UC San Diego

HIV-1 and Plasmodium falciparum malaria cause substantial morbidity in Sub-Saharan Africa, especially as co- infecting pathogens. However, many aspects of this interaction have not been fully delineated. We hypothesize that dual infection causes increased HIV expression and more rapid HIV disease progression and that activation of malaria-specific CD4+ T-cells in the presence of uncontrolled HIV replication leads to depletion of malaria -specific immunity. To better understand the effects of P. falciparum on HIV, we studied the interaction ex vivo using peripheral blood mononuclear cells (PBMCs) from human malaria naïve volunteers experimentally infected with P. falciparum in a malaria challenge trial and we used an in vitro co-culture system to study the mechanisms contributing to increased viral replication. To assess the effects of HIV on P. falciparum, we took advantage of a recently completed clinical trial of antiretroviral therapy to study the relationship between subpatent parasitemia (detection of parasites by methods more sensitive than blood smears, but without clinical malaria) and clinical disease and attempted to assess whether the HIV-1 protease inhibitor (PI) atazanavir reduced the rate of detection of plasma P. falciparum DNA. The ex vivo experiments showed an increase in HIV production and pro- inflammatory cytokine secretion that occurred after the parasitemia and generalized immune activation resolved, suggesting that enhanced HIV production is related to the development of anti-malaria immunity and may be mediated by pro-inflammatory cytokines. We also demonstrated that phagocytic, antigen presenting cells ingest P. falciparum infected red blood cells and stimulate CD4+ T-cells to produce HIV-1 in a cytokine- and contact-dependent manner. Lastly, subpatent parasitemia was not significantly associated with clinical malaria and HIV PI therapy did not decrease the prevalence of parasitemia. Taken together, our results suggest that while subpatent parasitemia may not lead to clinical disease, it may contribute to an increase in plasma HIV-1 RNA levels in untreated patients, especially upon repeat encounters with malaria parasites. It is plausible that any level of parasitemia may contribute to CD4+ T-cell activation, even in the presence of anti-retroviral therapy. Thus, it may be important to suppress parasitemia in HIV seropositive individuals, even if they are asymptomatic