Abrahams Melissa-Rose, Joseph Sarah B, Garrett Nigel, Tyers Lynn, Moeser Matthew, Archin Nancie, Council Olivia D, Matten David, Zhou Shuntai, Doolabh Deelan, Anthony Colin, Goonetilleke Nilu, Karim Salim Abdool, Margolis David M, Pond Sergei Kosakovsky, Williamson Carolyn, Swanstrom Ronald
Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Sci Transl Med. 2019 Oct 9;11(513). doi: 10.1126/scitranslmed.aaw5589.
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.
尽管抗逆转录病毒疗法（ART）在抑制HIV-1复制方面非常有效，但在治疗期间，病毒仍作为潜伏库存在于静息CD4 T细胞中。即使在感染后早期就开始ART治疗，这个潜伏库仍然会形成，但其形成的动态过程在很大程度上尚不清楚。与在急性感染期间开始治疗的个体相比，在慢性感染期间开始ART治疗的个体的病毒潜伏库通常更大，并且在基因上更加多样化，这与在未经治疗的感染过程中潜伏库持续形成的假设一致。为了确定病毒何时进入潜伏库，我们比较了9名接受治疗的HIV阳性女性静息外周CD4 T细胞中具有复制能力的病毒序列与治疗前纵向采集的血液中循环的病毒序列。我们发现，平均而言，从治疗后潜伏库中诱导出的独特病毒中，有71%在基因上与ART开始前正在复制的病毒最为相似。如果潜伏库是持续形成且一直长期存在的，那么这个比例将远远高于预期。我们得出结论，ART以一种允许大多数长期潜伏的HIV-1潜伏库形成或稳定的方式改变宿主环境，这为在治疗开始时限制潜伏库形成的新策略指明了方向。
