Multiple Origins of Virus Persistence during Natural Control of HIV Infection

Eli A. Boritz; Samuel Darko; Luke Swaszek; Gideon Wolf; David Wells; Xiaolin Wu; Amy R. Henry; Farida Laboune; Jianfei Hu; David Ambrozak; Marybeth S. Hughes; Rebecca Hoh; Joseph P. Casazza; Alexander Vostal; Daniel Bunis; Krystelle Nganou-Makamdop; James S. Lee; Stephen A. Migueles; Richard A. Koup; Mark Connors; Susan Moir; Timothy Schacker; Frank Maldarelli; Stephen H. Hughes; Steven G. Deeks; Daniel C. Douek

doi:10.1016/j.cell.2016.06.039

Multiple Origins of Virus Persistence during Natural Control of HIV Infection

Eli A. Boritz, Samuel Darko, Luke Swaszek, Gideon Wolf, David Wells, Xiaolin Wu, Amy R. Henry, Farida Laboune, Jianfei Hu, David Ambrozak, Marybeth S. Hughes, Rebecca Hoh, Joseph P. Casazza, Alexander Vostal, Daniel Bunis, Krystelle Nganou-Makamdop, James S. Lee, Stephen A. Migueles, Richard A. Koup, Mark ConnorsSusan Moir, Timothy Schacker, Frank Maldarelli, Stephen H. Hughes, Steven G. Deeks, Daniel C. Douek

Medicine - Infectious Disease and International Medicine

Research output: Contribution to journal › Article › peer-review

110 Scopus citations

Abstract

Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites, and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (T_FH) cells and non-T_FH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity.

Original language	English (US)
Pages (from-to)	1004-1015
Number of pages	12
Journal	Cell
Volume	166
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2016.06.039
State	Published - Aug 11 2016

Bibliographical note

Funding Information:
We thank the study participants for their involvement in the study. We thank S. Kosakovsky-Pond for help with phylogenetic analysis and C. Petrovas for helpful discussions. D.C.D. and E.A.B. are funded by the NIH Intramural Research Program. D.C.D. is also funded by the NIAID Division of AIDS and the NIH Office of AIDS Research. Additional funding came from AIDS Vaccine Discovery grant OPP1032325 from the Bill and Melinda Gates Foundation (to R.A.K.), the Delaney AIDS Research Enterprise (AI096109 to S.G.D.), NIAID K24 (AI069994 to S.G.D.), the UCSF/Gladstone Institute of Virology & Immunology CFAR (P30 AI027763 to S.G.D.), and federal funds from the NCI (to F.M. and S.H.H.).

Publisher Copyright:
© 2016

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Boritz, E. A., Darko, S., Swaszek, L., Wolf, G., Wells, D., Wu, X., Henry, A. R., Laboune, F., Hu, J., Ambrozak, D., Hughes, M. S., Hoh, R., Casazza, J. P., Vostal, A., Bunis, D., Nganou-Makamdop, K., Lee, J. S., Migueles, S. A., Koup, R. A., ... Douek, D. C. (2016). Multiple Origins of Virus Persistence during Natural Control of HIV Infection. Cell, 166(4), 1004-1015. https://doi.org/10.1016/j.cell.2016.06.039

Multiple Origins of Virus Persistence during Natural Control of HIV Infection. / Boritz, Eli A.; Darko, Samuel; Swaszek, Luke; Wolf, Gideon; Wells, David; Wu, Xiaolin; Henry, Amy R.; Laboune, Farida; Hu, Jianfei; Ambrozak, David; Hughes, Marybeth S.; Hoh, Rebecca; Casazza, Joseph P.; Vostal, Alexander; Bunis, Daniel; Nganou-Makamdop, Krystelle; Lee, James S.; Migueles, Stephen A.; Koup, Richard A.; Connors, Mark; Moir, Susan; Schacker, Timothy; Maldarelli, Frank; Hughes, Stephen H.; Deeks, Steven G.; Douek, Daniel C.

In: Cell, Vol. 166, No. 4, 11.08.2016, p. 1004-1015.

Research output: Contribution to journal › Article › peer-review

Boritz, EA, Darko, S, Swaszek, L, Wolf, G, Wells, D, Wu, X, Henry, AR, Laboune, F, Hu, J, Ambrozak, D, Hughes, MS, Hoh, R, Casazza, JP, Vostal, A, Bunis, D, Nganou-Makamdop, K, Lee, JS, Migueles, SA, Koup, RA, Connors, M, Moir, S, Schacker, T, Maldarelli, F, Hughes, SH, Deeks, SG & Douek, DC 2016, 'Multiple Origins of Virus Persistence during Natural Control of HIV Infection', Cell, vol. 166, no. 4, pp. 1004-1015. https://doi.org/10.1016/j.cell.2016.06.039

Boritz, Eli A. ; Darko, Samuel ; Swaszek, Luke ; Wolf, Gideon ; Wells, David ; Wu, Xiaolin ; Henry, Amy R. ; Laboune, Farida ; Hu, Jianfei ; Ambrozak, David ; Hughes, Marybeth S. ; Hoh, Rebecca ; Casazza, Joseph P. ; Vostal, Alexander ; Bunis, Daniel ; Nganou-Makamdop, Krystelle ; Lee, James S. ; Migueles, Stephen A. ; Koup, Richard A. ; Connors, Mark ; Moir, Susan ; Schacker, Timothy ; Maldarelli, Frank ; Hughes, Stephen H. ; Deeks, Steven G. ; Douek, Daniel C. / Multiple Origins of Virus Persistence during Natural Control of HIV Infection. In: Cell. 2016 ; Vol. 166, No. 4. pp. 1004-1015.

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abstract = "Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites, and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (TFH) cells and non-TFH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity.",

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AU - Henry, Amy R.

AU - Laboune, Farida

AU - Hu, Jianfei

AU - Ambrozak, David

AU - Hughes, Marybeth S.

AU - Hoh, Rebecca

AU - Casazza, Joseph P.

AU - Vostal, Alexander

AU - Bunis, Daniel

AU - Nganou-Makamdop, Krystelle

AU - Lee, James S.

AU - Migueles, Stephen A.

AU - Koup, Richard A.

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AU - Moir, Susan

AU - Schacker, Timothy

AU - Maldarelli, Frank

AU - Hughes, Stephen H.

AU - Deeks, Steven G.

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N2 - Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites, and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (TFH) cells and non-TFH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity.

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Multiple Origins of Virus Persistence during Natural Control of HIV Infection

Abstract

Bibliographical note

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