Abstract
The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins (Env). Binding to the CD4 receptor triggers a cascade of conformational changes in distant domains that move Env from a functionally “closed” State 1 to more “open” conformations, but the molecular mechanisms underlying allosteric regulation of these transitions are still elusive. Here, we develop chemical probes that block CD4-induced conformational changes in Env and use them to identify a potential control switch for Env structural rearrangements. We identify the gp120 β20–β21 element as a major regulator of Env transitions. Several amino acid changes in the β20–β21 base lead to open Env conformations, recapitulating the structural changes induced by CD4 binding. These HIV-1 mutants require less CD4 to infect cells and are relatively resistant to State 1-preferring broadly neutralizing antibodies. These data provide insights into the molecular mechanism and vulnerability of HIV-1 entry.
Highlights
The entry of human immunodeficiency virus type 1 (HIV-1) into target cells is mediated by the viral envelope glycoproteins (Env)
The entry of human immunodeficiency virus type 1 (HIV-1) into target cells is mediated by the interaction of viral envelope glycoproteins (Env) with the host CD4 receptor and CCR5/CXCR4 co-receptor[1,2,3,4,5,6,7]
The results provide a better understanding of the control of discrete HIV-1 Env transitions to downstream conformations on the virus entry pathway
Summary
The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins (Env). Several amino acid changes in the β20–β21 base lead to open Env conformations, recapitulating the structural changes induced by CD4 binding These HIV-1 mutants require less CD4 to infect cells and are relatively resistant to State 1-preferring broadly neutralizing antibodies. CD4 binding triggers a cascade of conformational changes in HIV-1 Env that result in the transition of the Env from the unliganded, metastable, high-energy state to downstream conformations These CD4-induced changes involve gp[120] (structural rearrangements in the V1/V2 and V3 loops at the trimer apex, formation of a bridging sheet, and exposure of the co-receptor-binding site) and gp[41] (formation/exposure of the heptad repeat 1 (HR1) coiled coil)[8,9,10,11,12]. The results provide a better understanding of the control of discrete HIV-1 Env transitions to downstream conformations on the virus entry pathway
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