TY - JOUR
T1 - Heightened resistance to host type 1 interferons characterizes HIV-1 at transmission and after antiretroviral therapy interruption
AU - Gondim, Marcos V.P.
AU - Sherrill-Mix, Scott
AU - Bibollet-Ruche, Frederic
AU - Russell, Ronnie M.
AU - Trimboli, Stephanie
AU - Smith, Andrew G.
AU - Li, Yingying
AU - Liu, Weimin
AU - Avitto, Alexa N.
AU - DeVoto, Julia C.
AU - Connell, Jesse
AU - Fenton-May, Angharad E.
AU - Pellegrino, Pierre
AU - Williams, Ian
AU - Papasavvas, Emmanouil
AU - Lorenzi, Julio C.C.
AU - Brenda Salantes, D.
AU - Mampe, Felicity
AU - Alexandra Monroy, M.
AU - Cohen, Yehuda Z.
AU - Heath, Sonya
AU - Saag, Michael S.
AU - Montaner, Luis J.
AU - Collman, Ronald G.
AU - Siliciano, Janet M.
AU - Siliciano, Robert F.
AU - Plenderleith, Lindsey J.
AU - Sharp, Paul M.
AU - Caskey, Marina
AU - Nussenzweig, Michel C.
AU - Shaw, George M.
AU - Borrow, Persephone
AU - Bar, Katharine J.
AU - Hahn, Beatrice H.
N1 - Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85099999057&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099999057&partnerID=8YFLogxK
U2 - 10.1126/SCITRANSLMED.ABD8179
DO - 10.1126/SCITRANSLMED.ABD8179
M3 - Article
C2 - 33441429
AN - SCOPUS:85099999057
SN - 1946-6234
VL - 13
JO - Science translational medicine
JF - Science translational medicine
IS - 576
M1 - eabd8179
ER -