Characterization of neutralization epitopes of simian immunodeficiency virus (SIV) recognized by rhesus monoclonal antibodies derived from monkeys infected with an attenuated SIV strain

A major limitation in the simian immunodeficiency virus (SIV) system has be en the lack of reagents with which to identify the antigenic determinants t hat are responsible for eliciting neutralizing antibody responses in macaqu es infected with attenuated SIV. Most of our information on SIV neutralizat ion determinants has come from studies with murine monoclonal antibodies (M Abs) produced in response to purified or recombinant SIV envelope proteins or intact SIV-infected cells for relatively short periods of time. While th ese studies provide some basic information on the potential immunogenic det erminants of SIV envelope proteins, it is unclear whether these murine MAbs identify epitopes relevant to antibody responses elicited in monkeys durin g infection with either wild-type or attenuated SIV strains. To accomplish maximum biological relevance, we developed a reliable method for the produc tion of rhesus monoclonal antibodies. In the present study, we report on th e production and characterization of a unique panel of monoclonal antibodie s derived from four individual monkeys inoculated with SIV/17E-CL as an att enuated virus strain at a time when protective immunity from pathogenic cha llenge was evident. Results from these studies identified at least nine bin ding domains on the surface envelope glycoprotein; these included linear de terminants in the V1, V2, cysteine loop (analogous to the V3 loop in human immunodeficiency virus type 1), and C5 regions, as well as conformational e pitopes represented by antibodies that bind the C-terminal half of gp120 an d those sensitive to defined mutations in the V4 region. More importantly, three groups of antibodies that recognize closely related, conformational e pitopes exhibited potent neutralizing activity against the vaccine strain. Identification of the epitopes recognized by these neutralizing antibodies will provide insight into the antigenic determinants responsible for elicit ing neutralizing antibodies in vivo that can be used in the design of effec tive vaccine strategies. (C) 2001 Academic Press.