Human immunodeficiency virus type 1 envelope glycoprotein gp120 (CD4-bound transition-state conformation) (HIV-1 gp120 (CD4-bound))

The HIV-1 gp120 in the CD4-bound transition-state conformation is a critical structural intermediate of the human immunodeficiency virus type 1 envelope glycoprotein. In its native, unliganded state, the gp120/gp41 trimer exists in a "closed" conformation that protects conserved epitopes from immune recognition. Upon binding to the host cell CD4 receptor, gp120 undergoes a significant conformational rearrangement into this "open" transition state, which involves the formation of a four-stranded bridging sheet and the exposure of the coreceptor binding site for CCR5 or CXCR4 [1, 3]. This structural transition is a mandatory step for the subsequent activation of the gp41 fusion machinery, which mediates the fusion of the viral and host cell membranes [3]. As a bottleneck in the viral life cycle, this conformation is a primary target for antiretroviral therapy and vaccine design. The FDA-approved drug fostemsavir (and its active metabolite temsavir) binds to gp120 to prevent the initial attachment to CD4, thereby blocking the transition to this state and inhibiting viral entry [2]. Additionally, investigational CD4-mimetic small molecules are designed to stabilize this transition-state conformation, which can prematurely expose highly conserved epitopes to neutralizing antibodies, offering a potential strategy for both treatment and prevention [4]. The high mutation rate of the HIV-1 envelope gene remains a significant challenge, as it allows the virus to develop resistance by altering the drug-binding pocket within the gp120 structure [2].

Other names

CD4-induced (CD4i) conformationOpen conformation of gp120Transition-state gp120gp120 CD4-bound stateCD4-induced state of Env

Inhibition of viral entry by preventing the conformational transition from the pre-fusion state to the CD4-bound state, or by stabilizing the transition state to expose vulnerable epitopes for neutralization [2, 4].