Cellular and molecular mechanisms involved in the establishment of HIV-1 latency

Abstract

Latently infected cells represent the major barrier to either a sterilizing or a functional HIV-1 cure. Multiple approaches to reactivation and depletion of the latent reservoir have been attempted clinically, but full depletion of this compartment remains a long-term goal. Compared to the mechanisms involved in the maintenance of HIV-1 latency and the pathways leading to viral reactivation, less is known about the establishment of latent infection. This review focuses on how HIV-1 latency is established at the cellular and molecular levels. We first discuss how latent infection can be established following infection of an activated CD4 T-cell that undergoes a transition to a resting memory state and also how direct infection of a resting CD4 T-cell can lead to latency. Various animal, primary cell, and cell line models also provide insights into this process and are discussed with respect to the routes of infection that result in latency. A number of molecular mechanisms that are active at both transcriptional and post-transcriptional levels have been associated with HIV-1 latency. Many, but not all of these, help to drive the establishment of latent infection, and we review the evidence in favor of or against each mechanism specifically with regard to the establishment of latency. We also discuss the role of immediate silent integration of viral DNA versus silencing of initially active infections. Finally, we discuss potential approaches aimed at limiting the establishment of latent infection.

Figure 1

Cellular pathways of the establishment of HIV-1 latency in CD4 T-cells. (A) Generation of memory CD4 T-cells. Transcriptionally active CD4+CD8+ (double positive) thymocytes transition to a resting state upon completion of thymopoiesis to become resting naïve CD4 T-cells. Naïve cells are activated upon encounter with antigen-bearing dendritic cells and undergo rapid clonal expansion. A small fraction of activated CD4 T-cells survive and transition to a resting state, to become resting memory CD4 T-cells. (B) Infection during deactivation. Infection of an activated thymocyte can result in active integration or immediate silent integration. Latency can be established upon the transition to a naïve CD4 T-cell. Infection of an activated CD4 T-cell can result in active integration or immediate silent integration. Latency can be established upon the transition to a resting memory CD4 T-cell. Note that for immediate silent integration into an activated thymocyte or an activated CD4 T-cell, latency has already been established at the virological level. Due to the rapid deaths of activated cells, only cells which transition to a resting state represent clinically relevant latent infections. (C) Direct resting cell infection. Infection of a naïve CD4 T-cell, or of a resting memory CD4 T-cell, results in immediate silent integration, i.e., latency. Note that the relative contributions of the pathways shown here are not known.