Abstract

In the quest for a functional cure or the eradication of HIV infection, it is necessary to know the sizes of the reservoirs from which infection rebounds after treatment interruption. Thus, we quantified SIV and HIV tissue burdens in tissues of infected nonhuman primates and lymphoid tissue (LT) biopsies from infected humans. Before antiretroviral therapy (ART), LTs contained >98% of the SIV RNA+ and DNA+ cells. With ART, the numbers of virus (v) RNA+ cells substantially decreased but remained detectable, and their persistence was associated with relatively lower drug concentrations in LT than in peripheral blood. Prolonged ART also decreased the levels of SIV- and HIV-DNA+ cells, but the estimated size of the residual tissue burden of 108 vDNA+ cells potentially containing replication-competent proviruses, along with evidence of continuing virus production in LT despite ART, indicated two important sources for rebound following treatment interruption. The large sizes of these tissue reservoirs underscore challenges in developing 'HIV cure' strategies targeting multiple sources of virus production.

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Acknowledgements

The authors thank S. Povolny and C. Olson for help with manuscript preparation and editing, and the Antiviral Pharmacology Laboratory at the University of Nebraska for quantification of ARV concentrations. This work was supported by grants UL1TR000114 (T.W.S.), AI096109 (J.D.E., L. Swainson, S.G.D., J.A., J.J., T.E.S., J.M.M., and T.W.S.), OD011107 (P.A.L.), AI124965 (C.V.F.), and AI074340 (J.G.C., G.J.B., T.H., A.K., J.A., J.J., T.E.S., M.H., S.P.C., J.S., C.V.F., A.T.H., and T.W.S.), and in part by federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E (J.D.E., C.D., and J.D.L.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Author information

Affiliations

  1. AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.

    • Jacob D Estes
    • , Gregory Q Del Prete
    • , Claire Deleage
    •  & Jeffrey D Lifson
  2. Joint Clinical Research Center, Kampala, Uganda.

    • Cissy Kityo
    •  & Francis Ssali
  3. Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Louise Swainson
    •  & Joseph M McCune
  4. Vaccine Research Center, National Institutes of Health, Bethesda, Maryland, USA.

    • Krystelle Nganou Makamdop
    •  & Daniel C Douek
  5. Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Steven G Deeks
  6. Department of Pathology and Laboratory Medicine, University of California, Sacramento, Sacramento, California, USA.

    • Paul A Luciw
  7. Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA.

    • Jeffrey G Chipman
    • , Gregory J Beilman
    •  & Torfi Hoskuldsson
  8. Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.

    • Alexander Khoruts
    • , Jodi Anderson
    • , Jacob Jasurda
    • , Thomas E Schmidt
    • , Michael Hafertepe
    • , Samuel P Callisto
    • , Hope Pearson
    • , Thomas Reimann
    • , Jared Schuster
    • , Jordan Schoephoerster
    •  & Timothy W Schacker
  9. Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA.

    • Peter Southern
    • , Katherine Perkey
    • , Liang Shang
    • , Stephen W Wietgrefe
    •  & Ashley T Haase
  10. College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.

    • Courtney V Fletcher

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Contributions

J.D.E. contributed to study design and oversight, sample analysis, and manuscript preparation. C.K. contributed to study design, oversight of the Uganda cohort, and manuscript preparation. F.S. contributed to management of the Ugandan cohort, including regulatory and sample management. L. Swainson, G.Q.D.P., J.A., C.D., J.J., T.E.S., M.H., S.P.C., H.P., T.R., J. Schuster, J. Schoephoerster, and K.P. contributed to sample analysis. P.S. contributed to sample and data analysis. K.N.M. contributed to sample collection and analysis, and data management. J.G.C., G.J.B., and T.H. performed surgery to collect LN and rectal samples from the Ugandan cohort. A.K. contributed to sample collection and study design. L. Shang performed the TSA/ELF assays and analysis. S.W.W. contributed to data analysis and provided technical support. C.V.F. contributed to drug-level data acquisition, sample analysis, and manuscript preparation. S.G.D., P.A.L., J.D.L., D.C.D., J.M.M., A.T.H., and T.W.S. contributed to study design, data analysis, and manuscript preparation

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Timothy W Schacker.

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