{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T20:01:31Z","timestamp":1787169691490,"version":"build-2736575974"},"reference-count":93,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,25]],"date-time":"2020-01-25T00:00:00Z","timestamp":1579910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["HHSN261200800001E"],"award-info":[{"award-number":["HHSN261200800001E"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Combination antiretroviral therapy (cART) controls but does not eradicate HIV infection; HIV persistence is the principal obstacle to curing infections. The proportion of defective proviruses increases during cART, but the dynamics of this process are not well understood, and a quantitative analysis of how the proviral landscape is reshaped after cART is initiated is critical to understanding how HIV persists. Here, we studied longitudinal samples from HIV infected individuals undergoing long term cART using multiplexed Droplet Digital PCR (ddPCR) approaches to quantify the proportion of deleted proviruses in lymphocytes. In most individuals undergoing cART, HIV proviruses that contain gag are lost more quickly than those that lack gag. Increases in the fraction of gag-deleted proviruses occurred only after 1\u20132 years of therapy, suggesting that the immune system, and\/or toxicity of viral re-activation helps to gradually shape the proviral landscape. After 10\u201315 years on therapy, there were as many as 3.5\u20135 times more proviruses in which gag was deleted or highly defective than those containing intact gag. We developed a provirus-specific ddPCR approach to quantify individual clones. Investigation of a clone of cells containing a deleted HIV provirus integrated in the HORMAD2 gene revealed that the cells underwent a massive expansion shortly after cART was initiated until the clone, which was primarily in effector memory cells, dominated the population of proviruses for over 6 years. The expansion of this HIV-infected clone had substantial effects on the overall proviral population.<\/jats:p>","DOI":"10.3390\/v12020136","type":"journal-article","created":{"date-parts":[[2020,1,27]],"date-time":"2020-01-27T07:41:11Z","timestamp":1580110871000},"page":"136","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Dynamic Shifts in the HIV Proviral Landscape During Long Term Combination Antiretroviral Therapy: Implications for Persistence and Control of HIV Infections"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1168-4773","authenticated-orcid":false,"given":"Elizabeth M.","family":"Anderson","sequence":"first","affiliation":[{"name":"HIV Dynamics and Replication Program, NCI, NIH, Frederick, MD 21702, USA"},{"name":"Department of Biology, The Catholic University of America, Washington, DC 20064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco R.","family":"Simonetti","sequence":"additional","affiliation":[{"name":"HIV Dynamics and Replication Program, NCI, NIH, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Gorelick","sequence":"additional","affiliation":[{"name":"Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn","family":"Hill","sequence":"additional","affiliation":[{"name":"HIV Dynamics and Replication Program, NCI, NIH, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica A.","family":"Gouzoulis","sequence":"additional","affiliation":[{"name":"HIV Dynamics and Replication Program, NCI, NIH, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Bell","sequence":"additional","affiliation":[{"name":"Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2049-5824","authenticated-orcid":false,"given":"Catherine","family":"Rehm","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Virus Persistence and Dynamics Section, VRC, NIAID, NIH, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli","family":"Boritz","sequence":"additional","affiliation":[{"name":"Virus Persistence and Dynamics Section, VRC, NIAID, NIH, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Wu","sequence":"additional","affiliation":[{"name":"Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Wells","sequence":"additional","affiliation":[{"name":"Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen H.","family":"Hughes","sequence":"additional","affiliation":[{"name":"HIV Dynamics and Replication Program, NCI, NIH, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venigalla","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Biology, The Catholic University of America, Washington, DC 20064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Coffin","sequence":"additional","affiliation":[{"name":"Department of Biology, Tufts University, Boston, MA 02155, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary F.","family":"Kearney","sequence":"additional","affiliation":[{"name":"HIV Dynamics and Replication Program, NCI, NIH, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Maldarelli","sequence":"additional","affiliation":[{"name":"HIV Dynamics and Replication Program, NCI, NIH, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kearney, M.F., Spindler, J., Shao, W., Yu, S., Anderson, E.M., O'Shea, A., Rehm, C., Poethke, C., Kovacs, N., and Mellors, J.W. 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