UC San Diego

As scientists work towards elucidating the various mechanisms HIV uses for infection and evasion of the immune system, a large focus has been on the HIV-1 protein Envelope (Env). Env is essential for the attachment and entry of virions, and is the target of neutralizing antibodies. The host-protein SERINC5 inhibits HIV infectivity of some but not all Envs. Our goal was to understand the relationship between Env and SERINC5.

The Env-SERINC5 relationship was discovered by investigating how the HIV-1 accessory protein Nef increases viral infectivity. Nef enhances infectivity by removing the host-protein SERINC5 from the plasma membrane, preventing SERINC5 from inhibiting viral infectivity at the level of entry. However, Nef’s ability to increase virion infectivity appears to be Env dependent.

We hypothesized that the conformation of the Env trimer determined the relative sensitivity to SERINC5. We used the monoclonal antibody 447 52D as a marker of trimer “openness”, and assessed if trimer “openness” and SERINC5 sensitivity were related. Using a luciferase infectivity assay to measure the infectivity of cell-free virions, we found that Envs that were sensitive to the antibody 447-52D were also relatively more sensitive to SERINC5. We also used a specific mutation in the V2 loop of the gp120 subunit of Env to “open” the trimer; this increased the sensitivity to SERINC5.

Our findings support the hypothesis that trimer conformation is associated with SERINC5 sensitivity. However, the findings also suggest that trimer “openness” is not the sole factor determining SERINC5 sensitivity.