Early antiretroviral therapy in SIV-infected rhesus macaques reveals a multiphasic, saturable dynamic accumulation of the rebound competent viral reservoir.
The rebound competent viral reservoir (RCVR)-virus that persists during antiretroviral treatment (ART) and can reignite systemic infection when treatment is stopped-is the primary barrier to eradicating HIV. We used time to initiation of ART during primary infection of rhesus macaques (RMs) after in...
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Public Library of Science (PLoS)
2024-04-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1012135&type=printable |
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| author | Brandon F Keele Afam A Okoye Christine M Fennessey Benjamin Varco-Merth Taina T Immonen Emek Kose Andrew Conchas Mykola Pinkevych Leslie Lipkey Laura Newman Agatha Macairan Marjorie Bosche William J Bosche Brian Berkemeier Randy Fast Mike Hull Kelli Oswald Rebecca Shoemaker Lorna Silipino Robert J Gorelick Derick Duell Alejandra Marenco William Brantley Jeremy Smedley Michael Axthelm Miles P Davenport Jeffrey D Lifson Louis J Picker |
| author_facet | Brandon F Keele Afam A Okoye Christine M Fennessey Benjamin Varco-Merth Taina T Immonen Emek Kose Andrew Conchas Mykola Pinkevych Leslie Lipkey Laura Newman Agatha Macairan Marjorie Bosche William J Bosche Brian Berkemeier Randy Fast Mike Hull Kelli Oswald Rebecca Shoemaker Lorna Silipino Robert J Gorelick Derick Duell Alejandra Marenco William Brantley Jeremy Smedley Michael Axthelm Miles P Davenport Jeffrey D Lifson Louis J Picker |
| author_sort | Brandon F Keele |
| collection | DOAJ |
| description | The rebound competent viral reservoir (RCVR)-virus that persists during antiretroviral treatment (ART) and can reignite systemic infection when treatment is stopped-is the primary barrier to eradicating HIV. We used time to initiation of ART during primary infection of rhesus macaques (RMs) after intravenous challenge with barcoded SIVmac239 as a means to elucidate the dynamics of RCVR establishment in groups of RMs by creating a multi-log range of pre-ART viral loads and then assessed viral time-to-rebound and reactivation rates resulting from the discontinuation of ART after one year. RMs started on ART on days 3, 4, 5, 6, 7, 9 or 12 post-infection showed a nearly 10-fold difference in pre-ART viral measurements for successive ART-initiation timepoints. Only 1 of 8 RMs initiating ART on days 3 and 4 rebounded after ART interruption despite measurable pre-ART plasma viremia. Rebounding plasma from the 1 rebounding RM contained only a single barcode lineage detected at day 50 post-ART. All RMs starting ART on days 5 and 6 rebounded between 14- and 50-days post-ART with 1-2 rebounding variants each. RMs starting ART on days 7, 9, and 12 had similar time-to-measurable plasma rebound kinetics despite multiple log differences in pre-ART plasma viral load (pVL), with all RMs rebounding between 7- and 16-days post-ART with 3-28 rebounding lineages. Calculated reactivation rates per pre-ART pVL were highest for RMs starting ART on days 5, 6, and 7 after which the rate of accumulation of the RCVR markedly decreased for RMs treated on days 9 and 12, consistent with multiphasic establishment and near saturation of the RCVR within 2 weeks post infection. Taken together, these data highlight the heterogeneity of the RCVR between RMs, the stochastic establishment of the very early RCVR, and the saturability of the RCVR prior to peak viral infection. |
| format | Article |
| id | doaj-art-65fa1fcf2796486fb2e2ddf45842dec6 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2024-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-65fa1fcf2796486fb2e2ddf45842dec62025-01-18T05:30:53ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-04-01204e101213510.1371/journal.ppat.1012135Early antiretroviral therapy in SIV-infected rhesus macaques reveals a multiphasic, saturable dynamic accumulation of the rebound competent viral reservoir.Brandon F KeeleAfam A OkoyeChristine M FennesseyBenjamin Varco-MerthTaina T ImmonenEmek KoseAndrew ConchasMykola PinkevychLeslie LipkeyLaura NewmanAgatha MacairanMarjorie BoscheWilliam J BoscheBrian BerkemeierRandy FastMike HullKelli OswaldRebecca ShoemakerLorna SilipinoRobert J GorelickDerick DuellAlejandra MarencoWilliam BrantleyJeremy SmedleyMichael AxthelmMiles P DavenportJeffrey D LifsonLouis J PickerThe rebound competent viral reservoir (RCVR)-virus that persists during antiretroviral treatment (ART) and can reignite systemic infection when treatment is stopped-is the primary barrier to eradicating HIV. We used time to initiation of ART during primary infection of rhesus macaques (RMs) after intravenous challenge with barcoded SIVmac239 as a means to elucidate the dynamics of RCVR establishment in groups of RMs by creating a multi-log range of pre-ART viral loads and then assessed viral time-to-rebound and reactivation rates resulting from the discontinuation of ART after one year. RMs started on ART on days 3, 4, 5, 6, 7, 9 or 12 post-infection showed a nearly 10-fold difference in pre-ART viral measurements for successive ART-initiation timepoints. Only 1 of 8 RMs initiating ART on days 3 and 4 rebounded after ART interruption despite measurable pre-ART plasma viremia. Rebounding plasma from the 1 rebounding RM contained only a single barcode lineage detected at day 50 post-ART. All RMs starting ART on days 5 and 6 rebounded between 14- and 50-days post-ART with 1-2 rebounding variants each. RMs starting ART on days 7, 9, and 12 had similar time-to-measurable plasma rebound kinetics despite multiple log differences in pre-ART plasma viral load (pVL), with all RMs rebounding between 7- and 16-days post-ART with 3-28 rebounding lineages. Calculated reactivation rates per pre-ART pVL were highest for RMs starting ART on days 5, 6, and 7 after which the rate of accumulation of the RCVR markedly decreased for RMs treated on days 9 and 12, consistent with multiphasic establishment and near saturation of the RCVR within 2 weeks post infection. Taken together, these data highlight the heterogeneity of the RCVR between RMs, the stochastic establishment of the very early RCVR, and the saturability of the RCVR prior to peak viral infection.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1012135&type=printable |
| spellingShingle | Brandon F Keele Afam A Okoye Christine M Fennessey Benjamin Varco-Merth Taina T Immonen Emek Kose Andrew Conchas Mykola Pinkevych Leslie Lipkey Laura Newman Agatha Macairan Marjorie Bosche William J Bosche Brian Berkemeier Randy Fast Mike Hull Kelli Oswald Rebecca Shoemaker Lorna Silipino Robert J Gorelick Derick Duell Alejandra Marenco William Brantley Jeremy Smedley Michael Axthelm Miles P Davenport Jeffrey D Lifson Louis J Picker Early antiretroviral therapy in SIV-infected rhesus macaques reveals a multiphasic, saturable dynamic accumulation of the rebound competent viral reservoir. PLoS Pathogens |
| title | Early antiretroviral therapy in SIV-infected rhesus macaques reveals a multiphasic, saturable dynamic accumulation of the rebound competent viral reservoir. |
| title_full | Early antiretroviral therapy in SIV-infected rhesus macaques reveals a multiphasic, saturable dynamic accumulation of the rebound competent viral reservoir. |
| title_fullStr | Early antiretroviral therapy in SIV-infected rhesus macaques reveals a multiphasic, saturable dynamic accumulation of the rebound competent viral reservoir. |
| title_full_unstemmed | Early antiretroviral therapy in SIV-infected rhesus macaques reveals a multiphasic, saturable dynamic accumulation of the rebound competent viral reservoir. |
| title_short | Early antiretroviral therapy in SIV-infected rhesus macaques reveals a multiphasic, saturable dynamic accumulation of the rebound competent viral reservoir. |
| title_sort | early antiretroviral therapy in siv infected rhesus macaques reveals a multiphasic saturable dynamic accumulation of the rebound competent viral reservoir |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1012135&type=printable |
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