Evolution of envelope-specific antibody responses in monkeys experimentally infected or immunized with simian immunodeficiency virus and its association with the development of protective immunity

Abstract

Previous studies of attenuated simian immunodeficiency virus (SIV) vaccines in rhesus macaques have demonstrated the development of broad protection against experimental challenge, indicating the potential for the production of highly effective immune responses to SIV antigens. However, the development of this protective immune status was found to be critically dependent on the length of time postvaccination with the attenuated virus strain, suggesting a necessary maturation of immune responses. In this study, the evolution of SIV envelopespecific antibodies in monkeys experimentally infected with various attenuated strains of SIV was characterized by using a comprehensive panel of serological assays to assess the progression of antibodies in longitudinal serum samples that indicate the development of protective immunity. In parallel studies, we also used the same panel of antibody assays to characterize the properties of SIV envelope-specific antibodies elicited by inactivated whole-virus and envelope subunit vaccines previously reported to be ineffective in producing protective immunity. The results of these studies demonstrate that the evolution of protective immunity in monkeys inoculated with attenuated strains of SIV is associated with a complex and lengthy maturation of antibody responses over the first 6 to 8 months postinoculation, as reflected in progressive changes in antibody conformational dependence and avidity properties. The establishment of long-term protective immunity at this time in general parallels the absence of further detectable changes in antibody responses and a maintenance of relatively constant antibody titer, avidity, conformational dependence, and the presence of neutralizing antibody for at least 2 years postinoculation. In contrast to the mature antibody responses elicited by the attenuated SIV vaccines, the whole-virus and envelope subunit vaccines in general elicited only immature antibody responses characterized by poor reactivity with native envelope proteins, low avidity, low conformational dependence, and the absence of neutralization activity against the challenge strain. Thus, these studies establish for the first time an association between the effectiveness of experimental vaccines and the capacity of the vaccine to produce a mature antibody response to SIV envelope proteins and further indicate that a combination of several antibody parameters (including titer, avidity, conformational dependence, and virus neutralization) are superior to any single antibody parameter as prognostic indicators to evaluate candidate AIDS vaccines.

Dissection of the humoral immune response toward an immunodominant epitope of HIV: a model for the analysis of antibody diversity in HIV+ individuals

“…For example, Cole et al have demonstrated that the evolution of protective immunity in monkeys inoculated with attenuated strains of SIV is associated with a complex and lengthy maturation of the humoral response over a prolonged period of 6 to 8 months postinoculation. This maturation is reflected in progressive increase in antibody titer and avidity (50). The extent of polyclonality of the response toward a given target must also be considered.…”

Factors Associated with Slow Disease Progression in Macaques Immunized with an Adenovirus-Simian Immunodeficiency Virus (SIV) Envelope Priming-gp120 Boosting Regimen and Challenged Vaginally with SIVmac251

“…Moreover, passive transfer of immune serum has protected macaques from infection (12,39,54,60). Primary-isolate neutralization and the development of a mature antibody response have also been correlated with protection of macaques against SIV infection (13,67). In contrast, macaques unable to mount an antibody response follow-ing exposure to SIV or SHIV quickly develop virulent infections and progress rapidly to AIDS and death (40,61,63).…”

A Pilot Study Comparing the Development of EIAV Env-Specific Antibodies Induced by DNA/Recombinant Vaccinia-Vectored Vaccines and an Attenuated Chinese EIAV Vaccine

“…Studies of lentiviral attenuated vaccines have indicated that sustained low levels of antigen presentation and consistent stimulation of the host immune system are required to achieve and sustain adequate immune maturation, thereby effectively protecting vaccinees against exposure to lentiviruses (2,4). These results suggest that other EIAV vaccines, such as DNA vaccines or live viral vector-based vaccines, might also be effective if they are based on regimens of multiple antigen exposure and/or sustained antigen presentation.…”