Exposure to Entry Inhibitors Alters HIV Infectiousness and Sensitivity to Broadly Neutralizing Monoclonal Antibodies.

BACKGROUND:The development of envelope-specific neutralizing antibodies that can interfere with viral entry into target cells is important for the development of an HIV-1 vaccine. Another means of blocking viral entry is through the use of entry inhibitors such as the CCR5 inhibitor maraviroc (MVC), which can also repel cell-free virus particles from the cell surface. For this reason, we hypothesized that exposure to entry inhibitors might alter viral infectiousness and sensitivity to antibody-mediated neutralization.METHODS:The CCR5-tropic HIV-1 variants BaL, AD8, and CC 1/85 were used to infect PM-1 cells in the presence of 2 entry inhibitors, enfuvirtide and MVC. After 4 hours, culture fluids were ultrafiltered and the infectiousness and susceptibility to broadly neutralizing antibodies (2F5, 4E10, 2G12, b12, VRC01, PG9) of viruses exposed to these entry inhibitors were assessed using TZM-bl cells.RESULTS:Viruses exposed to the entry inhibitor MVC exhibited lower infectiousness than controls. Enfuvirtide exposure increased AD8 sensitivity to 2F5, 4E10, VRC01, and b12 and increased BaL sensitivity to 4E10 while lowering BaL sensitivity to b12 and VRC01. MVC-exposed BaL became less susceptible to the gp120-specific antibodies b12, 2G12, and VRC01.CONCLUSIONS:Exposure to entry inhibitors altered HIV-1 infectiousness and sensitivity to gp120-specific neutralizing antibodies. This alteration of entry inhibitor-exposed virus has implications for the development of future entry inhibitors and for vaccine development.