Post-treatment control of HIV infection

Edited by Charles S. Peskin, New York University, Manhattan, NY, and approved March 13, 2015 (received for review October 8, 2014)
April 13, 2015
112 (17) 5467-5472

Significance

Recent reports suggest that antiretroviral therapy (ART) initiated early after HIV infection increases the likelihood of post-treatment control (PTC) in which plasma virus remains undetectable after treatment cessation. However, only a small fraction of patients treated early attain PTC. We develop a mathematical model of HIV infection that provides insight into these phenomena, suggesting that treatments restricting or reducing the latent reservoir size may allow immune responses to control infection posttreatment. Our model makes predictions about immune response strengths and latent reservoir sizes needed for a patient taken off treatment to exhibit PTC that may help guide future studies.

Abstract

Antiretroviral therapy (ART) for HIV is not a cure. However, recent studies suggest that ART, initiated early during primary infection, may induce post-treatment control (PTC) of HIV infection with HIV RNA maintained at <50 copies per mL. We investigate the hypothesis that ART initiated early during primary infection permits PTC by limiting the size of the latent reservoir, which, if small enough at treatment termination, may allow the adaptive immune response to prevent viral rebound (VR) and control infection. We use a mathematical model of within host HIV dynamics to capture interactions among target cells, productively infected cells, latently infected cells, virus, and cytotoxic T lymphocytes (CTLs). Analysis of our model reveals a range in CTL response strengths where a patient may show either VR or PTC, depending on the size of the latent reservoir at treatment termination. Below this range, patients will always rebound, whereas above this range, patients are predicted to behave like elite controllers. Using data on latent reservoir sizes in patients treated during primary infection, we also predict population-level VR times for noncontrollers consistent with observations.

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Acknowledgments

We thank Rustom Antia, Rob J. de Boer, John Mellors, George Shaw, Jonathan Li, and Laurent Hocqueloux for comments and discussions that helped improve this manuscript. This work was performed under the auspices of US Department of Energy Contract DE-AC52-06NA25396 and supported by National Institutes of Health Grants R01-AI028433, R01-OD011095, and UM1-AI100645.

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Supporting Information

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Information & Authors

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Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 112 | No. 17
April 28, 2015
PubMed: 25870266

Classifications

Submission history

Published online: April 13, 2015
Published in issue: April 28, 2015

Keywords

  1. HIV latency
  2. immune exhaustion
  3. HIV viral rebound
  4. mathematical modeling

Acknowledgments

We thank Rustom Antia, Rob J. de Boer, John Mellors, George Shaw, Jonathan Li, and Laurent Hocqueloux for comments and discussions that helped improve this manuscript. This work was performed under the auspices of US Department of Energy Contract DE-AC52-06NA25396 and supported by National Institutes of Health Grants R01-AI028433, R01-OD011095, and UM1-AI100645.

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Jessica M. Conway
Department of Mathematics, Pennsylvania State University, University Park, PA 16802; and
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545
Alan S. Perelson1 [email protected]
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545

Notes

1
To whom correspondence should be addressed. Email: [email protected].
Author contributions: J.M.C. and A.S.P. designed research, performed research, and wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Post-treatment control of HIV infection
    Proceedings of the National Academy of Sciences
    • Vol. 112
    • No. 17
    • pp. 5255-E2264

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