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

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.

Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant

“…We propose that enhanced innate immune antagonism by the B.1.1.7 lineage contributes to its transmission advantage, as has been observed for HIV, another emergent pandemic virus 17,18 . We hypothesise that more effective innate immune antagonism permits enhanced transmission through reduced and delayed host responses which otherwise protect cells from infection.…”

“…As IFN resistance correlates with enhanced transmission of other pandemic viruses 17,18 , we compared sensitivity to IFNβ inhibition of B.1.1.7 and first wave isolates. B.1.1.7 was consistently less sensitive to IFNβ pre-treatment over a wide dose range, compared to first wave isolate VIC (lineage B) (Fig.…”

“…Furthermore, it is unclear whether any of the B.1.1.7specific mutations impact the expression levels of viral proteins. In sum, the impact of these additional mutations on viral replication, transmission and pathogenesis has not been characterised.Innate immune responses can exert strong selective pressure during viral transmission [17][18][19] and play an important role in determining clinical outcomes to SARS-CoV-2 infection [20][21][22] . We therefore reasoned that B.1.1.7 may have evolved to enhance innate immune escape.…”

Persistent HIV-1 transcription in CD4+ T cells from ART-suppressed individuals can originate from biologically competent proviruses

“…However, recent studies suggest that viruses generated ex vivo in the Q-VOA assay have limited phylogenetic similarity to rebounding plasma viruses following an ATI. 35 , 36 Therefore, the extent to which current, viral outgrowth-based reservoir assays inform on the size and composition of the rebound competent reservoir, is unclear.…”

The Clonal Expansion Dynamics of the HIV-1 Reservoir: Mechanisms of Integration Site-Dependent Proliferation and HIV-1 Persistence

“…Second, upon latency reversal, cells harboring HIV-1 proviruses can be killed by CTLs and NK cells in vivo, but this immune selection pressure is not measured in standard viral outgrowth cultures (in which CD4 + T cells are cultured without CTLs and NK cells). Third, HIV-1 viruses that caused rebound need to survive in vivo immune selection pressures that do not exist in ex vivo viral outgrowth cultures, such as autologous immunoglobulins G (IgGs) [ 43 ] and type I interferon responses [ 44 ]. Fourth, HIV-1-infected cells may hide in anatomical sanctuaries (such as the central nervous system) [ 45 ] or immune sanctuaries (such as B cell follicles in the lymph node) [ 46 ] that may cause viral rebound but are not captured by peripheral blood sampling [ 46 ].…”