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Review
. 2020 Jan 24:10:3060.
doi: 10.3389/fmicb.2019.03060. eCollection 2019.

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

Amina Ait-Ammar  1 , Anna Kula  2 , Gilles Darcis  3 , Roxane Verdikt  1 , Stephane De Wit  4 , Virginie Gautier  5 , Patrick W G Mallon  5 , Alessandro Marcello  6 , Olivier Rohr  7 , Carine Van Lint  1
Affiliations
Review

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

Amina Ait-Ammar et al. Front Microbiol. .

Abstract

One of the most explored therapeutic approaches aimed at eradicating HIV-1 reservoirs is the "shock and kill" strategy which is based on HIV-1 reactivation in latently-infected cells ("shock" phase) while maintaining antiretroviral therapy (ART) in order to prevent spreading of the infection by the neosynthesized virus. This kind of strategy allows for the "kill" phase, during which latently-infected cells die from viral cytopathic effects or from host cytolytic effector mechanisms following viral reactivation. Several latency reversing agents (LRAs) with distinct mechanistic classes have been characterized to reactivate HIV-1 viral gene expression. Some LRAs have been tested in terms of their potential to purge latent HIV-1 in vivo in clinical trials, showing that reversing HIV-1 latency is possible. However, LRAs alone have failed to reduce the size of the viral reservoirs. Together with the inability of the immune system to clear the LRA-activated reservoirs and the lack of specificity of these LRAs, the heterogeneity of the reservoirs largely contributes to the limited success of clinical trials using LRAs. Indeed, HIV-1 latency is established in numerous cell types that are characterized by distinct phenotypes and metabolic properties, and these are influenced by patient history. Hence, the silencing mechanisms of HIV-1 gene expression in these cellular and tissue reservoirs need to be better understood to rationally improve this cure strategy and hopefully reach clinical success.

Keywords: HIV-1; cure; heterogeneity; latency; latency reversing agents; reservoirs.

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Figures

FIGURE 1
FIGURE 1
Schematic representation of the different transcriptional and post-transcriptional blocks involved in HIV-1 latency. During HIV-1 latency, several blocks preventing viral production have been described. These are represented by the methylation of the two CGIs surrounding the HIV-1 TSS and the deposit of repressive epigenetic marks (histone deacetylation and methylation) maintaining the repressive nucleosome nuc-1 positioned in the HIV-1 5′LTR promoter just downstream the TSS. The transcription initiation is also blocked because of the cytoplasmic sequestration of the positive NF-κB heterodimer p50–p65 and the phosphorylated NFAT and STAT5. The presence of repressive factors (such as CTIP2, TRIM22 and the binding of the homodimer p50–p50 to the NF-κB binding sites in the HIV-1 promoter) acts negatively on HIV-1 transcription initiation. The RNAPII, with its phosphorylated serine 5 (S5P) residue in its C-terminal domain, pauses and accumulates at the promoter-proximal region due to the binding of the negative factors NELF and DSIF. The elongation is also blocked by the absence of the master regulator of viral transcription Tat and by the sequestration of the positive transcriptional elongation factor P-TEFb into the inactive complex named 7SK snRNP. The splicing and export of HIV-1 transcripts are inefficient during latency due to the low expression level of post-transcriptional factors such as PTB, MATR3, and PSF. Finally, translation of viral transcripts could be inhibited by mechanisms involving mRNA degradation and sequestration in cytoplasmic granules.
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