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

Jacob D. Estes; Cissy Kityo; Francis Ssali; Louise Swainson; Krystelle Nganou Makamdop; Gregory Q. Del Prete; Steven G. Deeks; Paul A. Luciw; Jeffrey G. Chipman; Gregory J. Beilman; Torfi Hoskuldsson; Alexander Khoruts; Jodi Anderson; Claire Deleage; Jacob Jasurda; Thomas E. Schmidt; Michael Hafertepe; Samuel P. Callisto; Hope Pearson; Thomas Reimann; Jared Schuster; Jordan Schoephoerster; Peter Southern; Katherine Perkey; Liang Shang; Stephen W. Wietgrefe; Courtney V. Fletcher; Jeffrey D. Lifson; Daniel C. Douek; Joseph M. McCune; Ashley T. Haase; Timothy W. Schacker

doi:10.1038/nm.4411

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

Jacob D. Estes, Cissy Kityo, Francis Ssali, Louise Swainson, Krystelle Nganou Makamdop, Gregory Q. Del Prete, Steven G. Deeks, Paul A. Luciw, Jeffrey G. Chipman, Gregory J. Beilman, Torfi Hoskuldsson, Alexander Khoruts, Jodi Anderson, Claire Deleage, Jacob Jasurda, Thomas E. Schmidt, Michael Hafertepe, Samuel P. Callisto, Hope Pearson, Thomas ReimannJared Schuster, Jordan Schoephoerster, Peter Southern, Katherine Perkey, Liang Shang, Stephen W. Wietgrefe, Courtney V. Fletcher, Jeffrey D. Lifson, Daniel C. Douek, Joseph M. McCune, Ashley T. Haase, Timothy W. Schacker

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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 10 8 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.

Original language	English (US)
Pages (from-to)	1271-1276
Number of pages	6
Journal	Nature Medicine
Volume	23
Issue number	11
DOIs	https://doi.org/10.1038/nm.4411
State	Published - Nov 1 2017

Bibliographical note

Funding Information:
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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Estes, J. D., Kityo, C., Ssali, F., Swainson, L., Makamdop, K. N., Del Prete, G. Q., Deeks, S. G., Luciw, P. A., Chipman, J. G., Beilman, G. J., Hoskuldsson, T., Khoruts, A., Anderson, J., Deleage, C., Jasurda, J., Schmidt, T. E., Hafertepe, M., Callisto, S. P., Pearson, H., ... Schacker, T. W. (2017). Defining total-body AIDS-virus burden with implications for curative strategies. Nature Medicine, 23(11), 1271-1276. https://doi.org/10.1038/nm.4411

Estes, JD, Kityo, C, Ssali, F, Swainson, L, Makamdop, KN, Del Prete, GQ, Deeks, SG, Luciw, PA, Chipman, JG , Beilman, GJ, Hoskuldsson, T, Khoruts, A , Anderson, J, Deleage, C, Jasurda, J, Schmidt, TE, Hafertepe, M, Callisto, SP, Pearson, H, Reimann, T, Schuster, J, Schoephoerster, J, Southern, P, Perkey, K, Shang, L, Wietgrefe, SW, Fletcher, CV, Lifson, JD, Douek, DC, McCune, JM, Haase, AT & Schacker, TW 2017, 'Defining total-body AIDS-virus burden with implications for curative strategies', Nature Medicine, vol. 23, no. 11, pp. 1271-1276. https://doi.org/10.1038/nm.4411

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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 10 8 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.",

author = "Estes, {Jacob D.} and Cissy Kityo and Francis Ssali and Louise Swainson and Makamdop, {Krystelle Nganou} and {Del Prete}, {Gregory Q.} and Deeks, {Steven G.} and Luciw, {Paul A.} and Chipman, {Jeffrey G.} and Beilman, {Gregory J.} and Torfi Hoskuldsson and Alexander Khoruts and Jodi Anderson and Claire Deleage and Jacob Jasurda and Schmidt, {Thomas E.} and Michael Hafertepe and Callisto, {Samuel P.} and Hope Pearson and Thomas Reimann and Jared Schuster and Jordan Schoephoerster and Peter Southern and Katherine Perkey and Liang Shang and Wietgrefe, {Stephen W.} and Fletcher, {Courtney V.} and Lifson, {Jeffrey D.} and Douek, {Daniel C.} and McCune, {Joseph M.} and Haase, {Ashley T.} and Schacker, {Timothy W.}",

note = "Funding Information: 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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AU - Kityo, Cissy

AU - Ssali, Francis

AU - Swainson, Louise

AU - Makamdop, Krystelle Nganou

AU - Del Prete, Gregory Q.

AU - Deeks, Steven G.

AU - Luciw, Paul A.

AU - Chipman, Jeffrey G.

AU - Beilman, Gregory J.

AU - Hoskuldsson, Torfi

AU - Khoruts, Alexander

AU - Anderson, Jodi

AU - Deleage, Claire

AU - Jasurda, Jacob

AU - Schmidt, Thomas E.

AU - Hafertepe, Michael

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AU - Pearson, Hope

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AU - Schuster, Jared

AU - Schoephoerster, Jordan

AU - Southern, Peter

AU - Perkey, Katherine

AU - Shang, Liang

AU - Wietgrefe, Stephen W.

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AU - Lifson, Jeffrey D.

AU - Douek, Daniel C.

AU - McCune, Joseph M.

AU - Haase, Ashley T.

AU - Schacker, Timothy W.

N1 - Funding Information: 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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N2 - 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 10 8 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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Defining total-body AIDS-virus burden with implications for curative strategies

Abstract

Bibliographical note

UN SDGs

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