Mechanistic basis of post-treatment control of SIV after anti-α4β7 antibody therapy.
Treating macaques with an anti-α4β7 antibody under the umbrella of combination antiretroviral therapy (cART) during early SIV infection can lead to viral remission, with viral loads maintained at < 50 SIV RNA copies/ml after removal of all treatment in a subset of animals. Depletion of CD8+ lymph...
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Public Library of Science (PLoS)
2021-06-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189501 |
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| author | Chad R Wells Youfang Cao David P Durham Siddappa N Byrareddy Aftab A Ansari Nancy H Ruddle Jeffrey P Townsend Alison P Galvani Alan S Perelson |
| author_facet | Chad R Wells Youfang Cao David P Durham Siddappa N Byrareddy Aftab A Ansari Nancy H Ruddle Jeffrey P Townsend Alison P Galvani Alan S Perelson |
| author_sort | Chad R Wells |
| collection | DOAJ |
| description | Treating macaques with an anti-α4β7 antibody under the umbrella of combination antiretroviral therapy (cART) during early SIV infection can lead to viral remission, with viral loads maintained at < 50 SIV RNA copies/ml after removal of all treatment in a subset of animals. Depletion of CD8+ lymphocytes in controllers resulted in transient recrudescence of viremia, suggesting that the combination of cART and anti-α4β7 antibody treatment led to a state where ongoing immune responses kept the virus undetectable in the absence of treatment. A previous mathematical model of HIV infection and cART incorporates immune effector cell responses and exhibits the property of two different viral load set-points. While the lower set-point could correspond to the attainment of long-term viral remission, attaining the higher set-point may be the result of viral rebound. Here we expand that model to include possible mechanisms of action of an anti-α4β7 antibody operating in these treated animals. We show that the model can fit the longitudinal viral load data from both IgG control and anti-α4β7 antibody treated macaques, suggesting explanations for the viral control associated with cART and an anti-α4β7 antibody treatment. This effective perturbation to the virus-host interaction can also explain observations in other nonhuman primate experiments in which cART and immunotherapy have led to post-treatment control or resetting of the viral load set-point. Interestingly, because the viral kinetics in the various treated animals differed-some animals exhibited large fluctuations in viral load after cART cessation-the model suggests that anti-α4β7 treatment could act by different primary mechanisms in different animals and still lead to post-treatment viral control. This outcome is nonetheless in accordance with a model with two stable viral load set-points, in which therapy can perturb the system from one set-point to a lower one through different biological mechanisms. |
| format | Article |
| id | doaj-art-2f71c47237b549328fef5688e2b25ed3 |
| institution | OA Journals |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2021-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-2f71c47237b549328fef5688e2b25ed32025-08-20T02:18:04ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582021-06-01176e100903110.1371/journal.pcbi.1009031Mechanistic basis of post-treatment control of SIV after anti-α4β7 antibody therapy.Chad R WellsYoufang CaoDavid P DurhamSiddappa N ByrareddyAftab A AnsariNancy H RuddleJeffrey P TownsendAlison P GalvaniAlan S PerelsonTreating macaques with an anti-α4β7 antibody under the umbrella of combination antiretroviral therapy (cART) during early SIV infection can lead to viral remission, with viral loads maintained at < 50 SIV RNA copies/ml after removal of all treatment in a subset of animals. Depletion of CD8+ lymphocytes in controllers resulted in transient recrudescence of viremia, suggesting that the combination of cART and anti-α4β7 antibody treatment led to a state where ongoing immune responses kept the virus undetectable in the absence of treatment. A previous mathematical model of HIV infection and cART incorporates immune effector cell responses and exhibits the property of two different viral load set-points. While the lower set-point could correspond to the attainment of long-term viral remission, attaining the higher set-point may be the result of viral rebound. Here we expand that model to include possible mechanisms of action of an anti-α4β7 antibody operating in these treated animals. We show that the model can fit the longitudinal viral load data from both IgG control and anti-α4β7 antibody treated macaques, suggesting explanations for the viral control associated with cART and an anti-α4β7 antibody treatment. This effective perturbation to the virus-host interaction can also explain observations in other nonhuman primate experiments in which cART and immunotherapy have led to post-treatment control or resetting of the viral load set-point. Interestingly, because the viral kinetics in the various treated animals differed-some animals exhibited large fluctuations in viral load after cART cessation-the model suggests that anti-α4β7 treatment could act by different primary mechanisms in different animals and still lead to post-treatment viral control. This outcome is nonetheless in accordance with a model with two stable viral load set-points, in which therapy can perturb the system from one set-point to a lower one through different biological mechanisms.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189501 |
| spellingShingle | Chad R Wells Youfang Cao David P Durham Siddappa N Byrareddy Aftab A Ansari Nancy H Ruddle Jeffrey P Townsend Alison P Galvani Alan S Perelson Mechanistic basis of post-treatment control of SIV after anti-α4β7 antibody therapy. PLoS Computational Biology |
| title | Mechanistic basis of post-treatment control of SIV after anti-α4β7 antibody therapy. |
| title_full | Mechanistic basis of post-treatment control of SIV after anti-α4β7 antibody therapy. |
| title_fullStr | Mechanistic basis of post-treatment control of SIV after anti-α4β7 antibody therapy. |
| title_full_unstemmed | Mechanistic basis of post-treatment control of SIV after anti-α4β7 antibody therapy. |
| title_short | Mechanistic basis of post-treatment control of SIV after anti-α4β7 antibody therapy. |
| title_sort | mechanistic basis of post treatment control of siv after anti α4β7 antibody therapy |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189501 |
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