CD4-Induced Conformational Changes in the Human Immunodeficiency Virus Type 1 gp120 Glycoprotein: Consequences for Virus Entry and Neutralization

Abstract

Human immunodeficiency virus type 1 (HIV-1) entry into target cells involves sequential binding of the gp120 exterior envelope glycoprotein to CD4 and to specific chemokine receptors. Soluble CD4 (sCD4) is thought to mimic membrane-anchored CD4, and its binding alters the conformation of the HIV-1 envelope glycoproteins. Two cross-competing monoclonal antibodies, 17b and CG10, that recognize CD4-inducible gp120 epitopes and that block gp120-chemokine receptor binding were used to investigate the nature and functional significance of gp120 conformational changes initiated by CD4 binding. Envelope glycoproteins derived from both T-cell line-adapted and primary HIV-1 isolates exhibited increased binding of the 17b antibody in the presence of sCD4. CD4-induced exposure of the 17b epitope on the oligomeric envelope glycoprotein complex occurred over a wide range of temperatures and involved movement of the gp120 V1/V2 variable loops. Amino acid changes that reduced the efficiency of 17b epitope exposure following CD4 binding invariably compromised the ability of the HIV-1 envelope glycoproteins to form syncytia or to support virus entry. Comparison of the CD4 dependence and neutralization efficiencies of the 17b and CG10 antibodies suggested that the epitopes for these antibodies are minimally accessible following attachment of gp120 to cell surface CD4. These results underscore the functional importance of these CD4-induced changes in gp120 conformation and illustrate viral strategies for sequestering chemokine receptor-binding regions from the humoral immune response.

Interaction of the gp120 V1V2 loop with a neighboring gp120 unit shields the HIV envelope trimer against cross-neutralizing antibodies

“…Past investigations on the influence of the V1V2 loop on steering neutralization activity have been restricted to few, mostly highly neutralization-sensitive isolates (HxB2, LAI, SF162, R3A, and YU-2; Wyatt et al, 1993, 1995; Cao et al, 1997; Stamatatos and Cheng-Mayer, 1998; Stamatatos et al, 1998; Sullivan et al, 1998; Saunders et al, 2005; Laakso et al, 2007; Bontjer et al, 2009) and thus left a definite verdict on the potency of the V1V2 loop shielding effect against primary viruses pending. In this study, we generated a panel of six infection-competent V1V2 loop–deleted Env’s of tier 1 (NL4-3 and SF162), tier 2 (JR-FL*, RHPA, and REJO), and tier 3 (ZA110.c10.14) subtype B isolates by inserting the linker sequence Asp-Ala-Gly (DAG) as described previously (Fig.…”

Identifying epitopes of HIV-1 that induce protective antibodies

“…Interestingly, the antigenbinding fragment (Fab) and single-chain fragments of these CD4i-specific monoclonal antibodies do have neutralizing function 58,60 . The inability of the whole IgG CD4i-specific monoclonal antibody to neutralize can be explained by steric hindrance, given that the distance between the CD4i epitope on gp120 and the target cell membrane in molecular models seems too small to accommodate the entire IgG molecule 61,62,132 . If these observations are confirmed, the physical constraints on antibody access to the CD4i epitope will preclude the use of antibodies to this epitope as a barrier against infection with HIV-1.…”

Specific CD4 down-modulating compounds with potent anti-HIV activity

“…This could be explained by the fact that primary HIV-1 isolates are much less sensitive to neutralization by sCD4 than are laboratory-adapted HIV-1 strains, probably resulting from the lower affinity for CD4 and the reduced sCD4-induced gp120 shedding from the virions [23][24][25]. In addition, several reports demonstrated that soluble CD4 could activate the envelope glycoprotein gp120, making it competent to interact with the coreceptor, and thus could promote fusion/entry [22,26,27].…”