Neutralizing Antibody Response During Human Immunodeficiency Virus Type 1 Infection: Type and Group Specificity and Viral Escape

Abstract

The paradox that group-specific neutralizing antibodies (NA) exist in the majority of human immunodeficiency virus type 1 (HIV-1)-infected patients, whereas the NA response against autologous HIV-1 virus isolates is highly type-specific, motivated us to study the type-and group-specific NA responses generated upon presentation of escape virus, and the viral epitopes involved in the escape. Patients with demonstrable escape virus all developed group-specific NA, which were detectable after a delay and disappeared prior to disease development. The sera tested inhibited the binding of recombinant soluble gpl20mB to cell-associated CD4, but group-specific virus neutralization required binding of NA to HIV-1 prior to viral attachment to target cells.Consecutive escape virus isolates were tested for sensitivity to neutralization by heterologous sera. Only minor differences were demonstrated, suggesting that the majority of the change in neutralization sensitivity is driven by the selective pressure of type-specific NA. Furthermore, no differences were observed in sensitivity to neutralization by anti-carbohydrate neutralizing monoclonal antibodies or the lectin concanavalin A, indicating a conserved nature of certain carbohydrate neutralization epitopes during escape. Finally the V3 sequence of three sets of consecutive virus isolates were analysed revealing amino acid mutations in V3 sequences of all escape virus isolates. The biological significance of these variations was confirmed further by the demonstration of changes in sensitivity to neutralization by anti-V3 monoclonal antibodies. These results strongly suggest a participation of the NA response against the V3 loop in the immunoselection of escape virus.

Neutralization escape mutants of type A influenza virus are readily selected by antisera from mice immunized with whole virus: a possible mechanism for antigenic drift

“…Although it has been known for nearly half a century that escape mutants can be isolated using immune serum, they have emerged only after prolonged passage of viruses in vitro and usually with highly selected fractions of antiserum (influenza virus: Archetti & Horsfall, 1950;Isaacs, 1951;Laver & Webster, 1968;Fazekas de St Groth, 1978) or low concentrations of antiserum (foot-and-mouth disease virus: Rojas et al, 1992, HIV-I: Reitz et al, 1988McKeating et al, 1994) or in vivo where vaccination resulted in subprotective immunity (footand-mouth disease virus: Hyslop & Fagg, 1965, hepatitis B virus: Carman et al, 1990Harrison et al, 1991;Harrison & Zuckerman, 1992, 1993, treatment of persistent hepatitis B infection with MAb (McMahon et al, 1992), or during persistent infection (HIV-1 : Albert et al, 1990;Arendrup et al, 1992Arendrup et al, , 1993Nara et al, 1990a, b;Tremblay & Wainberg, 1990;Montefiori et al, 1991;Watkins et al, 1993;Schreiber et al, 1994). The favoured explanation of our data is that the mouse antisera capable of selecting escape mutants are functionally monoclonal; that is they contain a majority of neutralizing HA-specific, site A-specific antibodies whose epitope(s) overlap with that recognized by HC2.…”

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

“…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). The emergence in vivo of variants resistant to neutralization is correlated with mutations within this loop (Arendrup et al, 1993). This indicates that although neutralizing antibodies are unable to clear the infection * Author for correspondence.…”

All rabbits immunized with type A influenza virions have a serum haemagglutination-inhibition antibody response biased to a single epitope in antigenic site B

“…(HBV: Carman et al, 1990;Harrison et al, 1991Harrison et al, , 1994Harrison & Zuckerman, 1992. HIV-1 : Albert et al, 1990;Arendrup et al, 1992Arendrup et al, , 1993Nara et al, 1990a, b;Tremblay & Wainberg, 1990;Montefiori et al, 1991;Watkins et al, 1993;Schreiber et al, 1994. ) …”