SERINC5 is able to restrict HIV-1 infection by drastically impairing the infectivity of viral particles. Current studies have shown that HIV-1 Nef protein counters SERINC5 through down regulating SERINC5 from the cell surface and preventing virion incorporation of SERINC5. In addition, the Env proteins of some HIV-1 strains can also overcome SERINC5 inhibition. However, it is unclear how HIV-1 Env does so and why HIV-1 has two mechanisms to resist SERINC5 inhibition. Results of this study show that neither Env nor Nef prevents high-level ectopic SERINC5 from incorporation into HIV-1 particles, except that Env, but not Nef, is able to resist the inhibition of virion-associated SERINC5. Testing a panel of HIV-1 Env proteins from different subtypes reveals a high frequency of SERINC5-resistant Envs. Interestingly, the SERINC5-bearing viruses, although not inhibited by SERINC5 itself, become more sensitive to the CCR5 inhibitor maraviroc and some neutralizing antibodies compared to the SERINC5-free viruses, which suggests a possible influence of SERINC5 on Env function. We conclude that HIV-1 Env is able to overcome SERINC5 without preventing SERINC5 virion incorporation.
HIV-1 Nef has been known to enhance the infectivity of HIV-1 viral particles and maintain high viral loads in patients. However, the underlying molecular mechanism has remained elusive until the recent discovery of the antiviral activity of SERINC5. SERINC5 profoundly inhibits HIV-1, but is antagonized by Nef that prevents the incorporation of SERINC5 into viral particles. Here, we show that HIV-1 Env, but not Nef, is able to resist high-level SERINC5 without excluding SERINC5 from incorporation into viral particles. However, the virion-associated SERINC5 renders HIV-1 more sensitive to some broadly neutralizing antibodies. It is possible that, under the pressure of some neutralizing antibodies in vivo, HIV-1 needs Nef to remove SERINC5 from viral particles despite that viral Env is able to resist virion-associated SERINC5.