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Engaging innate immunity in HIV-1 cure strategies

Nature Reviews Immunology volume 22, pages 499–512 (2022)Cite this article

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Abstract

Combination antiretroviral therapy (ART) can block multiple stages of the HIV-1 life cycle to prevent progression to AIDS in people living with HIV-1. However, owing to the persistence of a reservoir of latently infected CD4+ T cells, life-long ART is necessary to prevent viral rebound. One strategy currently under consideration for curing HIV-1 infection is known as ‘shock and kill’. This strategy uses latency-reversing agents to induce expression of HIV-1 genes, allowing for infected cells to be cleared by cytolytic immune cells. The role of innate immunity in HIV-1 pathogenesis is best understood in the context of acute infection. Here, we suggest that innate immunity can also be used to improve the efficacy of HIV-1 cure strategies, with a particular focus on dendritic cells (DCs) and natural killer cells. We discuss novel latency-reversing agents targeting DCs as well as DC-based strategies to enhance the clearance of infected cells by CD8+ T cells and strategies to improve the killing activity of natural killer cells.

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Fig. 1: ‘Shock and kill’ strategies to eliminate CD4+ T cells latently infected with HIV-1.
Fig. 2: Ex vivo generation of monocyte-derived dendritic cells for therapeutic vaccination.
Fig. 3: Strategies to enhance natural killer cell-mediated killing of HIV-1-infected cells.

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  1. These authors contributed equally: Nathan L. Board, Milica Moskovljevic, Fengting Wu.

Authors and Affiliations

  1. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Nathan L. Board, Milica Moskovljevic, Fengting Wu, Robert F. Siliciano & Janet D. Siliciano

  2. Howard Hughes Medical Institute, Baltimore, MD, USA

    Robert F. Siliciano

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N.L.B., M.M. and F.W. contributed equally to all aspects of this article. R.F.S. and J.D.S. contributed substantially to the discussion of content and revision of the manuscript before submission.

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Glossary

Antiretroviral therapy

(ART). Treatment with drugs such as reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors or entry inhibitors that prevent ongoing HIV-1 replication.

Transmitted/founder viruses

The single or very few HIV-1 viral clones that establish productive infection of a new host during HIV-1 transmission.

Broadly neutralizing antibody

(bNAb). An antibody that binds to a conserved region of HIV-1 Env and that can neutralize a large diversity of viral isolates.

Antibody-dependent cellular cytotoxicity

(ADCC). The process by which a cytolytic immune effector cell (natural killer cell, monocyte, neutrophil or eosinophil) recognizes and lyses a target cell whose surface is bound by antibodies.

HIV-1 controllers

A small subset of people living with HIV-1 who maintain a low but detectable level of viraemia and high CD4+ T cell counts without antiretroviral therapy.

Analytical treatment interruption

A period during which people living with HIV-1 on ART temporarily stop therapy to evaluate the effects of a novel treatment on viral rebound.

Killer immunoglobulin-like receptor

(KIR). A family of natural killer cell receptors that interact with MHC class I molecules on the surface of target cells to regulate natural killer cell activation.

Antibody-dependent cellular phagocytosis

The process by which a phagocytic immune cell recognizes and engulfs a target cell whose surface is bound by antibodies, resulting in elimination of the target cell and MHC class II-dependent presentation of antigens derived from the target cell by the phagocyte.

Bispecific antibody

An engineered antibody that recognizes two distinct epitopes or antigens.

Alu-Gag PCR

A PCR method for measuring integrated HIV-1 DNA using primers that recognize Alu repeat elements in the host genome and the gag gene of the HIV-1 genome.

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Board, N.L., Moskovljevic, M., Wu, F. et al. Engaging innate immunity in HIV-1 cure strategies. Nat Rev Immunol 22, 499–512 (2022). https://doi.org/10.1038/s41577-021-00649-1

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