The multifaceted nature of HIV latency

Abstract

Although antiretroviral therapies (ARTs) potently inhibit HIV replication, they do not eradicate the virus. HIV persists in cellular and anatomical reservoirs that show minimal decay during ART. A large number of studies conducted during the past 20 years have shown that HIV persists in a small pool of cells harboring integrated and replication-competent viral genomes. The majority of these cells do not produce viral particles and constitute what is referred to as the latent reservoir of HIV infection. Therefore, although HIV is not considered as a typical latent virus, it can establish a state of nonproductive infection under rare circumstances, particularly in memory CD4+ T cells, which represent the main barrier to HIV eradication. While it was originally thought that the pool of latently infected cells was largely composed of cells harboring transcriptionally silent genomes, recent evidence indicates that several blocks contribute to the nonproductive state of these cells. Here, we describe the virological and immunological factors that play a role in the establishment and persistence of the pool of latently infected cells and review the current approaches aimed at eliminating the latent HIV reservoir.

Figure 1. Distinguishing HIV persistence and HIV latency.

During untreated HIV infection, the majority of infected cells are short-lived: HIV viremia is sustained by a dynamic process involving continuous rounds of de novo infection. Initiation of ART (blue dashed lines) leads to a dramatic reduction in the levels of viral replication and in the frequency of infected cells. Residual viremia persists and can originate from low levels of ongoing replication or, more likely, from the continuous production of viral particles from stable reservoirs. The majority of infected cells in PLHIV on ART do not produce viral particles and are defined as latently infected cells. Although the production of spliced transcripts or viral proteins is rare, a relatively large fraction of these cells produce short, abortive viral transcripts. Complete silencing of HIV genomes may also occur when epigenetic regulators repress the LTR transcriptional activity.

Figure 2. Models for the establishment of HIV latency.

Postactivation latency refers to a phenomenon by which activated productively infected CD4⁺ T cells revert back to a quiescent state, which is accompanied by the silencing of the HIV promoter. In preactivation latency, resting CD4⁺ T cells, which are usually refractory to HIV infection, become permissive and establish latency directly (i.e., in the absence of T cell activation).

Figure 3. Mechanisms and targets of HIV latency.

HIV silencing is regulated by key control elements acting on (i) HIV transcription initiation (histone acetylation/deacetylation, histone and DNA methylation, transcription factors), (ii) HIV transcription elongation (positive transcription elongation factor b [P-TEFb] and viral protein Tat), (iii) HIV RNA export (polypyrimidine tract–binding protein [PTB]), and (iv) HIV RNA degradation (miRNAs). Pathways promoting HIV expression are shown with black arrows, whereas those inhibiting HIV expression are shown in red. These pathways can be targeted in vivo (in italics) in order to reverse HIV latency (latency-reversing agents [LRAs], purple), promote HIV latency (latency-promoting agents [LPAs], blue), or edit the HIV genome (CRISPR/Cas9, green).