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Research Article
HIV

The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation

Melissa-Rose Abrahams https://orcid.org/0000-0002-1907-4929, Sarah B. Joseph https://orcid.org/0000-0001-9603-574X, Nigel Garrett https://orcid.org/0000-0002-4530-234X, Lynn Tyers https://orcid.org/0000-0002-0535-9165, Matthew Moeser https://orcid.org/0000-0002-1368-5171, Nancie Archin, Olivia D. Council, David Matten https://orcid.org/0000-0003-1085-4344, Shuntai Zhou https://orcid.org/0000-0002-8353-386X, Deelan Doolabh, Colin Anthony https://orcid.org/0000-0002-0108-6251, Nilu Goonetilleke, Salim Abdool Karim https://orcid.org/0000-0002-4986-2133, David M. Margolis https://orcid.org/0000-0001-5714-0002, Sergei Kosakovsky Pond, Carolyn Williamson https://orcid.org/0000-0003-0125-1226 [email protected], and Ronald Swanstrom https://orcid.org/0000-0001-7777-0773 [email protected]
Science Translational Medicine • 9 Oct 2019 • Vol 11, Issue 513 • DOI: 10.1126/scitranslmed.aaw5589
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Au revoir HIV reservoir?

Curing HIV requires eliminating the latent viral reservoir. To better understand how this reservoir is formed, Abrahams et al. examined longitudinal samples from nine South African women with HIV. HIV was grown from resting CD4+ T cells isolated after several years of antiretroviral therapy (ART) and compared to viral sequences from longitudinal samples collected before ART. They found that in most subjects, reservoir viral sequences were related to viruses present at the time of ART initiation. These results suggest that the majority of the latent reservoir is seeded in response to therapy and likely is not continually formed prior to ART. HIV treatment and cure efforts could potentially exploit this information to limit the size of the reservoir when treatment is initiated.

Abstract

Although antiretroviral therapy (ART) is highly effective at suppressing HIV-1 replication, the virus persists as a latent reservoir in resting CD4+ T cells during therapy. This reservoir forms even when ART is initiated early after infection, but the dynamics of its formation are largely unknown. The viral reservoirs of individuals who initiate ART during chronic infection are generally larger and genetically more diverse than those of individuals who initiate therapy during acute infection, consistent with the hypothesis that the reservoir is formed continuously throughout untreated infection. To determine when viruses enter the latent reservoir, we compared sequences of replication-competent viruses from resting peripheral CD4+ T cells from nine HIV-positive women on therapy to viral sequences circulating in blood collected longitudinally before therapy. We found that, on average, 71% of the unique viruses induced from the post-therapy latent reservoir were most genetically similar to viruses replicating just before ART initiation. This proportion is far greater than would be expected if the reservoir formed continuously and was always long lived. We conclude that ART alters the host environment in a way that allows the formation or stabilization of most of the long-lived latent HIV-1 reservoir, which points to new strategies targeted at limiting the formation of the reservoir around the time of therapy initiation.

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Supplementary Material

Summary

Fig. S1. Longitudinal MiSeq sampling depth for nine women from the CAPRISA 002 cohort.
Fig. S2. Timing of reservoir OGVs for participant CAP188.
Fig. S3. Timing of reservoir OGVs for participant CAP206.
Fig. S4. Timing of reservoir OGVs for participant CAP217.
Fig. S5. Timing of reservoir OGVs for participant CAP257.
Fig. S6. Timing of reservoir OGVs for participant CAP287.
Fig. S7. Timing of reservoir OGVs for participant CAP288.
Fig. S8. Timing of reservoir OGVs for participant CAP302.
Fig. S9. Timing of reservoir OGVs for participant CAP316.
Fig. S10. Timing of reservoir OGVs for participant CAP336.
Fig. S11. Estimates of OGV entry into the long-lived reservoir.
Fig. S12. Model of the relationship between viral suppression and formation of the long-lived HIV-1 reservoir.
Table S1. Data of participant viral loads.
Table S2. Data for timing of OGVs.

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Science Translational Medicine
Volume 11 | Issue 513
October 2019

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Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 4 January 2019
Accepted: 29 August 2019

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Acknowledgments

We would like to acknowledge all participants of the CAPRISA 002 acute infection cohort and the staff at the Vulindlela and eThekwini Clinical Research Sites, KwaZulu-Natal, South Africa. We would also like to thank J. Ambler and the Bioinformatics Support Team at UCT for assistance with pipeline development. Funding: This work was supported by the National Institutes of Health (NIH)—South African Medical Research Council (MRC) U.S.-South Africa Program for Collaborative Biomedical Research grants R01 AI115981 to C.W. and R.S. and an NIH award to the Collaboratory of AIDS Researchers for Eradication (UM1 AI126619). The CAPRISA 002 acute infection cohort study has been funded by the South African Department of Science and Technology and the National Research Foundation’s Centre of Excellence in HIV Prevention (grant no. UID: 96354), the South African Department of Health and the South African Medical Research Council Special Initiative on HIV Prevention (grant no. 96151), the NIH (U19 AI51794), USAID and CONRAD (USAID cooperative grant no. GP00-08-00005-00, subproject agreement no. PPA-09-046), the South African National Research Foundation (grant nos. 67385 and 96354), the South African Technology Innovation Agency, and the Fogarty International Center, NIH (D43 TW00231). The Centre for Infectious Diseases Research in Africa (CIDRI-Africa) is supported by core funding from the Wellcome Trust (203135/Z/16/Z). The work was also supported by the UNC Center for AIDS Research (NIH award P30 AI50410) and the UNC Lineberger Comprehensive Cancer Center (NIH award P30 CA16068). Author contributions: C.W. and R.S. proposed, designed, and supervised this study. M.-R.A., S.B.J., and N. Garrett directed all of the data collection, experiments, and data analyses. M.M., N.A., O.D.C., L.T., S.Z., and D.D. performed all of the experiments. Phylogenetic analyses were performed by S.K.P., C.A., M.M., and D.M. The manuscript was written by M.-R.A., S.B.J., N. Goonetilleke, C.W., and R.S. with editorial help from N. Garrett, S.A.K., D.M.M., and S.K.P. Competing interests: UNC is pursuing IP protection for Primer ID, and R.S. is listed as a coinventor and has received nominal royalties. All other authors declare that they have no competing interests. Data and materials availability: All data and computer code associated with this study are present in the paper and the Supplementary Materials or accessible at a publicly available websites (DOIs: 10.5281/zenodo.3370141, 10.5281/zenodo.3372204, and 10.5281/zenodo.3372202). The near full-length genome sequences are deposited in GenBank (accession nos. MN097551 to MN097697). The MiSeq sequences are deposited in the Sequencing Read Archive (accession nos. SAMN12126374 to SAMN12126459).

Authors

Affiliations

Melissa-Rose Abrahams* https://orcid.org/0000-0002-1907-4929
Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa.
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Sarah B. Joseph* https://orcid.org/0000-0001-9603-574X
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Nigel Garrett https://orcid.org/0000-0002-4530-234X
Centre for the AIDS Programme of Research in South Africa, University of KwaZulu- Natal, Durban 4013, South Africa.
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Lynn Tyers https://orcid.org/0000-0002-0535-9165
Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa.
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Matthew Moeser https://orcid.org/0000-0002-1368-5171
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Nancie Archin
UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
View all articles by this author
Olivia D. Council
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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David Matten https://orcid.org/0000-0003-1085-4344
Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa.
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Shuntai Zhou https://orcid.org/0000-0002-8353-386X
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Deelan Doolabh
Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa.
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Colin Anthony https://orcid.org/0000-0002-0108-6251
Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa.
View all articles by this author
Nilu Goonetilleke
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Salim Abdool Karim https://orcid.org/0000-0002-4986-2133
Centre for the AIDS Programme of Research in South Africa, University of KwaZulu- Natal, Durban 4013, South Africa.
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
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David M. Margolis https://orcid.org/0000-0001-5714-0002
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Sergei Kosakovsky Pond
Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA 19122, USA.
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Carolyn Williamson† https://orcid.org/0000-0003-0125-1226 [email protected]
Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa.
National Health Laboratory Services of South Africa, University of Cape Town, Cape Town 7925, South Africa.
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Ronald Swanstrom† https://orcid.org/0000-0001-7777-0773 [email protected]
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Funding Information

NIH/MRC: R01 AI115981

Notes

*
These authors contributed equally to this work.
†Corresponding author. Email: [email protected] (R.S.); [email protected] (C.W.)

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