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Eradicating HIV-1 infection: seeking to clear a persistent pathogen

Key Points

  • HIV-1 infection will remain an incurable disease until persistent, latent infection of long-lived memory CD4+ T cells is successfully targeted.

  • Resting memory CD4+ T cells are the best characterized reservoir of latent HIV-1 infection, but other potential cellular reservoirs of persistent, latent HIV-1 infection, including CD4+ memory stem cells and γδ T cells, have recently been reported. In addition, macrophages may be a source of persistent infection, but whether these cells harbour true latent infection is still unclear.

  • The mechanisms that control HIV-1 latency are multifactorial, and thus it will probably be necessary to combine complementary approaches to eradicate HIV-1 infection.

  • Humanized mouse and non-human primate models of HIV-1 will continue to have an essential role in HIV-1 eradication research. Development of reliable primary cell models of HIV-1 latency will also help in the evaluation of novel approaches.

  • Development of reliable, sensitive and tractable assays that are capable of measuring the in vivo impact of anti-latency compounds and eradication protocols in clinical trial evaluation is a key unmet need.

  • Histone deacetylase inhibitors have emerged as the leading anti-latency candidates to advance into the clinics. However, latency-reactivating agents alone will not be sufficient to clear infection, and strategies to enhance the immune response will also have to be used.

Abstract

Effective antiretroviral therapy (ART) blunts viraemia, which enables HIV-1-infected individuals to control infection and live long, productive lives. However, HIV-1 infection remains incurable owing to the persistence of a viral reservoir that harbours integrated provirus within host cellular DNA. This latent infection is unaffected by ART and hidden from the immune system. Recent studies have focused on the development of therapies to disrupt latency. These efforts unmasked residual viral genomes and highlighted the need to enable the clearance of latently infected cells, perhaps via old and new strategies that improve the HIV-1-specific immune response. In this Review, we explore new approaches to eradicate established HIV-1 infection and avoid the burden of lifelong ART.

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Figure 1: Mechanisms involved in the maintenance of HIV-1 latency and strategies to disrupt latency.
Figure 2: Current model systems to study HIV-1 latency.
Figure 3: Strategies to eliminate latently infected cells.
Figure 4: Barriers to HIV-1 eradication.

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Acknowledgements

The authors thank N. Goonetilleke for valuable input. Work in the authors' laboratories was supported by the National Institutes of Health grants AI096113, AI095052 and DA030156 to D.M.M. and AI50410 to the University of North Carolina Center for AIDS research.

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Correspondence to David M. Margolis.

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Competing interests

D.M.M. is a consultant for or clinical trial support from Merck, GlaxoSmithKline, Viiv Healthcare, Gilead, Bristol-Myers Squibb (BMS), Janssen Pharmaceuticals and Argos Therapeutics; he is also a common stockholder of Gilead. N.M.A., J.M.S., C.G. and N.S.-S. declare no competing interests.

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Glossary

Activated CD4+ T cells

Antigen-specific CD4+ T cells that have undergone stimulation of their T cell receptor–CD3 complexes. Activation of a T cell increases the surface expression of many proteins, including CD69 and CD25, and induces functional responses, such as proliferation and cytokine production.

HIV-1 reservoirs

Infected cell populations that enable the persistence of replication-competent HIV-1 in patients treated with antiretroviral therapy regimens in the order of years. The HIV-1 reservoir comprises both latent HIV-1 infection and other as-yet incompletely defined sources of persistent HIV-1.

Resting memory CD4+ T cells

Antigen-specific CD4+ T cells that have reverted to the G0 state of the cell cycle from a previously activated state but retain the capability to rapidly respond to a second antigenic exposure.

Latent HIV-1

Quiescent, replication-competent provirus that exists within a long-lived population of resting cells and that is capable of initiating new rounds of infection if therapy is interrupted.

Two-long terminal repeat circles

(2-LTR circles). The joining of the two ends of the linear unintegrated HIV-1 DNA (each end having a complete long terminal repeat) into a circularized form of DNA.

Homeostatic proliferation

A physiological process that controls stable and constant cell number without cellular differentiation. Interleukin-7 has a crucial role in maintaining normal T cell levels.

Central memory CD4+ T cells

(TCM cells). Antigen-specific CD4+ T cells that lack immediate effector function but that mediate rapid recall responses and have the capacity to migrate from the blood to the secondary lymphoid organs.

Transitional memory CD4+ T cells

(TTM cells). Antigen-specific T cells that transition to the effector memory state and have lost the surface expression of the homing receptor CC-chemokine receptor 7 but retain the expression of the tumour necrosis factor receptor CD27.

CD34+ haematopoietic progenitors

Human haematopoietic cells that give rise to the myeloid and lymphoid lineages and can be identified by the expression of CD34, CD150 and CD48, but that lack CD244. These cells typically comprise 5% of the total cell population in the bone marrow.

CD4+ memory stem cells

(TSCM cells). Antigen-specific T cells with a broadly naive phenotype but with high surface expression of CD95 (also known as Fas ligand), which is a type II transmembrane protein that is expressed at high levels by all memory cells.

Chou–Talalay method

A method in which a combination index (CI) is used to express the synergy of drugs. A CI < 1 indicates synergy, a CI = 1 suggests an additive effect and a CI > 1 is indicative of antagonism.

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Archin, N., Sung, J., Garrido, C. et al. Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol 12, 750–764 (2014). https://doi.org/10.1038/nrmicro3352

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