Relationship between intact HIV-1 proviruses in circulating CD4 +  T cells and rebound viruses emerging during treatment interruption

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The HIV-1 latent reservoir is the major barrier to cure. Analysis of the replication competent latent reservoir that can be induced in viral outgrowth assays (VOAs) showed little or no overlap with HIV viruses that emerge in plasma after treatment interruption. To determine whether intact proviruses amplified from DNA are more closely related to rebound viruses than those obtained from VOA, we sequenced HIV proviral genomes from CD4 ⁺ T cells of individuals who underwent analytical treatment interruption. We find that intact proviruses obtained from DNA overlap in part with those obtained by VOA, but do not overlap with rebound viruses. However, nearly half of all rebound sequences could be accounted for in part by recombination of intact near full-length sequences.

Abstract

Combination antiretroviral therapy controls but does not cure HIV-1 infection because a small fraction of cells harbor latent viruses that can produce rebound viremia when therapy is interrupted. The circulating latent virus reservoir has been documented by a variety of methods, most prominently by viral outgrowth assays (VOAs) in which CD4 ⁺ T cells are activated to produce virus in vitro, or more recently by amplifying proviral near full-length (NFL) sequences from DNA. Analysis of samples obtained in clinical studies in which individuals underwent analytical treatment interruption (ATI), showed little if any overlap between circulating latent viruses obtained from outgrowth cultures and rebound viruses from plasma. To determine whether intact proviruses amplified from DNA are more closely related to rebound viruses than those obtained from VOAs, we assayed 12 individuals who underwent ATI after infusion of a combination of two monoclonal anti–HIV-1 antibodies. A total of 435 intact proviruses obtained by NFL sequencing were compared with 650 latent viruses from VOAs and 246 plasma rebound viruses. Although, intact NFL and outgrowth culture sequences showed similar levels of stability and diversity with 39% overlap, the size of the reservoir estimated from NFL sequencing was larger than and did not correlate with VOAs. Finally, intact proviruses documented by NFL sequencing showed no sequence overlap with rebound viruses; however, they appear to contribute to recombinant viruses found in plasma during rebound.

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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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Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy.

Tae-Wook Chun, David Nickle, Jesse Justement … (2008)

Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source of persistent HIV in such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4(+) T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4(+) T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time. We demonstrate incomplete recoveries of CD4(+) T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy. In addition, we demonstrate higher frequencies of HIV infection in GALT, compared with PBMCs, in these aviremic individuals and provide evidence for cross-infection between these 2 cellular compartments. Together, these data provide a possible mechanism for the maintenance of viral reservoirs revolving around the GALT of HIV-infected individuals despite long-term viral suppression and suggest that the GALT may play a major role in the persistence of HIV in such individuals.

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Identification of Genetically Intact HIV-1 Proviruses in Specific CD4+ T Cells from Effectively Treated Participants.

Bonnie Hiener, Bethany Horsburgh, John-Sebastian Eden … (2017)

Latent replication-competent HIV-1 persists in individuals on long-term antiretroviral therapy (ART). We developed the Full-Length Individual Proviral Sequencing (FLIPS) assay to determine the distribution of latent replication-competent HIV-1 within memory CD4+ T cell subsets in six individuals on long-term ART. FLIPS is an efficient, high-throughput assay that amplifies and sequences near full-length (∼9 kb) HIV-1 proviral genomes and determines potential replication competency through genetic characterization. FLIPS provides a genome-scale perspective that addresses the limitations of other methods that also genetically characterize the latent reservoir. Using FLIPS, we identified 5% of proviruses as intact and potentially replication competent. Intact proviruses were unequally distributed between T cell subsets, with effector memory cells containing the largest proportion of genetically intact HIV-1 proviruses. We identified multiple identical intact proviruses, suggesting a role for cellular proliferation in the maintenance of the latent HIV-1 reservoir.

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Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc. Natl. Acad. Sci. U.S.A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 27 November 2018

Publication date (Electronic): 12 November 2018

Publication date PMC-release: 12 November 2018

Volume: 115

Issue: 48

Pages: E11341-E11348

Affiliations

[1] ^aLaboratory of Molecular Immunology, The Rockefeller University , New York, NY 10065;

[2] ^bLaboratory of Experimental Immunology, Institute of Virology, University Hospital Cologne , 50935 Cologne, Germany;

[3] ^cDepartment I of Internal Medicine, University Hospital Cologne , 50931 Cologne, Germany;

[4] ^dGerman Center for Infection Research , 50931 Cologne, Germany;

[5] ^eDepartment of Physics and Astronomy, University of California, Riverside , CA 92521;

[6] ^fCenter for Molecular Medicine Cologne, University of Cologne , 50931 Cologne, Germany;

[7] ^gHoward Hughes Medical Institute , The Rockefeller University , New York, NY 10065

Author notes

¹To whom correspondence should be addressed. Email: nussen@ 123456rockefeller.edu .

Contributed by Michel C. Nussenzweig, October 9, 2018 (sent for review August 6, 2018; reviewed by John W. Mellors and Sarah Palmer)

Author contributions: C.-L.L., L.B.C., M.C.N., and M.J. designed research; C.-L.L., L.N., and P.M. performed research; H.G., J.C.C.L., Y.Z.C., F.K., and M.C. contributed new reagents/analytic tools; C.-L.L., J.A.P., T.Y.O., J.B., M.C.N., and M.J. analyzed data; and C.-L.L., J.A.P., M.C.N., and M.J. wrote the paper.

Reviewers: J.W.M., University of Pittsburgh School of Medicine; and S.P., The Westmead Institute for Medical Research and University of Sydney.

Article

Publisher ID: 201813512

DOI: 10.1073/pnas.1813512115

PMC ID: 6275529

PubMed ID: 30420517

SO-VID: ef32cbd6-9a91-45df-977b-43af0ae14b83

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This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

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Relationship between intact HIV-1 proviruses in circulating CD4 ⁺ T cells and rebound viruses emerging during treatment interruption

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Most cited references 18

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

Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy.

Identification of Genetically Intact HIV-1 Proviruses in Specific CD4+ T Cells from Effectively Treated Participants.

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