An integrated overview of HIV-1 latency

Abstract

Despite significant advances in our understanding of HIV, a cure has not been realized for the more than 34 million infected with this virus. HIV is incurable because infected individuals harbor cells where the HIV provirus is integrated into the host's DNA but is not actively replicating and thus is not inhibited by antiviral drugs. Similarly, these latent viruses are not detected by the immune system. In this Review, we discuss HIV-1 latency and the mechanisms that allow this pathogenic retrovirus to hide and persist by exploiting the cellular vehicles of immunological memory.

Figure 1. HIV-1 Infection and Reactivation of CD4⁺ T cells

HIV-1 infects activated CD4⁺ T cells, which have increased nucleotide pools, cytokines, and transcription factors compared to non-activated cells. Most of these infected cells die due to cytopathic effects of the virus or lysis by HIV-specific CTLs. Cells that revert back to a resting memory T cell survive and may undergo homeostatic proliferation. Upon initiation of ART these latently infected cells persist. However, treatment of these cells with reactivating agents causes the cells to actively produce virus and ultimately leads to either spontaneous cell death or death through immune system clearance.

Figure 2. Major Mechanisms of HIV-1 Latency in CD4⁺ T cells

Sequestration of essential transcription factors, like NFAT and NF-κB, in the cytoplasm leads to silencing of viral gene expression. Two major mechanisms of transcriptional interference occur in latently infected cells. In promoter occlusion, the host promoter is positioned upstream of the provirus and the host RNA Pol II reads through the HIV-1 LTR, causing displacement of necessary transcription factors. In convergent transcription, provirus and the host gene are in the opposite orientation, leading to collision of the RNA Pol II complexes. Levels of CyclinT1, which forms P-TEFb and is important for HIV-1 transcription and Tat transactivation, are low in resting CD4⁺ T cells. DNA methylation and restrictive chromatin structures contribute to transcriptional silencing leading to HIV-1 latency.

Figure 3. Initiation of Transcription and Translational Elongation at the HIV-1 LTR

Following cellular activation or drug treatment NFAT and NF-κB translocate to the nucleus and bind sites at the HIV-1 LTR. NFAT and NF-κB recruit p300/CBP to the LTR, resulting in acetylation of histone tails and transcriptional activation. In the case of NF-κB, proteosomal degradation of IκBα permits NF-κB translocation and displacement of the p50 homodimers. This is followed by Tat-dependent elongation, in which Tat recruits the P-TEFb complex to TAR. Cdk9 phosphorylates the CTD of RNA Pol II, resulting in increased processivity. P-TEFb phosphorylates DSIF and NELF, resulting in removal of NELF from Pol II, converting DSIF into a positive elongation factor, thereby promoting productive elongation.