Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1.
PGT121 is a broadly neutralizing antibody in clinical development for the treatment and prevention of HIV-1 infection via passive administration. PGT121 targets the HIV-1 V3-glycan and demonstrated potent antiviral activity in a phase I clinical trial. Resistance to PGT121 monotherapy rapidly occurr...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2024-03-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1011518&type=printable |
| _version_ | 1797202072347607040 |
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| author | Tyler Cassidy Kathryn E Stephenson Dan H Barouch Alan S Perelson |
| author_facet | Tyler Cassidy Kathryn E Stephenson Dan H Barouch Alan S Perelson |
| author_sort | Tyler Cassidy |
| collection | DOAJ |
| description | PGT121 is a broadly neutralizing antibody in clinical development for the treatment and prevention of HIV-1 infection via passive administration. PGT121 targets the HIV-1 V3-glycan and demonstrated potent antiviral activity in a phase I clinical trial. Resistance to PGT121 monotherapy rapidly occurred in the majority of participants in this trial with the sampled rebound viruses being entirely resistant to PGT121 mediated neutralization. However, two individuals experienced long-term ART-free viral suppression following antibody infusion and retained sensitivity to PGT121 upon viral rebound. Here, we develop mathematical models of the HIV-1 dynamics during this phase I clinical trial. We utilize these models to understand the dynamics leading to PGT121 resistance and to identify the mechanisms driving the observed long-term viral control. Our modeling highlights the importance of the relative fitness difference between PGT121 sensitive and resistant subpopulations prior to treatment. Specifically, by fitting our models to data, we identify the treatment-induced competitive advantage of previously existing or newly generated resistant population as a primary driver of resistance. Finally, our modeling emphasizes the high neutralization ability of PGT121 in both participants who exhibited long-term viral control. |
| first_indexed | 2024-04-24T07:57:37Z |
| format | Article |
| id | doaj.art-d7081fcfeb604410b37e85281ccd19ab |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-24T07:57:37Z |
| publishDate | 2024-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-d7081fcfeb604410b37e85281ccd19ab2024-04-18T05:31:27ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582024-03-01203e101151810.1371/journal.pcbi.1011518Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1.Tyler CassidyKathryn E StephensonDan H BarouchAlan S PerelsonPGT121 is a broadly neutralizing antibody in clinical development for the treatment and prevention of HIV-1 infection via passive administration. PGT121 targets the HIV-1 V3-glycan and demonstrated potent antiviral activity in a phase I clinical trial. Resistance to PGT121 monotherapy rapidly occurred in the majority of participants in this trial with the sampled rebound viruses being entirely resistant to PGT121 mediated neutralization. However, two individuals experienced long-term ART-free viral suppression following antibody infusion and retained sensitivity to PGT121 upon viral rebound. Here, we develop mathematical models of the HIV-1 dynamics during this phase I clinical trial. We utilize these models to understand the dynamics leading to PGT121 resistance and to identify the mechanisms driving the observed long-term viral control. Our modeling highlights the importance of the relative fitness difference between PGT121 sensitive and resistant subpopulations prior to treatment. Specifically, by fitting our models to data, we identify the treatment-induced competitive advantage of previously existing or newly generated resistant population as a primary driver of resistance. Finally, our modeling emphasizes the high neutralization ability of PGT121 in both participants who exhibited long-term viral control.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1011518&type=printable |
| spellingShingle | Tyler Cassidy Kathryn E Stephenson Dan H Barouch Alan S Perelson Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1. PLoS Computational Biology |
| title | Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1. |
| title_full | Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1. |
| title_fullStr | Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1. |
| title_full_unstemmed | Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1. |
| title_short | Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1. |
| title_sort | modeling resistance to the broadly neutralizing antibody pgt121 in people living with hiv 1 |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1011518&type=printable |
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