Abstract
BackgroundOral infection of infant macaques with simian immunodeficiency virus (SIV) is a useful animal model to test interventions to reduce postnatal HIV transmission via breast-feeding. We previously demonstrated that immunization of infant rhesus macaques with either modified vaccinia virus Ankara (MVA) expressing SIV Gag, Pol and Env, or live-attenuated SIVmac1A11 resulted in lower viremia and longer survival compared to unimmunized controls after oral challenge with virulent SIVmac251 (Van Rompay et al., J. Virology 77:179–190, 2003). Here we evaluate the impact of these vaccines on oral transmission and evolution of SIV envelope variants.ResultsLimiting dilution analysis of SIV RNA followed by heteroduplex mobility assays of the V1–V2 envelope (env) region revealed two major env variants in the uncloned SIVmac251 inoculum. Plasma sampled from all infants 1 week after challenge contained heterogeneous SIV env populations including one or both of the most common env variants in the virus inoculum; no consistent differences in patterns of env variants were found between vaccinated and unvaccinated infants. However, SIV env variant populations diverged in most vaccinated monkeys 3 to 5 months after challenge, in association with the development of neutralizing antibodies.ConclusionsThese patterns of viral envelope diversity, immune responses and disease course in SIV-infected infant macaques are similar to observations in HIV-infected children, and underscore the relevance of this pediatric animal model. The results also support the concept that neonatal immunization with HIV vaccines might modulate disease progression in infants infected with HIV by breast-feeding.
Highlights
Oral infection of infant macaques with simian immunodeficiency virus (SIV) is a useful animal model to test interventions to reduce postnatal HIV transmission via breast-feeding
Three major questions were addressed: (i) Compared to the SIVmac251 virus inoculum, are few SIV envelope variants transmitted orally?, (ii) Is the lower viremia and better clinical outcome of vaccinated infants related to the initial genetic diversity of SIV env quasispecies?, and, (iii) Is the evolution of SIV envelope quasispecies during the course of infection associated with the development of SIV neutralizing antibody? We demonstrate that while the vaccines did not modulate oral transmission of viral variants, an association was found between vaccine-induced enhanced antiviral immune responses, increased env diversity, and a slower disease course
Characterization of variants in SIVmac251-5/98 virus stock heteroduplex mobility assay (HMA) analysis revealed that the undiluted SIVmac251-5/ 98 virus stock was comprised of a diverse population of V1–V2 env variants
Summary
Oral infection of infant macaques with simian immunodeficiency virus (SIV) is a useful animal model to test interventions to reduce postnatal HIV transmission via breast-feeding. The continued need for breast-feeding in developing countries due to nutritional or socio-economic reasons poses a considerable risk for postnatal mother-to-child transmission of HIV, and breastfeeding is estimated to account for 33–50% of infant HIV infections worldwide [1,2,3,4,5]. This dilemma underscores the need for a vaccine that, when administered shortly after birth to the infant, could protect against HIV transmission via breast-feeding. The presence in infants of different levels of transplacentally transferred HIV-specific maternal antibodies with differing anti-viral properties complicates assessments of HIV variant transmission
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