Heightened resistance to host type 1 interferons characterizes HIV-1 at transmission and after antiretroviral therapy interruption
- 13 January 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 13 (576)
- https://doi.org/10.1126/scitranslmed.abd8179
Abstract
Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their antiviral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally derived HIV-1 isolates from the plasma and CD4+ T cells of 26 individuals sampled longitudinally after transmission or after antiretroviral therapy (ART) and analytical treatment interruption. We determined the concentration of IFNα2 and IFNβ that reduced viral replication in vitro by 50% (IC50) and found consistent changes in the sensitivity of HIV-1 to IFN-I inhibition both across individuals and over time. Resistance of HIV-1 isolates to IFN-I was uniformly high during acute infection, decreased in all individuals in the first year after infection, was reacquired concomitant with CD4+ T cell loss, and remained elevated in individuals with accelerated disease. HIV-1 isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just before ART initiation. However, viruses that rebounded after treatment interruption displayed the highest degree of IFNα2 and IFNβ resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control affected by both ART and analytical treatment interruption. Although elevated at transmission, host innate pressures are the highest during viral rebound, limiting the viruses that successfully become reactivated from latency to those that are IFN-I resistant.Keywords
Funding Information
- National Institutes of Health (U01 AI 129825)
- National Institutes of Health (U01 AI 065279)
- National Institutes of Health (UM1 Al 126620)
- National Institutes of Health (P30 AI 045008)
- National Institutes of Health (UM1 AI 126619)
- National Institutes of Health (UM1 AI100663)
- Medical Research Council (MR/K012037)
- Bill and Melinda Gates Foundation (OPP1092074)
- National Institutes of Health (UM1 AI 144371)
- National Institutes of Health (R01 AI 111789)
- National Institutes of Health (R01 AI 114266)
- National Institutes of Health (T32 AI 007632)
- NIH Office of the Director (P30 AI027767)
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