HIV-1 Nef Responsiveness Is Determined by Env Variable Regions Involved in Trimer Association and Correlates with Neutralization Sensitivity

•HIV Env proteins differ profoundly in their responsiveness to Nef and glycoGag•HIV responsiveness to Nef and glycoGag correlates with neutralization sensitivity•Nef responsiveness and neutralization sensitivity can be switched simultaneously•Nef responsiveness is governed by the gp120 trimer-association domain

SummaryHIV-1 Nef and the unrelated murine leukemia virus glycoGag similarly enhance the infectivity of HIV-1 virions. We now show that the effects of Nef and glycoGag are similarly determined by variable regions of HIV-1 gp120 that control Env trimer association and neutralization sensitivity. Whereas neutralization-sensitive X4-tropic Env proteins conferred high responsiveness to Nef and glycoGag, particles bearing neutralization-resistant R5-tropic Envs were considerably less affected. The profoundly different Nef/glycoGag responsiveness of a neutralization-resistant and a neutralization-sensitive R5-tropic Env could be switched by exchanging their gp120 V1/V2 regions, which also switches their neutralization sensitivity. Within V1/V2, the same determinants governed Nef/glycoGag responsiveness and neutralization sensitivity, indicating that these phenotypes are mechanistically linked. The V1/V2 and V3 regions, which form an apical trimer-association domain, together determined the Nef and glycoGag responsiveness of an X4-tropic Env. Our results suggest that Nef and glycoGag counteract the inactivation of Env spikes with relatively unstable apical trimer-association domains.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slide