Accumulation of MxB/Mx2-resistant HIV-1 Capsid Variants During Expansion of the HIV-1 Epidemic in Human Populations

• Naturally occurring HIV-1capsid variants confer HIV-1 resistance to MxB.
• MxB-resistant capsid A116 is a major variant in HIV-1 Subtype C.
• HIV-1 capsid variant A116 is accumulating during expansion of the HIV-1 epidemic in China.
• MxB-resistant HIV-1 capsid variants maintain interaction with MxB.Interferon (IFN) is a key component of the innate immune response to exogenous pathogens. Human MxB has been identified as a potent inhibitor of HIV-1 induced by interferon. How HIV-1 escapes from MxB inhibition is not clear. This study demonstrates that capsid variations detected in primary HIV-1 isolates can mediate MxB resistance. MxB resistant capsid mutations can accumulate during HIV-1 transmission and are mostly enriched in Clade C HIV-1 that is the most rapidly expanding Clade throughout the world. Identification of the critical role of these capsid mutations in overcoming a host restriction factor may provide opportunities for the development of therapeutic interventions.

Recent studies have identified human myxovirus resistance protein 2 (MxB or Mx2) as an interferon induced inhibitor of HIV-1 replication. However, whether HIV-1 can overcome MxB restriction without compromise of viral fitness has been undefined. Here, we have discovered that naturally occurring capsid (CA) variants can render HIV-1 resistant to the activity of MxB without losing viral infectivity or the ability to escape from interferon induction. Moreover, these MxB resistant HIV-1 variants do not lose MxB recognition. Surprisingly, MxB resistant CA variants are most commonly found in the Clade C HIV-1 that is the most rapidly expanding Clade throughout the world. Accumulation of MxB resistant mutations is also observed during HIV-1 spreading in human populations. These findings support a potential role for MxB as a selective force during HIV-1 transmission and evolution.