた。ところが、多くの研究で用いられてきた検体はほとんどがSubtype Bと呼ばれる、欧米に患者数が多い検体であり、世界全体の約50％以上の患者が感染しているSubtype Cの検体についてはほとんど為されてこなかったのが現状である。本研究ではSubtype Cに感染し、その後ｃART療法を受けた患者八名の検体を用いた。そして果たしてcARTの成功と失敗とHIVウイルスが脳をリザーバーにするのか、否かについて研究し、HIVはstrainによってリザーバーの指向性があるのかについて先行研究から比較検討を行った。

Conclusion: 本研究の結果として、HIVウイルスはcARTの成功と失敗に関わらず脳をリザーバーにしていることが示された。加えて、Subtype Bを用いた先行研究でも今回と同様の結果が得られていることから、strainによるリザーバーの指向性は無いと著者らは結論付けている。今回のようにSubtype Cを用いたHIVリザーバーの研究は未知の領域が広い。このテーマに対するアプローチは引き続き複数のラボで行われる必要があるだろう。

 

 

Date: 2018.9.6

Name: Wei Keat TAN

Journal: Science Immunology

Title: CD4⁺ T cell–mediated HLA class II cross-restriction in HIV controllers 

Authors: Moran Galperin, Carine Farenc, Madhura Mukhopadhyay, Dhilshan Jayasinghe, Amandine Decroos, Daniela Benati1, Li Lynn Tan, Lisa Ciacchi, Hugh H. Reid, Jamie Rossjohn, Lisa A. Chakrabarti and Stephanie Gras

URL: http://immunology.sciencemag.org/content/3/24/eaat0687

Background: The rare patients, a.k.a elite controllers, who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. Previously, a set of unusual T-cell (public TCRs) receptors found in the CD4+ T cells of most elite controllers is able to recognize low levels of HIV peptide and recognize an array of HLAs. In the current study, they, therefore, observed public TCRs’ effects on immune response to infection, and what enables them to be activated by multiple HLAs.

Conclusion: In brief, this paper reported that the high-affinity public TCRs conferred anti-HIV cytotoxic activity to heterologous CD4+ and CD8+ T cells across multiple HLA-DR molecules. CD4+ and CD8+ T cells armed with one of the public TCRs (selected based on high frequency in elite controllers) effectively recognized and killed HIV-infected dendritic cells, at least in in vitro. This paper also determined the structure of the complexes formed when public TCRs interact with different HLAs holding bits of protein from HIV, and found that each TCR’s contact was primarily with the HIV-derived peptide rather than with the HLA itself.

 

 

Date:2018.7.26

Name: Megumi Murata

Journal: Nature Immunology

Title: Resistance of HIV-infected macrophages to CD8+ T lymphocyte–mediated killing drives activation of the immune system

Authors: Kiera L. Clayton, David R. Collins, Josh Lengieza, Musie Ghebremichael, Farokh Dotiwala, Judy Lieberman and Bruce D. Walker

URL: https://www.nature.com/articles/s41590-018-0085-3

Background: It has been suggested that infected macrophages contribute to the persistence and pathogenesis of HIV. Infected macrophages efficiently disseminate virus to CD4+ T cells via neutralization-evading cell-to-cell spread. Studies of animal models of HIV infection further support the proposal of in vivo infection and persistence of macrophages, even during combination antiretroviral therapy. CD8+ cytotoxic T lymphocytes (CTLs) control viral levels during and chronic stages of HIV infection. However, most studies have focused on the control of infected CD4+ T cells by CTLs, with less focus on infected macrophages. The efficiency of CTL-mediated killing of HIV-infected CD4+ T cells relative to that of HIV-infected macrophages is poorly characterized.Improved understanding of CTL responses to HIV-infected macrophages will inform strategies to eliminate this population and combat HIV-associated inflammation.

Conclusion: They characterized and compared the interactions of HIV-specific ex vivo CTLs with HIV-infected CD4+ T cell targets and macrophage targets. They found that macrophages were less susceptible to CTL-mediated killing than were CD4+ T cells and that this was an intrinsic characteristic of macrophages independent of HIV infection. Although CTL cytotoxic granules mediated the killing of both cell types, CD4+ T cells underwent rapid caspase-independent cell death, while macrophages underwent a slower granzyme B– and caspase-3-dependent death. Inefficient CTL-mediated killing of macrophages drove prolonged formation of synapses between effector cells and target cells, greater secretion of IFN-γ (a major macrophage-activating cytokine) from CTLs and induction of macrophage pro-inflammatory chemokines that recruited monocytes and T cells. Inefficient killing of macrophages by CTLs might contribute to chronic inflammation, a hallmark of chronic disease caused by HIV.

 

 

Date: 19.07.2018

Name: YALÇIN PISIL

Journal: Journal of Virology, August 2017,Volume 91,     Issue 15, e00677-17

Title: Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers

Authors: Rajesh P. Ringe,a Gabriel Ozorowski,b Kimmo Rantalainen,b Weston B. Struwe,c Katie Matthews,a* Jonathan L. Torres,b Anila Yasmeen,a Christopher A. Cottrell,b Thomas J. Ketas,a Celia C. LaBranche,e David C. Montefiori,d Albert Cupo,a Max Crispin,c,d Ian A. Wilson,b Andrew B. Ward,b Rogier W. Sanders,a,f P. J. Klasse,a John P. Moorea

URL: http://jvi.asm.org/content/91/15/e00677-17.full

Background: One successful stabilization strategy (SOSIP) involves introduction of an intermolecular disulfide bond (SOS) to link gp120 and gp41, a point substitution (I559P, i.e., IP) to maintain the gp41 subunits in their pre-fusion form, and truncation at residue 664 to improve trimer solubility. SOSIP trimers display the epitopes for multiple bNAbs but can also expose binding sites for some types of non-NAbs. Non-Nabs is binding to epitopes in the gp120 V3 region. It is presently uncertain whether antibodies against V3 can interfere with the induction of NAbs, but there are good arguments in favor of suppressing such “off-target” immune responses. Therefore, They have assessed how to minimize the exposure of V3 non-NAb epitopes and thereby reduce their immunogenicity by introducing N-glycans within the V3 region of BG505 SOSIP trimers.

Conclusion: A rabbit immunogenicity study showed that the glycan-modified SOSIP.664- E64K.M1M7 and parental SOSIP.664 trimers induced comparable titers of autologous tier-2 NAbs, but the tier-1 NAb titers elicited by the modified trimers were reduced. Reducing the immunogenicity of V3 and other non-NAb epitopes on germ line-targeting SOSIP trimers, including by using the glycan-masking method, may be worthwhile.

  

 

Date: 2018.7.5

Name: Hisatoshi Shida

Journal: Nature Medicine, 24, 847–856, 2018.

Title: HIV vaccine candidate activation of hypoxia and the inflammasome in CD14⁺ monocytes is associated with a decreased risk of SIV_mac251acquisition

Authors: Vaccari M, Fourati S, Gordon SN, Brown DR, Bissa M, Schifanella L, Silva de Castro I, Doster MN, Galli V, Omsland M, Fujikawa D, Gorini G, Liyanage NPM, Trinh HV, McKinnon KM, Foulds KE, Keele BF, Roederer M, Koup RA, Shen X, Tomaras GD, Wong MP, Munoz KJ, Gach JS, Forthal DN, Montefiori DC, Venzon DJ, Felber BK, Rosati M, Pavlakis GN, Rao M, Sekaly RP, Franchini G.

URL: https://www.ncbi.nlm.nih.gov/pubmed/29785023

Background: RV144 trial that is composed with priming of canarypox (ALVAC) vector expressing HIV-1 env followed by booster of gp120/alum lowered infection rate by 30%. To improve vaccine efficacy, the authors tested the ability of ALVAC–SIV, DNA–SIV and Ad26–SIV vaccine prime modalities together with two ALVAC–SIV+ gp120 protein boosts to reduce the risk of SIVmac251 acquisition in rhesus macaques.

Conclusion: They found that the DNA and ALVAC prime regimens were effective, but the Ad26 prime was not. The activation of hypoxia and the inflammasome in CD14+CD16− monocytes, gut-homing CCR5-negative CD4+ T helper 2 (TH2) cells and antibodies to variable region 2 correlated with a decreased risk of SIVmac251 acquisition. By contrast, signal transducer and activator of transcription 3 activation in CD16+ monocytes was associated with an increased risk of virus acquisition. The Ad26 prime regimen induced the accumulation of CX3CR1+CD163+ macrophages in lymph nodes and of long-lasting CD4+ TH17 cells in the gut and lungs. Our data indicate that the selective engagement of monocyte subsets following a vaccine prime influences long-term immunity, uncovering an unexpected association of CD14+ innate monocytes with a reduced risk of SIVmac251 acquisition.

 

 

Date: 2018.6.28

Name: Ejikeugwu Chika (Ph.D.)

Journal : Antiviral Research

Title: Adipocytes Impair Efficacy of Antiretroviral Therapy

Authors: Jacob Couturier, Lee C. Winchester, James W. Suliburk, Gregory K. Wilkerson, Anthony T. Podany, Neeti Agarwal, Corrine Ying Xuan Chua, Pramod N. Nehete, Bharti P. Nehete, Alessandro Grattoni, K. Jagannadha Sastry, Courtney V. Fletcher, Jordan E. Lake, Ashok Balasubramanyan and Dorothy E. Lewis

URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955795/

Background: HIV persistence is facilitated by inadequate distribution of antiretroviral drugs in cellular and anatomic reservoirs. For example, incomplete suppression of viral replication in lymph nodes is associated with decreased drug penetration. Adequate distribution of antiretroviral drugs to infected cells in HIV patients is critical for viral suppression. In humans and primates, HIV- and SIV-infected CD4 T cells in adipose tissues have recently been identified as reservoirs for infectious virus. To better characterize adipose tissue as a pharmacological sanctuary for HIV-infected cells, in vitro experiments were conducted to assess antiretroviral drug efficacy in the presence of adipocytes, and drug penetration in adipose tissue cells (stromal-vascular-fraction cells and mature adipocytes) was examined in treated humans and monkeys.

Conclusion: The study concluded that adipocytes significantly impact antiretroviral functions and that INSTIs penetrate adipose tissue more consistently than N(t)RTIs. Drug penetration into AT is important not only for controlling AT HIV reservoirs, but also because other major HIV reservoirs - such as lymph nodes, GALT and bone marrow - are lipid-rich or intricately associated with adipocytes/AT function. Complete targeting of viral reservoirs with ART should take into consideration the role of adipose tissue penetration and lipid-rich milieus.

 

  

Date: 2018.6.21

Name: Ai Himeno

Journal: Journal of Virology

Title: A novel strategy to adapt SHIV-E1 carrying env from an RV144 volunteer to rhesus macaques: coreceptor switch and final recovery of a pathogenic virus with exclusive R5 tropism 

Authors: Scinto HB, Gupta S, Thorat S, Mukhtar MM, Griffiths A, Delgado J, Plake E, Vyas HK, Strickland A, Byrareddy SN, Montefiori DC, LaBranche C, Pal R, Treece J, Orndorff S, Ferrari MG, Weiss D, Chenine AL, McLinden R, Michael N, Kim JH, Robb M, Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Ruprecht RM.

URL: http://jvi.asm.org/content/early/2018/05/03/JVI.02222-17.long

Background: Definitive experiments to decipher the mechanisms of the partial protection observed in RV144 require passive immunization studies in NHPs with a relevant test virus. They have generated such a virus by inserting env from an RV144 placebo recipient into a SHIV backbone with HIV-like LTRs (with two NFkB site). Furthermore, they devised a novel strategy, which in vivo transfection by intra-muscular inoculation of infectious proviral DNA and repeated administration of cell-free virus under ablation of both arms of adaptive immunity (depletion of CD8+Tcell, NK cell and B cell).

Conclusion: They report the successful construction, adaptation, and characterization of a SHIV-E that carries an HIV CRF01_AE envelope isolated. The final SHIV-E1p5 isolate, an exclusively R5 tropic virus with tier 2 neutralization phenotype, grown in rhesus PBMC, was mucosally transmissible and pathogenic. Earlier SHIV-E passages showed coreceptor switch, again mimicking HIV biology in humans. Their series of SHIV-E strains mirrors HIV transmission and disease progression in humans. SHIV-E1p5 represents a biologically relevant tool to assess prevention strategies.

 

 

Date: 2018.6.14

Name: Anna Hu

Journal: Journal of Experimental Medicine

Title: Spatial distribution and function of T follicular regulatory cells in human lymph nodes

Authors: Ismail Sayin, Andrea J. Radtke, Laura A. Vella, Wenjie Jin, E. John Wherry, Marcus Buggert, Michael R. Betts, Ramin S. Herati, Ronald N. Germain, David H. Canaday

URL: http://jem.rupress.org/content/early/2018/05/15/jem.20171940

Background: Follicular Regulatory T (Tfr) cells are an effector subset of regulatory T (Treg) cells. Sharing many characteristics with both Treg and Tfh cells, Tfr cells are also involved in humoral immunity, its principal known function being, to control germinal center responses by suppressing Tfh and B cell activity. Up to this point, it has been proposed that Tfr cells are located inside the germinal centers of lymph nodes and directly suppress Tfh and B cells accordingly. In terms of HIV, Tfr research remains to be an important topic due to its relationship with Tfh cells, a well-known reservoir for latent HIV. Recently, it has also been discovered that Tfr cells also have a potential to be infected with HIV as well and are possibly more permissive to infection than Tfh cells.

Conclusion: Through an examination of the spatial distribution, interacting partners, and function of Tfr cells in human lymph nodes, this paper has suggested two main points from its findings. First, they propose a model where Tfr cells regulate humoral immune response from the “outside-in.” This suggestion is in fact, a complete contradiction to earlier findings; however, this suggestion is supported by their observation that Tfr cells are mostly located in the T-B border and not the germinal center. Additionally, based on their finding of an enrichment of CD69+ Tfr cells at the T-B border and the ability for these CD69+ Tfr cells to produce GARP (a protein critical for the surface expression of latent TGF-b), they propose that Tfr cells may modulate antibody responses in a TGF-bdependent manner in mesenteric lymph nodes.

 

 

Date: 2018.6.7

Name: Tomoyuki Miura

Journal: Nature Medicine, 24: 610-616, 2018.

Title: A single injection of crystallizable fragment domain–modified antibodies elicits durable protection from SHIV infection

Authors: Gautam R, Nishimura Y, Gaughan N, Gazumyan A, Schoofs T, Buckler-White A, Seaman MS, Swihart BJ, Follmann DA, Nussenzweig MC, Martin MA

URL: https://www.ncbi.nlm.nih.gov/pubmed/29662199

Background: In the absence of an effective and safe vaccine against HIV-1, the administration of broadly neutralizing antibodies (bNAbs) represents a logical alternative approach to prevent virus transmission. This group previously reported that single intravenous (i.v.) injections of native 3BNC117 or 10-1074 bNAbs prevented virus acquisition in macaques following repeated low-dose (RLD) challenges with tier 2 SHIV_AD8-EO as compared to control monkeys that received no anti-HIV-1 neutralizing monoclonal antibodies.Therefore, this group examined two aspects of anti-HIV-1 immunoprophylaxis: (1) the long-term efficacy of the more potent 3BNC117 or 10-1074 bNAbs with the LS substitution in the crystallizable fragment to increase their half-lives infused individually through the i.v. route; and (2) the prevention of virus acquisition via the combination of LS-mutant 3BNC117 and 10-1074 monoclonal antibodies administered subcutaneously (s.c.). 

Conclusion: A single infusion of the 10-1074-LS monoclonal antibody protected four of six monkeys challenged on a weekly basis for more than 6 months. In addition and despite volume limitations (1.0 ml), s.c. combination immunoprophylaxis conferred protection in five of six monkeys against RLD challenge for a median of 20 weeks.

 

 

Date: 2018.5.31

Name: Ayaka Washizaki

Journal: Science translational medicine

Title: TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy

Authors: So-Yon Lim, Christa E. Osuna, Peter T. Hraber, Joe Hesselgesser, Jeffrey M. Gerold, Tiffany L. Barnes, Srisowmya Sanisetty, Michael S. Seaman, Mark G. Lewis, Romas Geleziunas, Michael D. Miller, Tomas Cihlar, William A. Lee, Alison L. Hill, James B. Whitney.

URL: http://stm.sciencemag.org/content/10/439/eaao4521

Background: HIV完治実現のため、Shock and kill療法が注目されている。Shock and kill療法に使うLRAとしてはすでに様々なものが注目されているが、未だ完治につながった例はない。 LRAの候補の一つであるTLR7はすでにHBV治療薬として臨床試験が進んでおり、type I IFNの産生を促す効果があることがわかっている。さらにHIVでもtype I IFNを介したinnate immunityの活性化によりHIV specificなCD8が誘導され、同時に潜伏感染細胞の再活性化もできることがex vitroの実験からわかっている。これらのことからTLR7 agonistはLRAとして有望視されている。今回、筆者たちはART下のSIVmac251感染アカゲザルに複数回のTLR7 agonistの経口投与を行い、投与前後のウイルスの再活性化、及びリザーバーサイズの検討を行った。

Conclusion: TLR7 agonistを投与すると一時的にPVLの上昇が認められた。さらにTLR7 agonist投与前後のリザーバーサイズを検討してみると、13頭中2頭でリザーバーサイズの顕著な縮小が見られた。この2頭についてはこの論文で行われた全ての実験において潜伏感染細胞の存在が認められなかった。また、ARTを辞めても、CD8 depletionを行なってもウイルスのリバウンドが認められなかった。このことから、TLR7 agonistが非常に有望なLRAであるということが示された。

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