Principal neutralizing domain of the human immunodeficiency virus type 1 envelope protein.

Abstract

The principal neutralizing determinant of human immunodeficiency virus type 1 (IIV-1) is located in the external envelope protein, gpl20, and has previously been mapped to a 24-amino acid-long sequence (denoted RP135). We show here that deletion of this sequence renders the envelope unable to elicit neutralizing antibodies. In addition, using synthetic peptide fragments of RP135, we have mapped the neutralizing determinant to 8 amino acids and found that a peptide ofthis size elicits neutralizing antibodies. This sequence contains a central Gly-Pro-Gly that is generally conserved between different HIV-1 isolates and is flanked by amino acids that differ from isolate to isolate. Antibodies elicited by peptides from one isolate do not neutralize two different isolates, and a hybrid peptide, consisting of amino acid sequences from two isolates, elicits neutralizing antibodies to both isolates. By using a mixture of peptides of this domain or a mixture of such hybrid peptides the type-specificity of the neutralizing antibody response to this determinant can perhaps be overcome.

The epitopes for natural polyreactive antibodies are rich in proline

“…The same sequence is present in the LAG-3 protein on the surface of lymphocytes and is suggested to be an exposed epitope (23,24). In addition, the neutralizing determinant of human immunodeficiency virus type I, which elicits neutralizing antibodies, is an eight amino acid peptide of the V3 loop containing a central conserved sequence Gly-Pro-Gly (25)(26)(27). Finally, Tax peptides, which were used to crystallize the T cell antigen receptor with the MHC, also contain proline (28).…”

Concurrent evolution of regions of the envelope and polymerase genes of human immunodeficiency virus type 1 observed during zidovudine (AZT) therapy

“…Briefly, topographical and temporal variation of the V3 regions was observed. Mutations occurring within the V3 sequences, and particularly changes occurring around the loop apex, might affect immune recognition (Javaherian et al, 1989;Takahashi et al, 1989), cell tropism and cytopathogenicity (Takeuchi et al, 1991;Fouchier et al, 1992). Conformationally sensitive epitopes encompassing regions of the CD4 binding domain, including the C4 region, and epitopes involving the V2, V3 and V4 regions have been described (Thali et al, 1994;McKeating et al, 1993; K a y m a n et al, 1994).…”

“…Both humoral and cell-mediated immune selection and constraints in cell tropism are potential causes for sequence change within the hypervariable (V) regions of env. The V1/V2, V3 and V4 regions as well as conserved region 4 (C4), located between V4 and V5, have all been shown to contain linear or conformationally sensitive neutralizing antibody or cytotoxic T cell (CTL) determinants (Javaherian et al, 1989;Thali et al, 1994;Kayman et al, 1994). In addition, mutations within several of these regions, in particular V3 and V1/V2, have been shown to affect cytopathogenicity and cell tropism (Takeuchi et al, …”

Rapid selection for an N-linked oligosaccharide by monoclonal antibodies directed against the V3 loop of human immunodeficiency virus type 1

“…The hypervariable V3 loop of gp 120 constitutes an important neutralizing determinant for strains of HIV-1 adapted to T cell lines (Goudsmit et al, 1988;Javaherian et al, 1989;Rusche et al, 1988). Variability within this loop is observed both inter-and intra-individually (Balfe et al,, 1990;Hahn et al, 1986;LaRosa et al, 1990;Wolfs et al, 1990).…”