Maturation of envelope‐specific antibody responses to linear determinants in monkeys inoculated with attenuated SIV

Abstract

We have previously used a panel of quantitative and qualitative serological assays to define a lengthy and complex maturation of envelope-specific antibody responses in monkeys experimentally infected with attenuated simian immunodeficiency virus (SIV) that is closely associated with the temporal development of enduring and protective immunity to experimental virus challenge. To elucidate in more detail the changes in antibody specificity associated with this maturation, we describe here 'domain-specific' serological studies to characterize the evolution of antibody responses to defined linear determinants of the SIV envelope protein. The results of these studies reveal for the first time distinguishing differences in the evolution of antibody populations to distinct envelope peptide segments, as determined by measurements of antibody titer and avidity, indicating different patterns of antibody maturation to distinct linear envelope antigenic determinants. Thus, these data demonstrate the potential for domain-specific serology to produce a high-resolution characterization of SIV-specific antibody responses that can be used to evaluate experimental vaccine responses and to identify potential immune correlates of protection.

Immunization of Newborn Rhesus Macaques with Simian Immunodeficiency Virus (SIV) Vaccines Prolongs Survival after Oral Challenge with Virulent SIVmac251

“…This pattern displayed by the MVA-SIVgpe-immunized group 4 monkeys is similar to that previously observed for some HIV-infected people (6). In contrast, the development of a high anti-SIV Env antibody response with a gradual increase in avidity and decrease of the conformational dependence observed for all four SIVmac1A11-immunized animals is consistent with that reported previously for juvenile and adult macaques infected with other attenuated or pathogenic strains of SIV (6,8) and indicates that antibody responses are broadening to also include fewer conformational epitopes (i.e., including linear epitopes) (7). Despite these different patterns, there was no detectable correlation between these changes in antibody quality and virus levels or disease progression, a finding that suggests that the role of antibody quality on virus replication and the disease course in infants is not clear.…”

“…2). For the purpose of further discussions, viral RNA levels were classified as high (Ͼ10 8 RNA copies/ml), moderate (between 10 7 and 10 8 RNA copies/ml), or low (Ͻ10 7 RNA copies/ml). For the unimmunized control animals ( Table 1, group 1), virus levels in plasma remained persistently high (four animals) or moderate (animal 31608) until the time of death (Fig.…”

Removal of N-Linked Glycosylation Sites in the V1 Region of Simian Immunodeficiency Virus gp120 Results in Redirection of B-Cell Responses to V3

“…For these assays, antibody reactivity to a panel of overlapping 20-mer synthetic peptides representing the 5Ј half of the SIVmac239 amino acid sequence was used. Plasma samples were diluted 1:200 and assayed for reactivity to individual peptides in a PLL peptide ELISA (12). Results from these studies are summarized in Fig.…”

“…To address the need for higher-resolution analyses of antibody responses to envelope glycoproteins, we have developed additional serological assays to monitor antibody responses to defined envelope domains (12). Plasma antibody responses to linear envelope determinants were measured in plasma samples taken 8, 24, and 40 weeks after infection with WT SIVmac239 or glycosylation mutant viruses.…”

“…Antibody responses directed to synthetic 20-mer peptides, overlapping by 10 amino acids and representing the first 350 amino acids of the SIVmac239 gp120 sequence (kindly provided by the NIH AIDS Research and Reference Reagent Program), were measured in a poly-L-lysine (PLL) peptide ELISA as described previously (12). Briefly, synthetic peptides were fixed in the PLL-coated wells of microtiter plates in an overnight incubation at room temperature.…”