Persistent effects of early infant diet and associated microbiota on the juvenile immune system.

Early infant diet has significant impacts on the gut microbiota and developing immune system. We previously showed that breast-fed and formula-fed rhesus macaques develop significantly different gut microbial communities, which in turn are associated with different immune systems in infancy. Breast-fed animals manifested greater T cell activation and proliferation and harbored robust pools of T helper 17 (TH17) cells. These differences were sustained throughout the first year of life. Here we examine groups of juvenile macaques (approximately 3 to 5 y old), which were breast-fed or formula-fed in infancy. We demonstrate that juveniles breast-fed in infancy maintain immunologic differences into the fifth year of life, principally in CD8(+) memory T cell activation. Additionally, long-term correlation networks show that breast-fed animals maintain persistent relationships between immune subsets that are not seen in formula-fed animals. These findings demonstrate that infant feeding practices have continued influence on immunity for up to 3 to 5 y after birth and also reveal mechanisms for microbial modulation of the immune system

Role of CD8+ cells in controlling replication of nonpathogenic Simian Immunodeficiency Virus SIVmac1A11

Infection of macaques with the avirulent molecular clone SIVmac1A11 results in transient low viremia and no disease. To investigate if this low viremia is solely due to intrinsic poor replication fitness or is mediated by efficient immune-mediated control, 5 macaques were inoculated intravenously with SIVmac1A11. Three animals that were depleted of CD8+ cells at the start of infection had more prolonged viremia with peak virus levels 1 to 2 logs higher than those of 2 animals that received a non-depleting control antibody. Thus, CD8+ cell-mediated immune responses play an important role in controlling SIVmac1A11 replication during acute viremia

Simian immunodeficiency virus (SIV) envelope quasispecies transmission and evolution in infant rhesus macaques after oral challenge with uncloned SIVmac251: increased diversity is associated with neutralizing antibodies and improved survival in previously immunized animals

BACKGROUND: 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. 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. RESULTS: Limiting 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. CONCLUSIONS: These 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

Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection.

BackgroundWe reported previously on the emergence and clinical implications of simian immunodeficiency virus (SIVmac251) mutants with a K65R mutation in reverse transcriptase (RT), and the role of CD8+ cell-mediated immune responses in suppressing viremia during tenofovir therapy. Because of significant sequence differences between SIV and HIV-1 RT that affect drug susceptibilities and mutational patterns, it is unclear to what extent findings with SIV can be extrapolated to HIV-1 RT. Accordingly, to model HIV-1 RT responses, 12 macaques were inoculated with RT-SHIV, a chimeric SIV containing HIV-1 RT, and started on prolonged tenofovir therapy 5 months later.ResultsThe early virologic response to tenofovir correlated with baseline viral RNA levels and expression of the MHC class I allele Mamu-A*01. For all animals, sensitive real-time PCR assays detected the transient emergence of K70E RT mutants within 4 weeks of therapy, which were then replaced by K65R mutants within 12 weeks of therapy. For most animals, the occurrence of these mutations preceded a partial rebound of plasma viremia to levels that remained on average 10-fold below baseline values. One animal eventually suppressed K65R viremia to undetectable levels for more than 4 years; sequential experiments using CD8+ cell depletion and tenofovir interruption demonstrated that both CD8+ cells and continued tenofovir therapy were required for sustained suppression of viremia.ConclusionThis is the first evidence that tenofovir therapy can select directly for K70E viral mutants in vivo. The observations on the clinical implications of the K65R RT-SHIV mutants were consistent with those of SIVmac251, and suggest that for persons infected with K65R HIV-1 both immune-mediated and drug-dependent antiviral activities play a role in controlling viremia. These findings suggest also that even in the presence of K65R virus, continuation of tenofovir treatment as part of HAART may be beneficial, particularly when assisted by antiviral immune responses

Empowering the people: Development of an HIV peer education model for low literacy rural communities in India

<p>Abstract</p> <p>Background</p> <p>Despite ample evidence that HIV has entered the general population, most HIV awareness programs in India continue to neglect rural areas. Low HIV awareness and high stigma, fueled by low literacy, seasonal migration, gender inequity, spatial dispersion, and cultural taboos pose extra challenges to implement much-needed HIV education programs in rural areas. This paper describes a peer education model developed to educate and empower low-literacy communities in the rural district of Perambalur (Tamil Nadu, India).</p> <p>Methods</p> <p>From January to December 2005, six non-governmental organizations (NGO's) with good community rapport collaborated to build and pilot-test an HIV peer education model for rural communities. The program used participatory methods to train 20 NGO field staff (Outreach Workers), 102 women's self-help group (SHG) leaders, and 52 barbers to become peer educators. Cartoon-based educational materials were developed for low-literacy populations to convey simple, comprehensive messages on HIV transmission, prevention, support and care. In addition, street theatre cultural programs highlighted issues related to HIV and stigma in the community.</p> <p>Results</p> <p>The program is estimated to have reached over 30 000 villagers in the district through 2051 interactive HIV awareness programs and one-on-one communication. Outreach workers (OWs) and peer educators distributed approximately 62 000 educational materials and 69 000 condoms, and also referred approximately 2844 people for services including voluntary counselling and testing (VCT), care and support for HIV, and diagnosis and treatment of sexually-transmitted infections (STI). At least 118 individuals were newly diagnosed as persons living with HIV (PLHIV); 129 PLHIV were referred to the Government Hospital for Thoracic Medicine (in Tambaram) for extra medical support. Focus group discussions indicate that the program was well received in the communities, led to improved health awareness, and also provided the peer educators with increased social status.</p> <p>Conclusion</p> <p>Using established networks (such as community-based organizations already working on empowerment of women) and training women's SHG leaders and barbers as peer educators is an effective and culturally appropriate way to disseminate comprehensive information on HIV/AIDS to low-literacy communities. Similar models for reaching and empowering vulnerable populations should be expanded to other rural areas.</p