Effective and targeted latency reversal in CD4⁺ T cells from individuals on long term combined antiretroviral therapy initiated during chronic HIV-1 infection

To date, an affordable, effective treatment for an HIV-1 cure remains only a concept with most “latency reversal” agents (LRAs) lacking specificity for the latent HIV-1 reservoir and failing in early clinical trials. We assessed HIV-1 latency reversal using a multivalent HIV-1-derived virus-like particle (HLP) to treat samples from 32 people living with HIV-1 (PLWH) in Uganda, US and Canada who initiated combined antiretroviral therapy (cART) during chronic infection. Even after 5–20 years on stable cART, HLP could target CD4⁺ T cells harbouring latent HIV-1 reservoir resulting in 100-fold more HIV-1 release into culture supernatant than by common recall antigens, and 1000-fold more than by chemotherapeutic LRAs. HLP induced release of a divergent and replication-competent HIV-1 population from PLWH on cART. These findings suggest HLP provides a targeted approach to reactivate the majority of latent HIV-1 proviruses among individuals infected with HIV-1.迄今为止，针对HIV-1治愈的可负担且有效的治疗手段仍仅停留在概念阶段：绝大多数潜伏期逆转剂（LRAs）对潜伏HIV-1储存库缺乏特异性，且在早期临床试验中宣告失败。本研究评估了多价HIV-1来源病毒样颗粒（HLP）的HIV-1潜伏期逆转效果，将其用于处理来自乌干达、美国及加拿大的32名HIV-1感染者（PLWH）的样本——这些感染者在慢性感染阶段即启动了联合抗逆转录病毒治疗（cART）。即便在接受稳定cART治疗5至20年后，HLP仍可靶向携带潜伏HIV-1储存库的CD4阳性T淋巴细胞，使培养上清液中的HIV-1释放量相较于常规回忆抗原高出100倍，较化疗类LRAs高出1000倍。HLP可诱导接受cART治疗的PLWH体内具有多样性且具备复制能力的HIV-1种群释放。上述研究结果表明，HLP可为重新激活HIV-1感染者体内绝大多数潜伏HIV-1前病毒提供一种靶向性策略。