Abstract
BackgroundIn most patients, current antiretroviral therapy (ART) regimens can rapidly reduce plasma viral load. However, even after years of effective treatment, a significant proportion of patients show residual plasma viremia below the clinical detection limit. Although residual viremia might be associated with increased chronic immune activation and morbidity, its origin and its potential role in the replenishment of the viral reservoir during suppressive ART is not completely understood. We performed an in-depth genetic analysis of the total and episomal cell-associated viral DNA (vDNA) repertoire in purified CD4+ T cell subsets of three HIV-infected individuals, and used phylogenetic analysis to explore its relationship with plasma viruses.ResultsThe predominant proviral reservoir was established in naïve or memory (central and transitional) CD4+ T cell subsets in patients harboring X4- or R5-tropic viruses, respectively. Regardless of the viral tropism, most plasma viruses detected under suppressive ART resembled the proviral reservoir identified in effector and transitional memory CD4+ T-cell subsets in blood, suggesting that residual viremia originates from these cells in either blood or lymphoid tissue. Most importantly, sequences in episomal vDNA in CD4+ T-cells were not well represented in residual viremia.ConclusionsViral tropism determines the differential distribution of viral reservoir among CD4+ T-cell subsets. In spite of viral tropism, the effector and transitional memory CD4+ T-cells subsets are the main source of residual viremia during suppressive ART, even though their contribution to the total proviral pool is small. However, the lack of concordance between residual viremia and viral variants driving de novo infection of CD4+ T cells on ART may reflect the predominance of defective plasma HIV RNA genomes. These findings highlight the need for monitoring the multiple viral RNA/DNA persistence markers, based on their differential contribution to viral persistence.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0282-9) contains supplementary material, which is available to authorized users.
Highlights
In most patients, current antiretroviral therapy (ART) regimens can rapidly reduce plasma viral load
Our results indicate that: (1) viral sequences in residual viremia are predominantly related to proviral sequences in effector and transitional memory CD4+ T-cells suggesting that residual viremia originates from these cells, and (2) there is limited sequence relationship between episomal viral DNA (vDNA) and plasma viral RNA, suggesting that viruses in plasma are not the source of the de novo infection events detected in peripheral CD4+ T-cells
For further ultra-deep sequencing analysis, we selected the five patients with the highest levels of total and episomal cellassociated vDNA in peripheral blood mononuclear cells (PBMCs); consistent proviral human immunodeficiency virus type 1 (HIV-1) Env amplification in the different subsets was obtained from 3 individuals at baseline and after viral suppression (Table 1; Fig. 1a)
Summary
Current antiretroviral therapy (ART) regimens can rapidly reduce plasma viral load. Antiretroviral treatment intensification does not lower the levels of residual viremia [13,14,15,16,17,18,19], and data from phylogenetic analyses of the viruses found in the plasma of ART-treated individuals show a lack of long-term genetic evolution [20,21,22,23] suggesting that residual viremia does not largely reflect ongoing viral replication Still, it is not fully established whether the source of this active viral production is a particular cell type or anatomical compartment, in which antiretroviral treatment might be preventing new infection events [24, 25]. This issue is of particular interest, as the therapeutic approaches to be considered when trying to reduce the chronic immune activation that is potentially derived from residual viremia will depend on the origin and specific target cell populations
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