Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1

Cassidy, Tyler; Stephenson, Kathryn E.; Barouch, Dan H.; Perelson, Alan S.

doi:10.1371/journal.pcbi.1011518

Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1

Journal Article · Fri Mar 29 04:00:00 EDT 2024 · PLoS Computational Biology (Online)

DOI:https://doi.org/10.1371/journal.pcbi.1011518· OSTI ID:2433941

^[1]; Stephenson, Kathryn E. ^[2]; Barouch, Dan H. ^[2]; ^[3]

University of Leeds (United Kingdom)
Beth Israel Deaconess Medical Center, Boston, MA (United States); MIT and Harvard, Cambridge, MA (United States). Ragon Institute of MGH
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 2433941

Report Number(s):: LA-UR--23-30547

Journal Information:: PLoS Computational Biology (Online), Journal Name: PLoS Computational Biology (Online) Journal Issue: 3 Vol. 20; ISSN 1553-7358

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

References (60)

Maximum likelihood inference for left-censored HIV RNA data Lynn, Henry S. Statistics in Medicine, Vol. 20, Issue 1 https://doi.org/10.1002/1097-0258(20010115)20:1<33::AID-SIM640>3.0.CO;2-O	journal	January 2000
Emergence of HIV-1 Drug Resistance During Antiretroviral Treatment Rong, Libin; Feng, Zhilan; Perelson, Alan S. Bulletin of Mathematical Biology, Vol. 69, Issue 6 https://doi.org/10.1007/s11538-007-9203-3	journal	April 2007
A Continuation Technique for Maximum Likelihood Estimators in Biological Models Cassidy, Tyler Bulletin of Mathematical Biology, Vol. 85, Issue 10 https://doi.org/10.1007/s11538-023-01200-0	journal	August 2023
Broadly Neutralizing Antibodies for HIV Eradication Stephenson, Kathryn E.; Barouch, Dan H. Current HIV/AIDS Reports, Vol. 13, Issue 1 https://doi.org/10.1007/s11904-016-0299-7	journal	February 2016
Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis Ramratnam, Bharat; Bonhoeffer, Sebastian; Binley, James The Lancet, Vol. 354, Issue 9192 https://doi.org/10.1016/S0140-6736(99)02035-8	journal	November 1999
Abortive HIV Infection Mediates CD4 T Cell Depletion and Inflammation in Human Lymphoid Tissue Doitsh, Gilad; Cavrois, Marielle; Lassen, Kara G. Cell, Vol. 143, Issue 5 https://doi.org/10.1016/j.cell.2010.11.001	journal	November 2010
Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody Schommers, Philipp; Gruell, Henning; Abernathy, Morgan E. Cell, Vol. 180, Issue 3 https://doi.org/10.1016/j.cell.2020.01.010	journal	February 2020
Dissecting How CD4 T Cells Are Lost During HIV Infection Doitsh, Gilad; Greene, Warner C. Cell Host & Microbe, Vol. 19, Issue 3 https://doi.org/10.1016/j.chom.2016.02.012	journal	March 2016
Modeling sequence evolution in acute HIV-1 infection Lee, Ha Youn; Giorgi, Elena E.; Keele, Brandon F. Journal of Theoretical Biology, Vol. 261, Issue 2 https://doi.org/10.1016/j.jtbi.2009.07.038	journal	November 2009
A new cell-based assay for measuring the forward mutation rate of HIV-1 Huang, K. J.; Wooley, D. P. Journal of Virological Methods, Vol. 124, Issue 1-2 https://doi.org/10.1016/j.jviromet.2004.11.010	journal	March 2005
Decay characteristics of HIV-1-infected compartments during combination therapy Perelson, Alan S.; Essunger, Paulina; Cao, Yunzhen Nature, Vol. 387, Issue 6629 https://doi.org/10.1038/387188a0	journal	May 1997
Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy Finzi, Diana; Blankson, Joel; Siliciano, Janet D. Nature Medicine, Vol. 5, Issue 5 https://doi.org/10.1038/8394	journal	May 1999
Broad neutralization coverage of HIV by multiple highly potent antibodies Walker, Laura M.; Huber, Michael; Doores, Katie J. Nature, Vol. 477, Issue 7365 https://doi.org/10.1038/nature10373	journal	September 2011
HIV therapy by a combination of broadly neutralizing antibodies in humanized mice Klein, Florian; Halper-Stromberg, Ariel; Horwitz, Joshua A. Nature, Vol. 492, Issue 7427 https://doi.org/10.1038/nature11604	journal	October 2012
Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117 Caskey, Marina; Klein, Florian; Lorenzi, Julio C. C. Nature, Vol. 522, Issue 7557 https://doi.org/10.1038/nature14411	journal	April 2015
Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys Borducchi, Erica N.; Cabral, Crystal; Stephenson, Kathryn E. Nature, Vol. 540, Issue 7632 https://doi.org/10.1038/nature20583	journal	November 2016
Early antibody therapy can induce long-lasting immunity to SHIV Nishimura, Yoshiaki; Gautam, Rajeev; Chun, Tae-Wook Nature, Vol. 543, Issue 7646 https://doi.org/10.1038/nature21435	journal	March 2017
Re-evaluating evolution in the HIV reservoir Rosenbloom, Daniel I. S.; Hill, Alison L.; Laskey, Sarah B. Nature, Vol. 551, Issue 7681 https://doi.org/10.1038/nature24634	journal	November 2017
Antibody 10-1074 suppresses viremia in HIV-1-infected individuals Caskey, Marina; Schoofs, Till; Gruell, Henning Nature Medicine, Vol. 23, Issue 2 https://doi.org/10.1038/nm.4268	journal	January 2017
Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells Siliciano, Janet D.; Kajdas, Joleen; Finzi, Diana Nature Medicine, Vol. 9, Issue 6 https://doi.org/10.1038/nm880	journal	May 2003
Modelling viral and immune system dynamics Perelson, Alan S. Nature Reviews Immunology, Vol. 2, Issue 1 https://doi.org/10.1038/nri700	journal	January 2002
Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys Borducchi, Erica N.; Liu, Jinyan; Nkolola, Joseph P. Nature, Vol. 563, Issue 7731 https://doi.org/10.1038/s41586-018-0600-6	journal	October 2018
Combination anti-HIV-1 antibody therapy is associated with increased virus-specific T cell immunity Niessl, Julia; Baxter, Amy E.; Mendoza, Pilar Nature Medicine, Vol. 26, Issue 2 https://doi.org/10.1038/s41591-019-0747-1	journal	February 2020
Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial Stephenson, Kathryn E.; Julg, Boris; Tan, C. Sabrina Nature Medicine, Vol. 27, Issue 10 https://doi.org/10.1038/s41591-021-01509-0	journal	October 2021
Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial Julg, Boris; Stephenson, Kathryn E.; Wagh, Kshitij Nature Medicine, Vol. 28, Issue 6 https://doi.org/10.1038/s41591-022-01815-1	journal	May 2022
Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition Gilbert, Peter B.; Huang, Yunda; deCamp, Allan C. Nature Medicine, Vol. 28, Issue 9 https://doi.org/10.1038/s41591-022-01953-6	journal	August 2022
Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model Wargo, Andrew R.; Huijben, Silvie; de Roode, Jacobus C. Proceedings of the National Academy of Sciences, Vol. 104, Issue 50 https://doi.org/10.1073/pnas.0707766104	journal	December 2007
Post-treatment control of HIV infection Conway, Jessica M.; Perelson, Alan S. Proceedings of the National Academy of Sciences, Vol. 112, Issue 17 https://doi.org/10.1073/pnas.1419162112	journal	April 2015
Virus dynamics and drug therapy Bonhoeffer, S.; May, R. M.; Shaw, G. M. Proceedings of the National Academy of Sciences, Vol. 94, Issue 13 https://doi.org/10.1073/pnas.94.13.6971	journal	June 1997
Bayes Factors Kass, Robert E.; Raftery, Adrian E. Journal of the American Statistical Association, Vol. 90, Issue 430 https://doi.org/10.1080/01621459.1995.10476572	journal	June 1995
Broadly neutralizing antibodies for HIV-1: efficacies, challenges and opportunities Liu, Yubin; Cao, Wei; Sun, Ming Emerging Microbes & Infections, Vol. 9, Issue 1 https://doi.org/10.1080/22221751.2020.1713707	journal	January 2020
Increased Turnover of T Lymphocytes in HIV-1 Infection and Its Reduction by Antiretroviral Therapy Mohri, Hiroshi; Perelson, Alan S.; Tung, Keith The Journal of Experimental Medicine, Vol. 194, Issue 9 https://doi.org/10.1084/jem.194.9.1277	journal	October 2001
Structural and practical identifiability analysis of partially observed dynamical models by exploiting the profile likelihood Raue, A.; Kreutz, C.; Maiwald, T. Bioinformatics, Vol. 25, Issue 15 https://doi.org/10.1093/bioinformatics/btp358	journal	June 2009
Comparison of approaches for parameter identifiability analysis of biological systems Raue, A.; Karlsson, J.; Saccomani, M. P. Bioinformatics, Vol. 30, Issue 10 https://doi.org/10.1093/bioinformatics/btu006	journal	January 2014
Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies Crooks, Amanda M.; Bateson, Rosalie; Cope, Anna B. Journal of Infectious Diseases, Vol. 212, Issue 9 https://doi.org/10.1093/infdis/jiv218	journal	April 2015
Density-Dependent Decay in HIV-1 Dynamics Holte, Sarah E.; Melvin, Ann J.; Mullins, James I. JAIDS Journal of Acquired Immune Deficiency Syndromes, Vol. 41, Issue 3 https://doi.org/10.1097/01.qai.0000199233.69457.e4	journal	January 2006
Cancer therapy: Attempt cure or manage drug resistance? Hansen, Elsa; Read, Andrew F. Evolutionary Applications, Vol. 13, Issue 7 https://doi.org/10.1111/eva.12994	journal	August 2020
Insight into treatment of HIV infection from viral dynamics models Hill, Alison L.; Rosenbloom, Daniel I. S.; Nowak, Martin A. Immunological Reviews, Vol. 285, Issue 1 https://doi.org/10.1111/imr.12698	journal	August 2018
HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time Perelson, A. S.; Neumann, A. U.; Markowitz, M. Science, Vol. 271, Issue 5255 https://doi.org/10.1126/science.271.5255.1582	journal	March 1996
Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection Lynch, Rebecca M.; Boritz, Eli; Coates, Emily E. Science Translational Medicine, Vol. 7, Issue 319 https://doi.org/10.1126/scitranslmed.aad5752	journal	December 2015
Mechanism of Neutralization by the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01 Li, Y.; O'Dell, S.; Walker, L. M. Journal of Virology, Vol. 85, Issue 17 https://doi.org/10.1128/JVI.00754-11	journal	June 2011
Nature, Position, and Frequency of Mutations Made in a Single Cycle of HIV-1 Replication Abram, Michael E.; Ferris, Andrea L.; Shao, Wei Journal of Virology, Vol. 84, Issue 19 https://doi.org/10.1128/JVI.00915-10	journal	July 2010
HIV-1 Fitness Cost Associated with Escape from the VRC01 Class of CD4 Binding Site Neutralizing Antibodies Lynch, Rebecca M.; Wong, Patrick; Tran, Lillian Journal of Virology, Vol. 89, Issue 8 https://doi.org/10.1128/JVI.03608-14	journal	January 2015
Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. Mansky, L. M.; Temin, H. M. Journal of virology, Vol. 69, Issue 8 https://doi.org/10.1128/jvi.69.8.5087-5094.1995	journal	January 1995
On Identifiability of Nonlinear ODE Models and Applications in Viral Dynamics Miao, Hongyu; Xia, Xiaohua; Perelson, Alan S. SIAM Review, Vol. 53, Issue 1 https://doi.org/10.1137/090757009	journal	January 2011
Vaccines and Broadly Neutralizing Antibodies for HIV-1 Prevention Stephenson, Kathryn E.; Wagh, Kshitij; Korber, Bette Annual Review of Immunology, Vol. 38, Issue 1 https://doi.org/10.1146/annurev-immunol-080219-023629	journal	April 2020
Likelihood based observability analysis and confidence intervals for predictions of dynamic models Kreutz, Clemens; Raue, Andreas; Timmer, Jens BMC Systems Biology, Vol. 6, Issue 1 https://doi.org/10.1186/1752-0509-6-120	journal	January 2012
Identification of parameter correlations for parameter estimation in dynamic biological models Li, Pu; Vu, Quoc Dong BMC Systems Biology, Vol. 7, Issue 1 https://doi.org/10.1186/1752-0509-7-91	journal	January 2013
Extremely High Mutation Rate of HIV-1 In Vivo Cuevas, José M.; Geller, Ron; Garijo, Raquel PLOS Biology, Vol. 13, Issue 9 https://doi.org/10.1371/journal.pbio.1002251	journal	September 2015
Antibiotics can be used to contain drug-resistant bacteria by maintaining sufficiently large sensitive populations Hansen, Elsa; Karslake, Jason; Woods, Robert J. PLOS Biology, Vol. 18, Issue 5 https://doi.org/10.1371/journal.pbio.3000713	journal	May 2020
Treatment-Mediated Alterations in HIV Fitness Preserve CD4+ T Cell Counts but Have Minimal Effects on Viral Load Vaidya, Naveen K.; Rong, Libin; Marconi, Vincent C. PLoS Computational Biology, Vol. 6, Issue 11 https://doi.org/10.1371/journal.pcbi.1001012	journal	November 2010
Residual Viremia in Treated HIV+ Individuals Conway, Jessica M.; Perelson, Alan S. PLOS Computational Biology, Vol. 12, Issue 1 https://doi.org/10.1371/journal.pcbi.1004677	journal	January 2016
Mathematical modeling to reveal breakthrough mechanisms in the HIV Antibody Mediated Prevention (AMP) trials Reeves, Daniel B.; Huang, Yunda; Duke, Elizabeth R. PLOS Computational Biology, Vol. 16, Issue 2 https://doi.org/10.1371/journal.pcbi.1007626	journal	February 2020
Pre-existing resistance in the latent reservoir can compromise VRC01 therapy during chronic HIV-1 infection Saha, Ananya; Dixit, Narendra M. PLOS Computational Biology, Vol. 16, Issue 11 https://doi.org/10.1371/journal.pcbi.1008434	journal	November 2020
Driving the Model to Its Limit: Profile Likelihood Based Model Reduction Maiwald, Tim; Hass, Helge; Steiert, Bernhard PLOS ONE, Vol. 11, Issue 9 https://doi.org/10.1371/journal.pone.0162366	journal	September 2016
Rapid Response to Selection, Competitive Release and Increased Transmission Potential of Artesunate-Selected Plasmodium chabaudi Malaria Parasites Pollitt, Laura C.; Huijben, Silvie; Sim, Derek G. PLoS Pathogens, Vol. 10, Issue 4 https://doi.org/10.1371/journal.ppat.1004019	journal	April 2014
Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection Wagh, Kshitij; Bhattacharya, Tanmoy; Williamson, Carolyn PLOS Pathogens, Vol. 12, Issue 3 https://doi.org/10.1371/journal.ppat.1005520	journal	March 2016
CD8+ lymphocyte control of SIV infection during antiretroviral therapy Cao, Youfang; Cartwright, Emily K.; Silvestri, Guido PLOS Pathogens, Vol. 14, Issue 10 https://doi.org/10.1371/journal.ppat.1007350	journal	October 2018
Bayesian Model Selection in Social Research Raftery, Adrian E. Sociological Methodology, Vol. 25 https://doi.org/10.2307/271063	journal	January 1995
Influenza Virus Infection Model With Density Dependence Supports Biphasic Viral Decay Smith, Amanda P.; Moquin, David J.; Bernhauerova, Veronika Frontiers in Microbiology, Vol. 9 https://doi.org/10.3389/fmicb.2018.01554	journal	July 2018

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60 APPLIED LIFE SCIENCES
Biological Science
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Phase I clinical investigation
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antibody therapy
broadly neutralizing antibody
mathematical models
microbial mutation
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Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1

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Figures / Tables (8)

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