CD4 activation of HIV fusion

Abstract

The primary cellular receptor for the human immunodeficiency viruses type 1 (HIV-1) and type 2 (HIV-2) is the CD4 antigen. HIV infection of CD4+ cells is initiated by binding of the virus to the cell surface, via a high affinity interaction between CD4 and the HIV outer envelope glycoprotein, gp120. The development of model systems using soluble recombinant forms of CD4 (sCD4) has allowed kinetic and thermodynamic analyses of CD4 binding to gp120, and study of the post-binding events leading to virus-cell membrane fusion. It has thus been demonstrated that the affinity of sCD4 for gp120 on virions or HIV-infected cells depends on both the primary sequence and the tertiary structure of gp120 in the membrane. With cell-line adapted isolates of HIV-1, sCD4 binding induces conformational changes in gp120, leading to the complete dissociation of gp120 from the transmembrane glycoprotein, gp41, and exposing cryptic epitopes of gp41. Similar observations have been made with cell-anchored CD4; exposure of cryptic gp41 epitopes occurs at the fusion interface between clusters of CD4-expressing and HIV-infected cells. Thus, for HIV-1, CD4 induces exposure of fusogenic components of gp41 which triggers virus-cell membrane coalescence. This is termed receptor-mediated activation of fusion. With primary isolates of HIV-1 and the related lentiviruses, HIV-2 and simian immunodeficiency virus (SIV), the CD4-induced molecular rearrangements in gp120 are more subtle, implying that there is a spectrum of responses to sCD4 binding. The high-affinity binding site on CD4 for gp120 is necessary and probably sufficient for activation of HIV fusion, although other regions of CD4 may indirectly influence viral entry. There are two regions on the envelope glycoproteins which are recognized as playing a role in HIV entry: the N-terminus of gp41 and the gp120 V3 loop. The roles of these domains are discussed.

Antigenic Analysis of HIV Type 1 External Envelope (Env) Glycoprotein C2 Region: Implication for the Structure of Env

“…However, a recent study by Moore and co-workers8 indicated that among the constant domains of gpl20env only the Cl and a portion of C4 seem to be accessible to MAb on native monomeric molecule. Although C2 was considered to be poorly accessible, we wished to analyse the antigenicity of a particular region extending from residue 273 to 288 (EEVVIRSAN-FTDNAKT) because there are several lines of evidence suggesting that this region plays a role in the early events of viral infection: (1) We have previously reported that the lectin jacalin, which binds to CD4 and inhibits HIV infection, shows a 14 amino acid peptide presenting high similarities (8 common residues and 2 conservative charges) with the amino acid sequence 273-288 of the C2 domain of gp\2(¥nv. This peptide (VVVRSLTFKTNKKT), at high concentration, demonstrated antiviral properties on some HIV-1 isolates.9 (2) It has also been reported10 that the vasoactive intestinal peptide (VIP), which has been claimed to interact with CD4,11 presents a fragment ' of high similarity (5 identical residues and 1 conservative charge) with this gpl20 sequence (HSDAVFTDNYTR); this peptide has been shown to antagonize in vitro neuronal cell death induced by gpl20c"v.12 (3) The antiviral property of another peptide (ASTTTNYT) showing similarities with the gpl20e"v region extending from residue 280 to 287 has been reported.13 (4) Apart from the information derived from the peptide approach, other results obtained from mutagenesis suggest an involvement of this region in HIV-1 infection: The 286A/V mutation is responsible for the generation of an escape mutant virus insensitive to anti-V3 MAb neutralization, suggesting that this region may interact with V3 or indirectly affect the structure of V3.14 The 284 D/N mutation alters the association of gpl20env' with gp41e"v and this mutant virus has lost its infectivity.15 (6) Finally, a mutant virus expressing the double mutation 283 T/M and 287 K/V is insensitive to soluble CD4 (sCD4) treatment.16…”

Variants of Human Immunodeficiency Virus Type 1 That Efficiently Use CCR5 Lacking the Tyrosine-Sulfated Amino Terminus Have Adaptive Mutations in gp120, Including Loss of a Functional N-Glycan

“…The human immunodeficiency virus type 1 (HIV-1) infection pathway involves a sequential process whereby reversible binding to the CD4 receptor induces a conformational change in the viral gp120-gp41 trimeric complexes that exposes or induces formation of previously inaccessible epitopes in both gp120 and gp41 and dramatically enhances gp120 affinity for a coreceptor (46,57,65,69,71,73,75). Energetic studies have suggested that the gp120 subunit has a high entropy or conformational flexibility that inhibits binding of antibodies or other ligands and that binding to CD4 substantially reduces this flexibility, thus enhancing the subsequent binding of gp120 to additional ligands by an energetic (entropic) mechanism (36,47).…”

Determinants of Human Immunodeficiency Virus Type 1 Resistance to gp41-Derived Inhibitory Peptides

“…During the course of viral infection, gp120 and gp41 are involved in the fusion process between membranes of HIV-1 and host cells expressing CD4 and certain coreceptors (2,4,13,(15)(16)(17). After receptor binding, structural rearrangements of the gp41 subunit are thought to play a role in membrane fusion (23,31,39,40) in a poorly understood process which has often been compared to that used by the hemagglutinin HA2 protein of influenza (7,9,54).…”