Targeting HIV latency: resting memory T cells, hematopoietic progenitor cells and future directions

Abstract

Current therapy for HIV effectively suppresses viral replication and prolongs life, but the infection persists due, at least in part, to latent infection of long-lived cells. One favored strategy toward a cure targets latent virus in resting memory CD4⁺ T cells by stimulating viral production. However, the existence of an additional reservoir in bone marrow hematopoietic progenitor cells has been detected in some treated HIV-infected people. This review describes approaches investigators have used to reactivate latent proviral genomes in resting CD4⁺ T cells and hematopoietic progenitor cells. In addition, the authors review approaches for clearance of these reservoirs along with other important topics related to HIV eradication.

Keywords::

• antiviral therapy
• HDAC inhibitors
• hematopoietic progenitor cells
• HIV latency
• HIV/AIDS
• resting memory CD4⁺ T cells

Acknowledgements

The authors would like to thank R Najafi, V Sebastian, V Terry and T Zaikos for careful reading of the manuscript.

Financial and competing interests disclosure

NT Sebastian was supported by the University of Michigan (Cellular and Molecular Biology Distinguished Student Fellowship), NIH Medical Scientist Training Program Grant T32-GM007863 and NIH Cellular and Molecular Biology Training Grant T32-GM007315. This work was supported by the Burroughs Wellcome Foundation and NIH RO1 AI096962. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• HIV forms a latent infection that allows the virus to persist despite therapy.

• The best-studied latent reservoir of HIV is in resting memory CD4⁺ T cells, including central memory, transitional memory and stem central memory T-cell subsets.

• Bone marrow HSPCs can be latently infected and viral genomes have been detected in these cells in a subset of HIV-infected people.

• HDAC and DNA methylation inhibitors have been tested to reverse latent HIV in CD4⁺ T cells and HSPCs, but more strategies are needed to boost the efficacy of these compounds.

• Agents that result in increased availability of host factors, such as NF-κB or pTEFb, can increase transcription of the latent genome and contribute to reactivation of latent infection.

• Immune-modulating compounds may antagonize latent infection, but are not ideal as treatments due to their non-specific effects on HSPCs and immune cells.

• Two major strategies for clearance of reactivated latent infection are activation of cell death pathways or the patient’s own immune system.

• Important questions to be considered in future studies include: Which HIV reservoirs should we target? How can we attain a functional cure? What are the alternative approaches to a cure?

Notes