ABSTRACT
Monoclonal antibodies (MAbs) that neutralize human immunodeficiency virus type 1 (HIV-1) have been isolated from HIV-1-infected individuals or animals immunized with recombinant HIV-1 envelope (Env) glycoprotein constructs. The epitopes of these neutralizing antibodies (NAbs) were shown to be located on either the variable or conserved regions of the HIV-1 Env and to be linear or conformational. However, one neutralizing MAb, 2909, which was isolated from an HIV-1-infected subject, recognizes a more complex, quaternary epitope that is present on the virion-associated functional trimeric Env spike of the SF162 HIV-1 isolate. Here, we discuss the isolation of 11 anti-HIV NAbs that were isolated from three rhesus macaques infected with the simian/human immunodeficiency virus SHIV(SF162P4) and that also recognize quaternary epitopes. A detailed epitope mapping analysis of three of these rhesus antibodies revealed that their epitopes overlap that of the human MAb 2909. Despite this overall similarity in binding, however, differences in specific amino acid and glycosylation pattern requirements for MAb 2909 and the rhesus MAbs were identified. These results highlight similarities in the B-cell responses of humans and macaques to structurally complex neutralization epitopes on related viruses, HIV-1 and SHIV.
Subject(s)
Antibodies, Neutralizing/immunology , HIV Antibodies/immunology , HIV Infections/immunology , HIV-1/immunology , Amino Acid Substitution , Animals , Epitopes , Gene Products, env/chemistry , Gene Products, env/immunology , Glycosylation , Humans , Macaca mulatta , Simian Acquired Immunodeficiency Syndrome/immunology , Virion/immunology , env Gene Products, Human Immunodeficiency Virus/chemistry , env Gene Products, Human Immunodeficiency Virus/immunologyABSTRACT
For many years only two human monoclonal antibodies (HMAbs) recognizing the CD4 induced (CD4i) epitopes of HIV-1 gp120 existed. Although a number of new CD4i HMAbs have been published recently, we have noted that in most attempts to produce HMAbs using EBV transformation a majority of antibodies produced in culture are lost within a few weeks. To determine what kinds of antibodies are made in these cultures we devised a semiquantitative culture to assess the frequency of B cells capable of producing antibodies and a microcompetition assay to determine what kinds of antibodies were made. Our results show that in three patients started on HAART during acute infection the most frequently produced antibodies binding to gp120 were directed against the CD4i epitopes. Our observations suggest that CD4i epitopes are much more immunogenic than had been previously appreciated. It is possible that envelope glycoproteins shed from virions and perhaps complexed with CD4 are responsible for eliciting these antibodies. The preservation of well regulated immune responses in these patients, together with repeated exposure to viral antigens (i.e. env), may explain the presence of larger than usual numbers of env-specific B cells that could be detected in EBV transformed cultures.
