REACH: Research Enterprise to Advance a Cure for HIV

REACH：推进艾滋病毒治疗的研究企业

• 批准号: 10618402
• 负责人: Marina Caskey
• 金额: $ 556.74万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618402
• 关键词: Address; Adherence; African; Aftercare; Antibody Therapy; Automobile Driving; Back; Basic Science; Biological Products; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Categories; Cells; Cellular Immunity; Chronic; Clinic; Clinical; Communities; Cytolysis; Development; Disease remission; Evaluation; HIV; Humoral Immunities; Immune; Immune response; Individual; Infection; Integration Host Factors; Macrophage; Mediating; Natural Killer Cells; Persons; Pharmaceutical Preparations; Population; Population Heterogeneity; Positioning Attribute; Predisposition; Procedures; Recording of previous events; Research; Research Personnel; Resistance; Role; Source; System; T cell response; T-Lymphocyte; Translating; Viral; Virus; Virus Latency; Woman; Work; antiretroviral therapy; collaboratory; community engagement; community partnership; comorbidity; design; experience; flexibility; high risk; improved; industry partner; insight; integration site; neutralizing antibody; next generation; nonhuman primate; novel; pandemic disease; pre-clinical; prevent; programs; psychosocial; response; social stigma; success; translational pipeline; viral rebound

PROJECT SUMMARY/ABSTRACT Despite the success of standard antiretroviral therapy (ART), the need for an HIV cure remains compelling, both to improve the lives of PWH and to bring about the end of the pandemic. Strategies for an HIV cure fall under two categories: those that seek ART-free ‘remission’, and those targeting a classical cure or ‘eradication’. While precedents exist for both scenarios, the latter have only been achieved with bone marrow transplantation. In contrast, although naturally occurring immune-mediated control of HIV (remission) is relatively rare, many such cases have been described. Our proposed “Martin Delaney Collaboratory for HIV Cure Research” program is entitled “REACH” - Research Enterprise to Advance a Cure for HIV. The central theme of REACH is that cellular immune responses (NK and T-cells), combined with next generation virus-neutralizing biologics, can be harnessed to achieve durable remission and eradication of HIV reservoirs. The proposed research focuses on closing gaps in our understanding of the fundamentals of the system that we are trying to perturb, i.e.: the HIV reservoir in relation to cellular immunity, as the means to achieve real progress towards effective and viable HIV cure strategies. Our approach centers around three research foci, which emphasize back to basics science, but connect this with discovery to translational pipelines directed towards both remission and eradication. The proposed objectives, broadly defined, aim to: (1) redefine the three-way relationship between the persistent HIV reservoir, CD8+ T-cells, and rebound virus at the levels of: single cells, individuals, and diverse populations, (2) harness conventional and unconventional (bNAb-induced) CD8+ T-cells responses, in combination with bNAbs and ‘next generation’ biologics, to achieve durable control of HIV replication, and (3) develop a discovery-to- translation pipeline to overcome multiple barriers to the eradication of HIV reservoirs by CTL/NK cells. These studies will be rooted in a strong basic science program that will contextualize results with novel insights into barriers to immune-mediated reservoir elimination, including the role of the proviral integration site and of viral and host factors influencing immune susceptibility. Our program prioritizes the study of diverse populations, including African populations infected with non-B subtype virus, and women – both to advance towards a cure for all, and to benefit from diverse perspectives as a source of fundamental insights. These objectives will be realized by a group of accomplished investigators of diverse expertise and with strong collaborative histories, along with community and industry partners.

项目总结/摘要 尽管标准抗逆转录病毒疗法（ART）取得了成功，但对艾滋病毒治愈的需求仍然迫切， 以改善威尔斯亲王医院的生活及终结疫症。艾滋病毒治疗策略属于 分为两类：寻求无ART“缓解”的患者和以经典疗法或“根除”为目标的患者。而 这两种情况都有先例，后者只有通过骨髓移植才能实现。在 相反，尽管自然发生的免疫介导的HIV控制（缓解）相对罕见，但许多这样的免疫调节剂可以抑制HIV。 案件已经描述。我们提议的“马丁·德莱尼艾滋病治疗研究合作实验室”计划是 名为“REACH”-促进艾滋病毒治疗的研究企业。REACH的中心主题是， 免疫应答（NK和T细胞）与下一代病毒中和生物制剂相结合， 实现持久缓解和根除艾滋病毒宿主。拟议的研究重点是 弥补我们对我们试图扰乱的系统基本要素的理解方面的差距，即：艾滋病毒 与细胞免疫有关的储存库，作为实现有效和可行的艾滋病毒的真实的进展的手段 治愈策略我们的方法围绕三个研究重点，强调回归基础科学， 将这一发现与针对缓解和根除的转化管道联系起来。的 拟议的目标，广泛定义，旨在：（1）重新定义持久的艾滋病毒之间的三方关系， 储库，CD 8 + T细胞和反弹病毒在单细胞，个体和不同群体的水平，（2） 利用常规和非常规（bNAb诱导的）CD 8 + T细胞应答，与bNAb组合 和“下一代”生物制剂，以实现对艾滋病毒复制的持久控制，以及（3）开发一种发现， 翻译管道，以克服多重障碍，以消除艾滋病毒水库的CTL/NK细胞。这些 研究将植根于一个强大的基础科学计划，将结果与新的见解， 免疫介导的水库消除的障碍，包括前病毒整合位点和病毒的作用， 影响免疫易感性的宿主因素。我们的计划优先考虑不同人群的研究，包括 感染非B亚型病毒的非洲人口和妇女-两者都朝着治愈所有人的方向前进， 从不同的观点中受益，作为基本见解的来源。这些目标将通过一个 一组具有不同专业知识和强大合作历史的有成就的调查人员，沿着 社区和行业合作伙伴。

项目成果

Hide and seek: for HIV-infected CD4+ T cells, playing well comes with maturity.

捉迷藏：对于感染 HIV 的 CD4 T 细胞来说，玩得好意味着成熟。

• DOI: 10.1172/jci158872
• 发表时间: 2022
• 期刊: The Journal of clinical investigation
• 作者: Leyre,Louise;Jones,RBrad
• 通讯作者: Jones,RBrad

Whack-a-virus: HIV-specific T cells play an exhausting game.

打击病毒：HIV 特异性 T 细胞玩着一场令人筋疲力尽的游戏。

• DOI: 10.1016/j.chom.2023.08.013
• 发表时间: 2023
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Herrera,Alberto;Jones,RBrad
• 通讯作者: Jones,RBrad

bayroot: Bayesian sampling of HIV-1 integration dates by root-to-tip regression.

• DOI: 10.1093/ve/veac120
• 发表时间: 2023
• 期刊: Virus evolution
• 影响因子: 5.3

Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen.

改用基于整合酶抑制剂的抗逆转录病毒治疗方案后，循环中具有复制能力的潜伏 HIV 感染静息 CD4 T 细胞暂时增加。

• DOI: 10.1101/2023.05.12.23289896
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Ferreira,Roux-Cil;Reynolds,StevenJ;Capoferri,AdamA;Baker,Owen;Brown,ErinE;Klock,Ethan;Miller,Jernelle;Lai,Jun;Saraf,Sharada;Kirby,Charles;Lynch,Briana;Hackman,Jada;Gowanlock,SarahN;Tomusange,Stephen;Jamiru,Samiri;Anok,Ag
• 通讯作者: Anok,Ag

Immunogenicity of COVID-19 vaccines and their effect on HIV reservoir in older people with HIV.

• DOI: 10.1016/j.isci.2023.107915
• 发表时间: 2023-10-20
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Matveev, Vitaliy A.;Mihelic, Erik Z.;Benko, Erika;Budylowski, Patrick;Grocott, Sebastian;Lee, Terry;Korosec, Chapin S.;Colwill, Karen;Stephenson, Henry;Law, Ryan;Ward, Lesley A.;Sheikh-Mohamed, Salma;Mailhot, Genevieve;Delgado-Brand, Melanie;Pasculescu, Adrian;Wang, Jenny H.;Qi, Freda;Tursun, Tulunay;Kardava, Lela;Chau, Serena;Samaan, Philip;Imran, Annam;Copertino Jr, Dennis C.;Chao, Gary;Choi, Yoojin;Reinhard, Robert J.;Kaul, Rupert;Heffernan, Jane M.;Jones, R. Brad;Chun, Tae-Wook;Moir, Susan;Singer, Joel;Gommerman, Jennifer;Gingras, Anne-Claude;Kovacs, Colin;Ostrowski, Mario
• 通讯作者: Ostrowski, Mario