HIV-1 proviral landscapes distinguish posttreatment controllers from noncontrollers

Abstract

HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups. Quantification of total but not intact proviral genome copies predicted sustained HIV remission as 81% of NCs, but none of the PTCs had a total proviral genome greater than 4 copies per million peripheral blood mononuclear cells (PBMCs). The results highlight the restricted intact and defective HIV reservoir in PTCs and suggest that total proviral genome burden could act as the first biomarker for identifying PTCs. Total and defective but not intact proviral copy numbers correlated with levels of cell-associated HIV RNA, activated NK cell percentages, and both HIV-specific CD4+ and CD8+ responses. These results support the concept that defective HIV genomes can lead to viral antigen production and interact with both the innate and adaptive immune systems.

Longitudinal study reveals HIV-1–infected CD4+ T cell dynamics during long-term antiretroviral therapy

“…Fewer sequences were obtained per time point from controllers (average 13, range 3-25), consistent with the lower frequency of latently infected cells in these individuals (50)(51)(52). translated to yield viral proteins recognized by cytotoxic T lymphocytes (CTLs) (17,27,28,(33)(34)(35). If this is the case, then depletion of intact and certain defective HIV-1 proviruses should occur over long periods of time in PLWH on suppressive ART, and a cure may eventually be achieved with strategies that accelerate such depletion.…”

HIV Subtype and Nef-Mediated Immune Evasion Function Correlate with Viral Reservoir Size in Early-Treated Individuals

“…Primarily comprising long-lived resting memory CD4 ϩ T cells (2)(3)(4) that harbor integrated replication-competent HIV in a nearly transcriptionally quiescent state (5)(6)(7), these viral reservoirs can reactivate at any time to produce infectious virions (7)(8)(9)(10)(11)(12). As individuals with smaller latent HIV reservoirs should be more amenable to cure, remission, and/or posttreatment virological control (13)(14)(15), the identification of clinical, immunological, and other determinants of reservoir size is a priority.…”

Sex-specific innate immune selection of HIV-1 in utero is associated with increased female susceptibility to infection

“…Since DNA viral load is currently the best predictor of posttreatment control of viraemia 16,17 , or 'functional cure' of HIV following ART discontinuation, these data prompt the hypothesis that male infants following in utero-HIV transmission have greater cure potential than do females.…”