Homotypic antibody responses to fresh clinical isolates of human immunodeficiency virus.
Human immunodeficiency virus type 1 (HIV-1) exhibits extensive genomic and antigenic diversity, which is thought to contribute to the failure of the host's immune response to control infection and prevent clinical progression. Part of this failure may be due to utilization by the virus of antigenic variation as a means to escape protective immune responses. Antibody-escape variants of HIV-1 were studied here using fresh clinical isolates and autologous plasmas. HIV-1 was isolated from the plasma of seven people who were all seropositive for at least 2 years, and symptomatic sometime during that period. Isolated viruses were confirmed as HIV-1 by the presence of reverse transcriptase activity in infected culture supernatants, and by positive immunofluorescence using human monoclonal antibody to HIV-1 core protein. Plasma from these people were positive by Western immunoblot (DuPont) for most major HIV-1 (strain IIIB) antigens. These plasmas neutralized three laboratory strains of HIV-1 (i.e., IIIB, RF, and MN) but did not neutralize the homotypic strain in five cases, and had greatly reduced neutralizing titers against the homotypic strain in two cases. Homotypic neutralizing antibodies were absent in autologous plasma obtained 3 months later. When antibody titers were measured by fixed-cell indirect immunofluorescence assays (IFAs), high titers of IgG (1:6400 to 1:25,600) were detected against HIV-1 IIIB, while low titers of only 1:20 to 1:160 were detected against homotypic viral antigens at the time of virus isolation, and remained low 12 and 16 weeks later. No class IgA, IgD, IgE, or IgM antibodies to homotypic viral antigens, as possible IgG-blocking antibodies, were detected by fixed-cell IFAs. Cross-reactions with heterologous donor's plasmas were observed in some cases, and in these cases the cross-reactions were unidirectional. Live-cell IFAs detected IgG in patient's plasma to HIV-1 IIIB-infected cells but not to cells infected with homotypic isolates. These results suggest that it is common for neutralization-resistant HIV-1 variants to appear during the course of infection, and that all or most antigens of these variants are capable of escaping antibody recognition.
Montefiori, DC; Zhou, IY; Barnes, B; Lake, D; Hersh, EM; Masuho, Y; Lefkowitz, LB
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