Structure/Function Studies Involving the V3 Region of the HIV-1 Envelope Delineate Multiple Factors that Affect Neutralization Sensitivity.

Publication Type:

Journal Article


Journal of virology, Volume 90, Issue 2, p.636-649 (2016)


Antibodies (Abs) specific for the V3 loop of the HIV-1 gp120 envelope neutralize most Tier 1 and many Tier 2 viruses and are present in essentially all HIV-infected individuals as well as immunized humans and animals. Vaccine-induced V3 Abs are associated with reduced HIV infection rates in humans, and affected the nature of transmitted viruses in infected vaccinees despite the fact that V3 is often occluded in the envelope trimer. Here, we link structural and experimental data showing how conformational alterations of the envelope trimer render viruses exceptionally sensitive to V3 Abs. The experiments interrogated the neutralization sensitivity of pseudoviruses with single amino acid mutations in various regions of gp120 that were predicted to alter packing of the V3 loop in the Env trimer. The results indicate that the V3 loop is meta-stable in the envelope trimer on the virion surface, flickering between states in which V3 is either occluded or available for binding to chemokine receptors (leading to infection) and to V3 Abs (leading to virus neutralization). The "spring loaded" V3 in the envelope trimer is easily "released" by disruption of the stability of the "V3 pocket" in the unliganded trimer or disruption of favorable V3/pocket interactions. Formation of the V3 pocket requires appropriate positioning of the V1V2 domain, which is in turn dependent on the conformation of the bridging sheet, and on the stability of the V1V2 B-C strand-connecting loop. IMPORTANCE: Antibodies levels to the third variable regions (V3) of the HIV envelope protein correlate with reduced HIV infection rates. Previous studies showed that V3 is often occluded as it sits in a pocket of the envelope trimer on the surface of virions, however, the trimer is flexible, allowing occluded portions of the envelope (like V3) to flicker into an exposed position that binds antibodies. Here we provide a systematic interrogation of mechanisms by which single amino acid changes in various regions of gp120: (a) render viruses sensitive to neutralization by V3 antibodies, (b) result in altered packing of the V3 loop, and (c) activate an "open" conformation that exposes V3 to the effects of V3 Abs. Taken together, these and previous studies explain how V3 antibodies can protect against HIV-1 infection, and why they should be one of the targets of vaccine-induced antibodies.