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There is currently no curative treatment for HIV-1 infection. However, some individuals (defined as posttreatment controllers) durably control viremia after the discontinuation of antiretroviral therapy (ART). Although the ability to achieve this HIV-1 remission status is enhanced by early treatment initiation, the mechanisms leading to posttreatment HIV-1 control remain unclear. We retrospectively explored the immunogenetic characteristics of long-term posttreatment controllers from the ANRS VISCONTI study and persons monitored since primary HIV-1 infection in the ANRS PRIMO cohort and evaluated their influence on clinical parameters and outcome after ART discontinuation. We identified a major histocompatibility complex (MHC)-related fingerprint favoring sustained HIV-1 remission. HLA-B∗35 alleles, which are associated with rapid progression to AIDS during natural HIV-1 infection, were paradoxically overrepresented among posttreatment controllers and had a positive impact on outcome after treatment discontinuation in people who began therapy during primary infection. Specifically, the influence of HLA-B∗35 alleles was observed when they were carried in combination with other HLA class I alleles expressing Bw4 and C2 ligands of killer immunoglobulin-like receptors (KIRs) in a genetic context that favors KIR education of natural killer (NK) cells (Bw4TTC2 genotype). Accordingly, posttreatment controllers with HLA-B∗35 alleles carry distinct KIR genotypes and NK cells. The combination of HLA-B∗35 with Bw4TTC2 genotype, associated with KIR education of NK cells, was abundant among posttreatment HIV-1 controllers and promoted viral control after interruption of early-initiated antiretroviral treatment. These results support a role of NK cells in sustained HIV-1 remission. The VISCONTI study and the PRIMO cohort are funded by the ANRS-MIE. • Paradoxical frequency of HLA-B∗35 alleles among HIV-1 posttreatment controllers • HLA-B∗35 linked to earlier ART start and higher chance of posttreatment control • Bw4 and C2 KIR ligands are abundantly found in combination with HLA-B∗35 in PTCs • Genotype favoring KIR education of NK cells linked to posttreatment control Current antiretroviral treatments efficiently block HIV-1 infection, but they need to be continued for life, as a rapid viral rebound occurs if the treatment is stopped. This study analyzed 27 extraordinary individuals who maintained the virus controlled for multiple years despite the interruption of the treatment. The scientists found genetic traits associated with NK cell education overrepresented in these individuals. The presence of these genetic factors was associated with decreased risk of viral rebound after treatment interruption in people who were diagnosed and treated in the first weeks following HIV-1 infection. These results support a key role of NK cells in the control of HIV-1 off antiretroviral treatment and may guide the development of new immunotherapies against HIV-1. Understanding the mechanisms underlying HIV-1 control after interruption of antiretroviral treatment may guide the development of immunotherapies aiming at HIV remission. Essat, Chapel et al. identified a fingerprint combining HLA-B∗35 with NK cell-related immunogenetic traits that was associated with posttreatment HIV-1 control, supporting the role of NK cells in long-term HIV remission.
Essat et al. (Mon,) studied this question.