Heightened resistance to type 1 interferons characterizes HIV-1 at transmission and following analytical treatment interruption
By
Marcos VP Gondim,
Scott Sherrill-Mix,
Frederic Bibollet-Ruche,
Ronnie M Russell,
Stephanie Trimboli,
Andrew G Smith,
Yingying Li,
Weimin Liu,
Alexa N Avitto,
Julia DeVoto,
Jesse Connell,
Angharad E Fenton-May,
Pierre Pellegrino,
Ian Williams,
Emmanouil Papasavvas,
Julio C.C. Lorenzi,
D Brenda Salantes,
Felicity Mampe,
M Alexandra Monroy,
Yehuda Z. Cohen,
Sonya Heath,
Michael S Saag,
Luis J Montaner,
Ronald G. Collman,
Janet M Siliciano,
Robert F. Siliciano,
Lindsey Plenderleith,
Paul M Sharp,
Marina Caskey,
Michel C Nussenzweig,
George M Shaw,
Persephone Borrow,
Katharine J Bar,
Beatrice H. Hahn
Posted 28 Aug 2020
medRxiv DOI: 10.1101/2020.08.24.20181149
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 anti-viral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally-derived HIV-1 isolates from plasma and CD4+ T cells of 26 individuals sampled longitudinally following transmission and/or after antiretroviral therapy (ART) and analytical treatment interruption (ATI). Determining the concentration of IFN2 and IFN{beta} that reduced HIV-1 replication by 50% (IC50), we found remarkably consistent changes in the sensitivity of viruses to IFN-I inhibition, both across individuals and over time. IFN-I resistance was uniformly high during acute infection, decreased in all subjects in the first year post-infection, was reacquired concomitant with CD4+ T cell loss, and remained elevated in subjects with accelerated disease. Isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just prior to ART initiation. However, viruses that rebounded following treatment interruption displayed the highest levels of IFN2 and IFN{beta} resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate immune responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control impacted by both ART and ATI. Although elevated at transmission, IFN-mediated pressures are the highest during viral rebound, limiting the viruses that successfully reactivate from latency.
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