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Defining total-body AIDS-virus burden with implications for curative strategies

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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Figure 1
Figure 2: Quantitative image analysis of SIV vRNA+ cells in untreated SIV infection.
Figure 3: Quantitative image analysis of vRNA+ and vDNA+ cells in groups with untreated and treated SIV and SHIV infections.
Figure 4: Intracellular concentrations of TFV-DP, FTC-TP, and DRV in LNs, gut, and rectum, as compared with simultaneous measurements in PBMCs in six RMs.
Figure 5: Virus-producing cells in two SIV-infected RMs during ART, detected by ISH/TSA.
Figure 6: Frequency of vRNA and vDNA+ cells/ g in LN and rectal biopsies from HIV+ Ugandans before and during ART.

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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.

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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

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Correspondence to Timothy W Schacker.

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Estes, J., Kityo, C., Ssali, F. et al. Defining total-body AIDS-virus burden with implications for curative strategies. Nat Med 23, 1271–1276 (2017). https://doi.org/10.1038/nm.4411

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