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.
Highlights
Infected cells represent the major barrier to either a sterilizing or a functional HIV-1 cure
This review focuses on how HIV-1 latency is established at the cellular and molecular levels, and discusses potential approaches to limit the establishment of latent reservoirs
It has been proposed that epigenetic silencing might have a greater role in cell lines than in primary cells [71], since several other mechanisms of establishment of latency, including limited availability of transcription factors, P-TEFb, and the nuclear export factor PTB are mainly associated with quiescent cells and might be less important in actively dividing cells
Summary
The establishment of HIV-1 latency is a complex process, which likely results from the convergence of multiple mechanisms (Table 1). This is an open question, the evidence suggests that these different routes of establishment of latency can all occur under different circumstances It is not yet known whether the establishment of latency might differ between memory CD4 T-cell subsets, for example in TCM compared to TTM. Little is known about how latency can be established in other cell types, which might exhibit important differences compared to CD4 T-cells It is unclear how well the different models of latency establishment recapitulate this process in patients. MAW modified parts of the manuscript in his role as Head of the Laboratory. Both authors read and approved the final manuscript
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