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.

We examined the rates of variant population turnover of the V1-V2 and V4-V5 hypervariable domains of the human immunodeficiency virus type 1 (HIV-1) gp120 molecule in longitudinal plasma samples from 14 men with chronic HIV-1 infection using heteroduplex tracking assays (HTA). Six men had high rates of CD4 ؉ T-cell loss, and eight men had low rates of CD4 ؉ T-cell loss over 2.5 to 8 years of infection. We found that V1-V2 and V4-V5 env populations changed dramatically over time in all 14 subjects; the changes in these regions were significantly correlated with each another over time. The subjects with rapid CD4 loss had significantly less change in their env populations than the subjects with slow CD4 loss. The two subjects with rapid CD4 loss and sustained low CD4 counts (<150/l for at least 2 years) showed stabilization of their V1-V2 and V4-V5 populations as reflected by low levels of total change in HTA pattern and low HTA indices (a novel measure of the emergence of new bands and band distribution); this stabilization was not observed in other subjects. The stabilization of env variant populations at low CD4 counts following periods of rapid viral evolution suggests that selective pressure on env, likely from new immune responses, is minimal when CD4 counts drop dramatically and remain low for extended periods of time.Human immunodeficiency virus type 1 (HIV-1) infection of an individual generates a population of related but distinct cocirculating viral variants (15). This high level of genetic diversity allows HIV-1 to adapt quickly to multiple selective pressures, including neutralizing antibodies, cytotoxic T lymphocytes, and antiretroviral drugs (17,21,(32)(33)(34)42). The highest level of diversity within the HIV genome is found in the env gene. The five hypervariable domains, named V1 through V5, form loops on the outside of the gp120 molecule (22). The V3 loop is involved in binding a chemokine receptor for viral entry after gp120 binds the CD4 receptor (40,43). Changes in the V3 domain determine in part whether HIV utilizes CCR5 (R5 variants) or CXCR4 (X4 variants) chemokine coreceptors (6). The V1-V2 loop is thought to interact with the V3 loop within the gp120 trimer on the virion surface (5, 23). The V4 and V5 domains are on a different face of gp120 than V1-V2 and V3 are (22) and are not directly involved in receptor binding.The V1-V2 and V4-V5 regions of gp120 are highly variable in sequence and length within an infected individual and between infected individuals (19,37,41). The domains are heavily glycosylated, and changes in the location and number of N-and O-linked glycosylation sites in the V1-V2 and V4-V5 regions are associated with escape from neutralization (reviewed in reference 29). Removal of some of the glycosylation sites from the V1 and V2 regions results in increased immunogenicity of the domains (31) and has been shown in one study to redirect the immune response toward V3 rather than V1-V2 (7). Sequence changes observed in V1-V2 and V3 to V5, including insertions, deletions, an...