Abstract
The persistence of human immunodeficiency virus type 1 (HIV-1) in latent reservoirs is a major barrier to HIV cure. Reservoir establishment depends on low viral expression that may be related to provirus integration sites (IS). In vitro, in cell lines and primary T cells, latency is associated with specific IS through reduced viral expression mediated by transcriptional interference by host cellular promoters, reverse orientation, and the presence of specific epigenetic modifiers. In primary T cell models of latency, specific IS are associated with intracellular viral antigen expression that is not directly related to cell activation. In contrast, in patient CD4+ T cells, there is enrichment for IS in genes controlling cell cycle and survival and in some clonally expanded T cell subpopulations. Multiple insertion sites within some specific genes may suggest that integrated HIV can increase the host’s T cell survival.
Highlights
Despite combination antiretroviral therapy that can effectively control viral replication and normalize immune function, human immunodeficiency virus (HIV) remains a global health issue
We focus on understanding the effect of human immunodeficiency virus type 1 (HIV-1) integration in the in vitro models of latency and the recent data identifying some integration sites (IS) that may directly determine the persistence of latency either by favoring infected cell survival or by maintaining low viral expression
A correlation between viral antigen expression and specific genomic markers has been shown within different in vitro models of HIV latency, but the correlations have not translated to the general features of IS that extend across multiple models of latency in primary CD4+ T cells
Summary
Despite combination antiretroviral therapy (cART) that can effectively control viral replication and normalize immune function, human immunodeficiency virus (HIV) remains a global health issue. GDR gene dense region, NP nuclear periphery, TAHM transcriptional associated histone modification, GD gene dessert, TSS transcription start site, TU transcriptional unit, NR not reported, rCD4 resting CD4 cells, HAG highly active genes, AG active gene, PBMC peripheral blood mononuclear cells, MLV murine leukemia virus, ASLV avian sarcoma-leukosis virus, Ac acute, Ch chronic, lat latent, pat patient genes could increase the HIV-1 transcription by >10 fold, while integration at opposite orientation reduced the HIV-1 gene expression by 4-folds [47] These observations highlighted that low level of viral expression is not because of lack of transcriptional activity at the site of proviral integration and it might be due to the presence of factors blocking the transcription at the site of integration by transcriptional interferences (TI) [19, 47–49]. It will be important to expand studies of IS in T cell subpopulations isolated from patients on long-term therapy to determine how viral expression may be controlled by particular epigenetic markers and gene-specific control mechanisms in the specific subpopulations that contribute most to the size of the latent reservoir
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