A Conserved HIV gp120 Glycoprotein Structure Involved in Chemokine Receptor Binding

Abstract

The entry of primate immunodeficiency viruses into target cells depends on a sequential interaction of the gp120 envelope glycoprotein with the cellular receptors, CD4 and members of the chemokine receptor family. The gp120 third variable (V3) loop has been implicated in chemokine receptor binding, but the use of the CCR5 chemokine receptor by diverse primate immunodeficiency viruses suggests the involvement of an additional, conserved gp120 element. Through the use of gp120 mutants, a highly conserved gp120 structure was shown to be critical for CCR5 binding. This structure is located adjacent to the V3 loop and contains neutralization epitopes induced by CD4 binding. This conserved element may be a useful target for pharmacologic or prophylactic intervention in human immunodeficiency virus (HIV) infections.

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 + T Cells

“…Targeting stages of the HIV entry process with antiretroviral drugs is a productive method of inhibiting HIV replication, as demonstrated by the potent antiviral effects of small-molecule CCR5 antagonists and fusion inhibitors (23,35,49). As with other antiretroviral drugs, HIV can develop resistance to entry inhibitors, and a detailed understanding of viral and host determinants of resistance will be critical to the optimal clinical use of these agents.The coreceptor binding site that is induced by CD4 engagement consists of noncontiguous regions in the bridging sheet and V3 loop of gp120 (4,18,42,43,50). Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sul-…”

“…The coreceptor binding site that is induced by CD4 engagement consists of noncontiguous regions in the bridging sheet and V3 loop of gp120 (4,18,42,43,50). Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sulfated tyrosine residues in the NЈ terminus of CCR5, and (ii) the crown of the V3 loop is thought to engage the extracellular loops (ECLs), particularly ECL2, of CCR5 (10-12, 14, 18, 28).…”

Quaternary protein mimetics of gp41 elicit neutralizing antibodies against HIV fusion‐active intermediate state

“…The synthetic 3a mimetics, featuring linked parallel peptide strands to stabilize interstrand hydrophobic protein-protein interactions, are thus truncated versions of the gp41 quaternary structure and maintain the antigenic, solvent-accessible surface. Examination of such 3a mimetics as vaccine candidates has revealed that the mimetics: (1) to show protein-like characteristics and enhanced antiviral activity compared to monomers with parameters correlating to the putative bioactive quaternary prefusion state of gp41; (2) are immunogenic and capable of inducing gp41-specific antibodies that inhibit HIV entry at 31.58C; (3) 3a C-HR mimetic-induced antisera are potentially more effective at neutralizing X4 and R5 viruses than 3a-N-HR mimetic antisera.…”

“…In particular, the fusion protein gp41 undergoes large-scale conformational changes with discrete intermediate states during the fusion event. [1][2][3][4] A current model of such an entry process involves the initial binding of gp120 to the primary cell surface receptor CD4 and chemokine coreceptor CXCR4 or CCR5. 5,6 Following receptor-binding events and the subsequent attendant conformational changes, the dissociation of gp120 from gp41 results in…”

Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug

“…Binding of CD4 to gp120 induces significant conformational changes that result in the formation of a third domain termed the bridging sheet. This domain consists of two pairs of anti-parallel bsheets that link the inner and outer domains, and plays a major role in interacting with the viral co-receptors [80].…”