Massanella Marta, Bender Ignacio Rachel A, Lama Javier R, Pagliuzza Amélie, Dasgupta Sayan, Alfaro Ricardo, Rios Jessica, Ganoza Carmela, Pinto-Santini Delia, Gilada Trupti, Duerr Ann, Chomont Nicolas
Centre de Recherche du CHUM, Montreal, QC, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada.
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Lancet Microbe. 2021 May;2(5):e198-e209. doi: 10.1016/S2666-5247(21)00010-0. Epub 2021 Mar 23.
Early antiretroviral therapy (ART) initiation (ie, within 3 months of infection) limits establishment of the HIV reservoir. However, the effect of early ART initiation on the long-term dynamics of the pool of infected cells remains unclear.
In this longitudinal analysis, we included cisgender men who have sex with men (MSM) and transgender women (aged 18-54 years) at high risk for HIV infection, enrolled in the ongoing longitudinal MERLIN study in Peru between Oct 28, 2014, and Nov 8, 2018. Participants were eligible if they had been infected with HIV less than 90 days before enrolment, and if they had cryopreserved peripheral blood mononuclear cell (PBMC) samples. Participants were stratified into three groups on the basis of whether they initiated ART at 30 days or less (acute group), at 31-90 days (early group), or more than 24 weeks (deferred group) after the estimated date of detectable infection. PBMC samples were collected before ART initiation and longitudinally for up to 4 years on ART. The main outcomes were to establish the size of the HIV reservoir before ART initiation and to assess the effect of the timing of ART initiation on the decay of the HIV reservoir over 4 years follow-up. We quantified viral load, and isolated CD4 cells to quantify total HIV DNA, integrated HIV DNA and 2-long terminal repeat circles. Longitudinal analysis of active and inducible HIV reservoirs were measured by quantifying the frequency of CD4 cells producing multiply-spliced HIV RNA ex vivo and after in-vitro stimulation with a tat/rev induced limiting dilution assay (TILDA). A mixed-effects model from the time of ART initiation was used to measure longitudinal decays in viral loads and each HIV reservoir measure in each of the three groups.
We included 56 participants in this analysis, all of whom were MSM: 15 were in the acute group, 19 were in the early group, and 22 were in the deferred group. Participants in all three groups had similar levels of all HIV reservoir markers before ART initiation. All participants, including those in the acute group, had a pool of transcriptionally silent HIV-infected cells before ART initiation, as indicated by a substantial increase in TILDA measures upon stimulation. Longitudinal analysis over 4 years of ART revealed a biphasic decay of all HIV persistence markers, with a rapid initial decline followed by a slower decay in all participants. During the first-phase decay, the half-lives of both total and integrated HIV DNA and TILDA measures were significantly shorter in the acute group than in the early and deferred groups. During the second-phase decay, HIV reservoir markers continued to decline only in participants in the acute group.
Participants who initiated ART within 30 days or less of HIV infection showed a steeper and more sustained decay in HIV reservoir measures, suggesting long-term benefit of acute ART initiation on reservoir clearance.
The US National Institutes of Health and the Canadian Institutes for Health Research.
早期启动抗逆转录病毒疗法（ART）（即感染后3个月内）可限制HIV储存库的建立。然而，早期启动ART对受感染细胞池长期动态变化的影响尚不清楚。
在这项纵向分析中，我们纳入了有感染HIV高风险的与男性发生性关系的顺性别男性（MSM）和跨性别女性（年龄18 - 54岁），他们参与了2014年10月28日至2018年11月8日在秘鲁进行的正在进行的纵向MERLIN研究。如果参与者在入组前感染HIV少于90天，且有冷冻保存的外周血单个核细胞（PBMC）样本，则符合入选条件。根据参与者在估计可检测感染日期后30天及以内（急性组）、31 - 90天（早期组）或超过24周（延迟组）启动ART，将参与者分为三组。在ART启动前及启动后长达4年的时间里纵向收集PBMC样本。主要结局是确定ART启动前HIV储存库的大小，并评估ART启动时间对4年随访期间HIV储存库衰减的影响。我们对病毒载量进行了定量，并分离CD4细胞以定量总HIV DNA、整合HIV DNA和2 - 长末端重复序列环。通过在体外和用tat/rev诱导的有限稀释分析（TILDA）进行体外刺激后定量产生多重剪接HIV RNA的CD4细胞频率，对活跃和可诱导的HIV储存库进行纵向分析。使用从ART启动时开始的混合效应模型来测量三组中病毒载量和每个HIV储存库指标随时间的衰减情况。
我们在该分析中纳入了56名参与者，他们均为MSM：15名在急性组，19名在早期组，22名在延迟组。三组参与者在ART启动前所有HIV储存库标志物水平相似。所有参与者，包括急性组的参与者，在ART启动前都有一群转录沉默的HIV感染细胞，这通过刺激后TILDA测量值的大幅增加得以表明。对ART治疗4年的纵向分析显示，所有HIV持续存在标志物呈双相衰减，所有参与者最初快速下降，随后衰减变慢。在第一阶段衰减期间，急性组总HIV DNA和整合HIV DNA以及TILDA测量值的半衰期显著短于早期组和延迟组。在第二阶段衰减期间，仅急性组参与者的HIV储存库标志物继续下降。
在HIV感染后30天及以内启动ART的参与者在HIV储存库指标方面显示出更陡峭且更持续的衰减，这表明急性启动ART对储存库清除具有长期益处。
美国国立卫生研究院和加拿大卫生研究院。
