Timing of initiation of anti-retroviral therapy predicts post-treatment control of SIV replication

• Type of Material: Article
• Authors: Mykola Pinkevych, University of New South Wales; Steffen S. Docken, University of New South Wales; Afam A. Okoye, Vaccine and Gene Therapy Institute; Christine M. Fennessey, Frederick National Laboratory for Cancer Research; Gregory Q. Del Prete, Frederick National laboratory for Cancer Research; Eugenia Del Pino, Emory University; Justin L. Harper, Emory University; Michael r. Betts, University of Pennsylvania; Mirko Paiardini, Emory University; brandon F. Keele, Frederick national Laboratory for Cancer Research; Miles P. Davenport, University of New South Wales
• Language: English
• Date: 2023-10-06
• Publisher: PLOS
• Publication Version: Final Published Version
• Copyright Statement: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
• License: Creative Commons Attribution 1.0 Generic
• Final Published Version (URL): https://doi.org/10.1371/journal.ppat.1011660
• Title of Journal or Parent Work: PLoS Pathogens
• Volume: 19
• Issue: 10
• Start Page: e1011660
• Grant/Funding Information: This work was supported by NIH grants NIAID P01AI131338 (to MPD, MP, and MRB); NIAID R21/R33AI116171, NHLBI, NIDDK, NIMH, NINDS, NIDA, NIAID, UM1AI164562, NIAID U42OD011023, and P51OD011132 (to MP). MPD is supported by an NHMRC Investigator grant (1173027) and an NHMRC Program grant (1149990). AAO is supported by NIH grants UM1AI126611, P51OD011092 and AI144993. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024 and HHSN261201500003I (to BFK).
• Keywords: infectious disease; HIV infection; treatment interruption
• Research Categories: Biology, Virology; Health Sciences, Immunology; Health Sciences, Public Health

Abstract

One approach to ‘functional cure’ of HIV infection is to induce durable control of HIV replication after the interruption of antiretroviral therapy (ART). However, the major factors that determine the viral ‘setpoint’ level after treatment interruption are not well understood. Here we combine data on ART interruption following SIV infection for 124 total animals from 10 independent studies across 3 institutional cohorts to understand the dynamics and predictors of post-treatment viral control. We find that the timing of treatment initiation is an important determinant of both the peak and early setpoint viral levels after treatment interruption. During the first 3 weeks of infection, every day of delay in treatment initiation is associated with a 0.22 log10 copies/ml decrease in post-rebound peak and setpoint viral levels. However, delay in initiation of ART beyond 3 weeks of infection is associated with higher post-rebound setpoint viral levels. For animals treated beyond 3 weeks post-infection, viral load at ART initiation was the primary predictor of post-rebound setpoint viral levels. Potential alternative predictors of post-rebound setpoint viral loads including cell-associated DNA or RNA, time from treatment interruption to rebound, and pre-interruption CD8+ T cell responses were also examined in the studies where these data were available. This analysis suggests that optimal timing of treatment initiation may be an important determinant of post-treatment control of HIV.