Sub-Saharan Africa represents 10% of the world's population but more than 70% of the world's HIV/AIDS cases. While it remains controversial whether HIV transmission and/or disease progression in sub-Saharan Africa differ from those seen in industrialized countries, the high prevalence of parasitic worm infections may contribute to an exacerbation of HIV/AIDS. Such infections not only cause chronic immune activation, but can also skew the immune response towards a T-helper type 2 (Th2) cytokine profile. Both factors may accelerate HIV disease progression in coinfected individuals. In addition, animal model studies have shown that vaccines that normally induce strong cellular immunity failed to do so in Schistosoma mansoni-infected animals. This raises concerns that CTL response-based AIDS vaccines may not generate sufficient cellular immunity in individuals with helminth infections. We have generated a simian-human immunodeficiency virus (SHIV) that encodes env of a primary HIV clade C isolate from sub-Saharan Africa. This virus was adapted to rhesus macaques, transmitted mucosally, and caused AIDS in one monkey, from which we generated an infectious molecular clone, SHIV-1157ipd3. This new R5 virus replicated to high levels in monkey PBMC. Pilot studies show that S. mansoni co-infection intensifies SHIV clade C viremia. We therefore postulate that chronic helminth infection will exacerbate SHIV clade C-induced pathology. We furthermore hypothesize that the predominant Th2 cytokine milieu induced by parasite infection will significantly lower the efficacy of candidate CTL-inducing AIDS vaccines but not the efficacy of vaccines designed to generate neutralizing antibodies. The overall goal of this proposal is to dissect the host-pathogen dynamics in SHIV clade C / S. mansoni coinfected macaques and to assess antiviral immune responses.
The specific aims are to address the following questions: 1. Are S. mansoni infected macaques more susceptible to rectally or intravenously transmitted virus compared to parasite-free macaques? These experiments will be conducted with SHIV-1157ipd3. 2. Does coinfection with S. mansoni increase viremia and disease progression in macaques with chronic SHIV- 1157ipd3 infection and/or enhance viral shedding into mucosal fluids? 3. Does S. mansoni infection alter the immunogenicity and efficacy of AIDS vaccine candidates by skewing the host cytokine milieu? Efficacy will be tested through SHIV-1157ipd3 challenge. a) Are immunogenicity and efficacy of CTL response-based lentiviral vaccines reduced when given to macaques with S. mansoni infection compared to parasite-free animals? b) Is the efficacy of a neutralizing antibody response-based AIDS vaccine altered by S. mansoni coinfection? The proposed studies are significant because of their focus on the interactions of two pathogens that have major public health impacts in sub-Saharan Africa, where a safe and effective AIDS vaccine is most urgently needed. These studies will provide valuable information whether parasitic helminth infections significantly alter HIV/AIDS pathogenesis and/or immunogenicity and efficacy of two different AIDS vaccine strategies.
