1536. Latent Cell Proliferation Sustains the HIV Reservoir on Long-term ART—A Mathematical Modeling Study with Implications for Cure
Session: Poster Abstract Session: HIV Pathogenesis and Reservoir and Cure
Friday, October 28, 2016
Room: Poster Hall
Posters
  • ERD_IDWeek_poster_ff.pdf (5.8 MB)
  • Background: Viral latency prevents timely HIV cure. Thus, cure efforts have focused on eliminating the reservoir of latently infected cells. However, substantial controversy surrounds a fundamental question: what sustains the reservoir – ongoing viral replication and infection of new cells or proliferation of existing latent cells? Given that antiretroviral therapy (ART) rapidly suppresses measurable viral loads in the blood, ongoing viral replication on ART could occur only if ART was not reaching the infected cells producing new virus, implying the presence of a drug sanctuary. Recently published data demonstrated divergence in HIV sequences sampled early in HIV treatment, suggesting ongoing infection of new cells. In contrast, several earlier studies reported minimal viral evolution and instead found expansion of homotypic viral sequences after several years of ART, suggesting proliferation of latent cells as the mechanism sustaining the latent reservoir.

    Methods: Using a mathematical model of HIV dynamics, we explored the possible role of drug sanctuaries and proliferation of latent cells in HIV persistence. Our model uses published estimates of the three phases of viral decay on ART to define three infected cell states: productive infection, pre-integration latency, and post-integration latency and measures the degree of viral diversity expected as a function of time on ART.

    Results: Our model predicts that the percentage of latently infected cells born of new infection, rather than proliferation, decreases dramatically as time on ART increases. Conversely, the percentage arising from proliferation increases over time on ART. While we are able to reproduce realistic viral load data with a model that includes a drug sanctuary during the early months of ART, its importance in sustaining chronic HIV infection diminishes over time due to decreased activation of CD4+ T cells on ART.

    Conclusion: Given that drug sanctuaries—and thus, ongoing viral evolution—do not sustain chronic HIV infection on ART, enhancing ART delivery to drug sanctuary sites would not decrease the HIV reservoir and cure HIV. Rather, eradication strategies should strive to eliminate existing reservoir cells.

    Elizabeth Duke, MD1,2, Daniel Reeves, PhD2, Adam Spivak, MD3 and Joshua Schiffer, MD, MSc1,2, (1)Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, (2)Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, (3)Department of Internal Medicine, Division of Infectious Diseases, University of Utah School of Medicine, Salt Lake City, UT

    Disclosures:

    E. Duke, None

    D. Reeves, None

    A. Spivak, None

    J. Schiffer, None

    Findings in the abstracts are embargoed until 12:01 a.m. CDT, Wednesday Oct. 26th with the exception of research findings presented at the IDWeek press conferences.