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  • Review Article
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HIV-1 dynamics in vivo: implications for therapy

Nature Reviews Microbiology volume 1, pages 181–190 (2003)Cite this article

Key Points

  • Human immunodeficiency virus type 1 (HIV-1) replicates to high levels through all stages of infection, resulting in a progressive depletion of CD4+ T lymphocytes. Highly active antiretroviral therapy (HAART) has led to a significant reduction of HIV-1-related morbidity and mortality.

  • Therapeutic interventions that are aimed at perturbing the equilibrium between HIV-1 production and clearance rates have helped to elucidate the dynamic nature of HIV-1 replication in vivo.

  • Over the past eight years, minimal estimates for the turnover rates of virions and infected cell populations have been refined. The half-life of productively infected CD4+ T lymphocytes is approximately 17 hours; the turnover rate of virions is even faster, with a half-life of less than one hour. In an untreated, chronically infected individual with an average plasma viraemia (for example, 104–105 HIV-1 RNA copies ml−1), more than 10 billion virions are produced and cleared daily.

  • Although most free virions are generated by short-lived productively infected CD4+ T lymphocytes, a small proportion (1–7%) originates from several longer-lived infected cell populations (for example, macrophages, resting T lymphocytes, follicular dendritic cells).

  • HAART suppresses viral replication but fails to completely eliminate HIV-1 from an infected individual. Latently infected memory CD4+ T lymphocytes constitute a stable reservoir from which replication competent HIV-1 can emerge even after prolonged, seemingly suppressive, HAART. The half-life of this reservoir is long (6–44 months).

  • Another important obstacle towards eliminating HIV-1 is the persistence of ongoing, low-level viral replication, even in cases with complete suppression of plasma viraemia during HAART.

Abstract

The advent of potent combination antiretroviral therapy has been an important breakthrough in the treatment of HIV-1 infection, resulting in marked reductions in HIV-1-related morbidity and mortality. Antiretroviral therapy has also provided researchers with a powerful tool to perturb the equilibrium of viral production and viral clearance, allowing them to dissect the underlying dynamics that control the pathogenesis of AIDS. Here, we review our current understanding of the sources of HIV-1 production, the estimates for the virion and the host-cell half-lives, and the pathways of virion trafficking and clearance. We also discuss the obstacles that result from the ability of HIV-1 to remain dormant for a prolonged period of time in a subset of long-lived cells, despite an apparently effective antiretroviral treatment.

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Figure 1: Schematic representation of the HIV-1 life cycle.
Figure 2: The natural course of HIV-1 infection on the basis of the longitudinal evolution of the two key surrogate markers — plasma viraemia and CD4+ T-lymphocyte count54.
Figure 3: Short-term viral decay kinetics of HIV-1 in vivo in response to chemotherapeutic interventions show that the turnover of virions and productively infected T lymphocytes is extremely rapid.
Figure 4: Schematic summary of the turnover rates of virions and the relative contribution of the different HIV-1-infected cell populations.
Figure 5: Large-volume plasma apheresis provides the possibility of disrupting the balance between virion production and clearance without the need for pharmacological interventions.
Figure 6: Experimental procedures used to assess the differential trafficking of CD4+ T lymphocytes and SIV particles in the SIV-rhesus macaque model.

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Acknowledgements

We attempted to give a comprehensive overview of the current understanding of the field but it was impossible to cover every publication in this review, and we wish to apologize for any oversight. We thank L. Chakrabarti, I. Chen, M. Di Mascio, D. Gurner and L. C. F. Mulder for the critical reading of the manuscript and G. Cardué for assistance with the graphics.

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Authors and Affiliations

  1. The Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Avenue, New York, 10016, New York, USA

    Viviana Simon, David D. Ho & David D. Ho

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  1. Viviana Simon
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  2. David D. Ho
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Correspondence to David D. Ho.

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Competing interests

D. Ho sits on the scientific advisor board for ViroLogic, Osel, Achillion and VivoQuest. Products or work from these companies are not discussed in the review. V. Simon has no competing financial interests.

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DATABASES

Infectious Disease Information

AIDS

LocusLink

CCR5

CD4

CXCR4

FURTHER INFORMATION

Aaron Diamond AIDS Research Center

Los Alamos HIV Sequence Database

UNAIDS

Glossary

PLASMA VIRAEMIA

The quantity of cell-free HIV-1 virions detected in the plasma compartment of an infected individual (expressed as HIV-1 RNA copies or virion equivalents per millilitre of plasma).

RESERVOIR

Any compartment, be it a specific cell population or an anatomical site, that serves as a source of replicating virus and has distinct kinetics of viral replication.

LATENCY

A post-integration state of replicative dormancy, wherein minimal or no HIV gene expression occurs in a cell, despite the replication competence of the integrated virus.

VIRAL SET-POINT

The relatively stable level of plasma viraemia observed after the peak of plasma viraemia associated with acute infection. The viral set-point has been shown to be predictive of long-term prognosis.

CD4+ T LYMPHOCYTES

T-lymphocyte subpopulation that expresses the CD4 receptor. CD4+ helper cells recognize antigens presented by HIV-1 infected cells and are essential for orchestrating specific immune responses. The progressive loss of CD4+ helper cells is the hallmark of AIDS.

HAART

(Highly Active Antiretroviral Treatment). Consists of a minimum of three drugs that inhibit the activity of the viral enzymes reverse transcriptase or protease. The first compound of a third drug class, the fusion inhibitors, has recently been approved for treatment.

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Simon, V., Ho, D. HIV-1 dynamics in vivo: implications for therapy. Nat Rev Microbiol 1, 181–190 (2003). https://doi.org/10.1038/nrmicro772

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