Coinfection with S. mansoni significantly increased viral replication and induced alterations in the T-cell subsets in monkeys with chronic, clinically stable SHIV clade C infection. From week 5 after S. mansoni exposure onward, coinfected animals shed parasite eggs in the stool, developed eosinophilia, and expressed mRNA of the Th2 cytokine IL-4 at significantly higher levels than animals without schistosomiasis. Compared to virus-only controls, viral replication was significantly increased in the coinfected monkeys. Although the spikes in plasma viral RNA were transient, they coincided with the acute stage of schistosomiasis, when Th2 responses are strongest. In contrast to virus-only controls, the percentage of CD4+ CD29+ memory T cells decreased in the coinfected group starting from week 5 after coinfection until the end of follow-up.
The results of the present study support our previous observation that parasite infection upregulates R5 SHIV clade C replication (15
). In the earlier pilot study, no parasite-free, virus-only control group was enrolled in parallel to the coinfected group. Data from the present prospective, controlled trial support the hypothesis that S. mansoni
infection and the ensuing establishment of the Th2-skewed cytokine milieu reactivate latent virus and may promote immunologic deterioration.
Previous studies have demonstrated that a decrease in the percentage of CD4+
memory T cells is an early sign of immune dysfunction and a prognostic parameter for the development of subsequent immunodeficiency (4
). In our primate studies (4
; unpublished data), depletion of CD4+
memory T cells preceded the loss of absolute numbers of CD4+
T cells by several months to years. Within the time of follow-up of the current two groups of monkeys, we did not observe significant changes in either absolute CD4+
T-cell counts or CD4+
The transient character of the viral reactivation could possibly be ascribed to the transient nature of schistosome infections in rhesus macaques. Although these animals are permissive hosts for schistosomiasis in that they allow establishment of patent infections, most monkeys clear the parasites following the acute phase of infection without treatment intervention (30
). In humans, where schistosome infections are more persistent, the elevation of plasma viremia may similarly be prolonged. From these data, we cannot predict whether persons with chronic schistosomiasis would similarly experience increased viral replication or if only persons who have acute schistosomiasis would be affected. However, the observation that coinfected persons who received early treatment for their schistosomiasis demonstrated significantly lower increases in viral loads and CD4+
T-cell declines compared to persons whose treatment was delayed for as little as 3 months argues strongly that any schistosome infection in HIV-positive individuals promotes immunologic deterioration (24
Nonhuman primate studies, while imperfect models of human infection for schistosomes or immunodeficiency viruses, may provide important insights into disease progression and extend the ability to address questions that are difficult to evaluate in human populations. For example, our previous rhesus coinfection study (15
) showing that acute immunodeficiency virus replication is elevated in schistosome-infected monkeys and our present study showing reactivation of viral replication during the acute phase of schistosomiasis would be impossible to assess in humans. Another area in which the primate coinfection model may prove useful is the assessment of HIV-1 vaccine efficacy in the presence of helminths. The effects of schistosomiasis and other helminthic infections on the modulation of immune responses are well established (3
), and alterations in response to vaccination as a consequence of schistosome infection have been demonstrated (35
). It is likely that human field trials testing the efficacy of HIV candidate vaccines will take place in Africa and Asia, areas with a high incidence of HIV infections. However, potentially effective vaccines may show suboptimal results if such clinical trials are confounded by the immune activation and/or cytokine profiles that may be shifted by helminth infections that predominate in the developing world. Well-planned studies utilizing the nonhuman primate model for parasite-immunodeficiency virus coinfection as described here, in which pathogens, timing, route, and dose can be controlled, may yield critical adjunctive information for the successful implementation of HIV-1 and other vaccination programs.