Persistent HIV-1 replication maintains the tissue reservoir during therapy

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Abstract

Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site of viral production, storage of viral particles in immune complexes, and viral persistence. Whilst combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. A spatial dynamic model of persistent viral replication and spread explains why the development of drug resistance is not a foregone conclusion under conditions where drug concentrations are insufficient to completely block virus replication. These data provide fresh insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and refill the viral reservoir despite potent antiretroviral therapy.

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Most cited references 36

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Dating of the human-ape splitting by a molecular clock of mitochondrial DNA.

H Kishino, T Yano, M. Hasegawa (1984)

A new statistical method for estimating divergence dates of species from DNA sequence data by a molecular clock approach is developed. This method takes into account effectively the information contained in a set of DNA sequence data. The molecular clock of mitochondrial DNA (mtDNA) was calibrated by setting the date of divergence between primates and ungulates at the Cretaceous-Tertiary boundary (65 million years ago), when the extinction of dinosaurs occurred. A generalized least-squares method was applied in fitting a model to mtDNA sequence data, and the clock gave dates of 92.3 +/- 11.7, 13.3 +/- 1.5, 10.9 +/- 1.2, 3.7 +/- 0.6, and 2.7 +/- 0.6 million years ago (where the second of each pair of numbers is the standard deviation) for the separation of mouse, gibbon, orangutan, gorilla, and chimpanzee, respectively, from the line leading to humans. Although there is some uncertainty in the clock, this dating may pose a problem for the widely believed hypothesis that the pipedal creature Australopithecus afarensis, which lived some 3.7 million years ago at Laetoli in Tanzania and at Hadar in Ethiopia, was ancestral to man and evolved after the human-ape splitting. Another likelier possibility is that mtDNA was transferred through hybridization between a proto-human and a proto-chimpanzee after the former had developed bipedalism.

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Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.

J. Gallant, R Brookmeyer, J Margolick … (1998)

The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.

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Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection.

Tae-Wook Chun, Lucy Carruth, Diana Finzi … (1997)

The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus and viral RNA in plasma and of infectious virus, viral DNA and viral messenger RNA species in infected cells all suggest that HIV-1 replication continues throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent reservoirs for the virus. We show here that during the asymptomatic phase of infection there is an extremely low total body load of latently infected resting CD4+ T cells with replication-competent integrated provirus (<10(7) cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including resting and activated CD4+ T cells and macrophages.

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Author and article information

Contributors

Ramon Lorenzo-Redondo

Helen R. Fryer

Trevor Bedford

Eun-Young Kim

John Archer

Sergei L. Kosakovsky Pond

Yoon-Seok Chung

Sudhir Penugonda

Jeffrey Chipman

Courtney V. Fletcher

Timothy W. Schacker

Michael H. Malim

Andrew Rambaut

Ashley T. Haase

Angela R. McLean

Steven M. Wolinsky

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 28 December 2015

Publication date (Electronic): 27 January 2016

Publication date (Print): 4 February 2016

Publication date PMC-release: 27 July 2016

Volume: 530

Issue: 7588

Pages: 51-56

Affiliations

Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60011, USA.

Institute for Emerging Infections, Department of Zoology, University of Oxford, Oxford, OX1 3PS, UK.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60011, USA.

Centro de Investigação em Biodiversidade e Recursos Genéticos Universidade do Porto, Vairão, Portugal.

Department of Medicine, University of California, San Diego, CA 92093, USA.

Center for Infectious Disease Research, Korean National Institutes of Health, Osong, Korea.

Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60011, USA.

Department of Surgery, University of Minnesota, Minneapolis, MN, 55455 USA.

Antiviral Pharmacology Laboratory, University of Nebraska Medical Center, College of Pharmacy, Omaha, NE 68198, USA.

Division of Infectious Diseases, University of Minnesota, Minneapolis, MN 55455, USA.

Department of Infectious Diseases, King's College London, Guy's Hospital, London, UK.

Centre for Immunology, Infection and Evolution, University of Edinburgh, Edinburgh, UK.

Department of Microbiology, University of Minnesota, Minneapolis, MN 55455, USA.

Institute for Emerging Infections, Department of Zoology, University of Oxford, Oxford, OX1 3PS, UK.

Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60011, USA.

Author notes

Correspondence and requests for materials should be addressed to Steven Wolinsky

Article

Manuscript ID: NIHMS746503

DOI: 10.1038/nature16933

PMC ID: 4865637

PubMed ID: 26814962

SO-VID: c287825a-d51a-4cb9-8083-4cceb180c4fc

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Persistent HIV-1 replication maintains the tissue reservoir during therapy

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Most cited references 36

Dating of the human-ape splitting by a molecular clock of mitochondrial DNA.

Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.

Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection.

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