Research ArticleHIV

Heightened resistance to host type 1 interferons characterizes HIV-1 at transmission and after antiretroviral therapy interruption

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Science Translational Medicine  13 Jan 2021:
Vol. 13, Issue 576, eabd8179
DOI: 10.1126/scitranslmed.abd8179

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Putting pressure on HIV

Type 1 interferons provide early host immune defense against viruses, including HIV-1, by promoting expression of proteins that have direct or indirect antiviral activity. It remains unclear how viruses that persist long term, such as HIV-1, escape type 1 interferon–mediated pressure. Gondim et al. characterize interferon resistance in HIV-1 isolates acquired from HIV-1–infected individuals over several years. The authors found that HIV-1 isolates acquired at the time of initial infection or during interruption of antiretroviral therapy were the most resistant to type 1 interferons. These findings underpin the importance of type 1 interferons in controlling HIV-1 infection in the host.


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.

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