Molecular Control of HIV and SIV Latency

Abstract

The HIV latent reservoirs are considered as the main hurdle to viral eradication. Numerous mechanisms lead to the establishment of HIV latency and act at the transcriptional and post-transcriptional levels. A better understanding of latency is needed in order to ultimately achieve a cure for HIV. The mechanisms underlying latency vary between patients, tissues, anatomical compartments, and cell types. From this point of view, simian immunodeficiency virus (SIV) infection and the use of nonhuman primate (NHP) models that recapitulate many aspects of HIV-associated latency establishment and disease progression are essential tools since they allow extensive tissue sampling as well as a control of infection parameters (virus type, dose, route, and time).

Tackling HIV Persistence: Pharmacological versus CRISPR-Based Shock Strategies

“…HIV-1 latency can be established (and maintained) by different mechanisms that operate at the transcriptional level. Transcriptional regulation of HIV-1 gene expression and latency results from a complex and dynamic interplay of multiple factors that act at the initiation, but mostly the elongation phase of transcription [ 43 , 44 ]. The underlying molecular mechanisms are only partially understood and remain the focus of intense research, including topics like epigenetic modification of the HIV-1 long-terminal repeat (LTR) promoter, the absence of transcription factors or the presence of repressive factors.…”

Epigenetic Modulation of CD8+ T Cell Function in Lentivirus Infections: A Review

“…SIV integrates into the host genome at preferred integration sites [ 62 , 63 ]. Similar to HIV, SIV undergoes histone de-acetylation in long terminal repeats (LTRs) and these changes contribute to latency [ 64 , 65 ]. CTLs are unable to clear latently SIV-infected cells [ 66 ].…”

“…Epigenetic changes in the FIV and SIV proviruses have been extensively studied to understand HIV latency which have enabled the testing of ARVs in both the disease models. The FIV and SIV LTR regions of promoters have de-acetylated and methylated histones similar to HIV infection resulting in latency [ 42 , 64 , 65 ]. Unlike during HIV infection, the FIV proviral promoter is not hypermethylated in latently infected CD4 + T cells and monocytes isolated from peripheral blood of FIV-infected cats [ 132 ].…”

“…During the asymptomatic phase of SIV infection, H4 is de-acetylated in the brain whereas in the acute phase, high levels of acetylated H4 are detected [ 64 ]. As described in previous sections, HDAC and HMT inhibitors such as SAHA and valproic acid have been tested in these two animal models successfully reactivating latent FIV/SIV in vitro and ex vivo [ 25 , 65 ]. Studies exploring the role of epigenetics in immune cells responding to lentivirus infections is limited.…”

Dendritic Cells Potently Purge Latent HIV-1 in TCR-Activated Cells via the PI3K-Akt-mTOR Pathway: Implications for Shock and Killl Strategies and Reservoir Analysis

“…Resting memory CD4 + T cells are the main cell type harboring latent HIV-1 in patients after prolonged therapy (Perelson et al, 1996;Wei et al, 1995), but T cells with shorter half-lives, such as effector T cells, can also harbor latent HIV-1 (Chavez et al, 2015;van der Sluis et al, 2013). Latency is established and maintained through multiple mechanisms that act at transcriptional and posttranscriptional levels (Darcis et al, 2017). At the transcriptional level, accessibility of the HIV-1 LTR promoter could be blocked in repressive chromatin structures (which can be overcome with histone deacetylase (HDAC) inhibitors) or by the sequestration of transcription initiation factors such as NF-ĸB/NFAT/AP-1.…”