Pathogenesis of Rebound SIV/HIV Viremia after Antiretrovral Therapy

抗逆转录病毒治疗后反弹 SIV/HIV 病毒血症的发病机制

• 批准号: 10224629
• 负责人: Richard D'Aquila
• 金额: $ 151.18万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224629
• 关键词: APOCEC3G gene; Address; Aftercare; Anatomy; Anti-Infective Agents; Biopsy; Cell model; Cells; Colon; Disease remission; Early treatment; FRAP1 gene; Female; Future; Goals; HIV; HIV Infections; Human; Immune; Individual; Infection; Interruption; Intervention; Laboratories; Macaca; Mediating; Memory; Metabolic; Modeling; Mucous Membrane; Mus; Myeloid Cell Activation; Myeloid Cells; Observational Study; Outcome; Pathogenesis; Predisposition; Production; Proviruses; Receptor Activation; Research; Risk; SIV; Source; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Tissue Model; Tissues; Tonsil; Toxic effect; Viral reservoir; Viremia; Virion; Virus; Virus Latency; activation product; antiretroviral therapy; base; cell type; cytokine; design; humanized mouse; in vivo; inhibitor/antagonist; innovation; insight; microbial; novel; programs; reactivation from latency; reproductive tract; response; tool; treatment strategy; viral rebound

Project Summary This program project will add to understanding the pathogenesis of SIV/HIV viremia rebound with the long-term goal of innovating therapeutic strategies enabling sustained remission of HIV infection in a “best-case” scenario. This scenario involves initiating antiretroviral therapy (ART) soon after infection (“early ART”) and stopping it after a defined duration - along with short-term use of a new, adjunctive treatment strategy that will markedly increase the proportion of subjects with sustained remission after stopping early ART. This proposal will define the cells in mucosal and other tissues that SIV/HIV persistently infects early after infection; characterize T cell activation-triggered mechanisms hypothesized to both initiate virus production after early ART stops as well as to cause a cascade of target cell susceptibility and virus infectivity that leads to viremia rebound; and begin testing mechanism-informed, cell-based interventions to interrupt these “vicious cycles.” Aims address the following 3 hypotheses about rebound after stopping early ART. 1. Persistent virus reservoirs are established in mucosal cells soon after infection, and initiate viremia rebound. We will identify the cell types/subtypes in which SIV initially establishes latency in colon and female reproductive tract mucosa in the first days after mucosal infection of macaques; determine if those “virus reservoir” cells remain in the mucosa during suppressive ART in vivo; study virus production from those cells off-ART in cell / tissue models ex vivo, humanized DRAG mice, and macaques in vivo; and design/perform a pilot observational study of humans. 2. Temporarily inhibiting mechanistic target of rapamycin (mTOR) will decrease both virus production from cellular reservoirs and susceptibility of new target cells to infection. We will characterize cellular mechanisms downstream of mTOR activity that initiate virus production from reservoir cells, and increase target cell susceptibility to infection, via T cell receptor (TCR) activation, microbial product activation of myeloid cells, and T cell activation by myeloid cell-derived cytokines. Effects of catalytic mTOR inhibitors will be studied in macaques in vivo, established ex vivo cellular models of latency/reactivation, as well as new models using colon mucosal biopsies, excised tonsil tissue, and humanized DRAG mice. 3. Temporarily increasing virion APOBEC3G (A3G) will decrease virus infectivity. In the ex vivo models and humanized mice, we will test the hypotheses that T cell reservoirs have low A3G levels before Vif is expressed; that tool compounds (”A3G- boosters”) will increase A3G levels in Vif-positive virions produced from them; that boosted A3G-mediated decreased virus spread will add to mTOR inhibitor effects to diminish uninfected target T cell susceptibility to rebounding infection; and that mTOR inhibition will enhance A3G booster effects on virion A3G content.

项目总结

项目成果

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo.

• DOI: 10.1172/jci.insight.162290
• 发表时间: 2022-11-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Samer, Sadia;Thomas, Yanique;Arainga, Mariluz;Carter, Crystal;Shirreff, Lisa M.;Arif, Muhammad S.;Avita, Juan M.;Frank, Ines;McRaven, Michael D.;Thuruthiyil, Christopher T.;Heybeli, Veli B.;Anderson, Meegan R.;Owen, Benjamin;Gaisin, Arsen;Bose, Deepanwita;Simons, Lacy M.;Hultquist, Judd F.;Arthos, James;Cicala, Claudia;Sereti, Irini;Santangelo, Philip J.;Lorenzo-Redondo, Ramon;Hope, Thomas J.;Villinger, Francois J.;Martinelli, Elena
• 通讯作者: Martinelli, Elena

HIV-1 infected humanized DRAGA mice develop HIV-specific antibodies despite lack of canonical germinal centers in secondary lymphoid tissues.

• DOI: 10.3389/fimmu.2022.1047277
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3