This study is the first direct evidence showing that helminth infection significantly increases host susceptibility to mucosal AIDS virus transmission in primates. Systemic infection of S. mansoni
-infected rhesus macaques was established by low doses of virus that remained sub-infectious in parasite-free hosts, and the difference in viral dose needed to successfully establish systemic infection was surprisingly large. Furthermore, peak vRNA levels were also significantly elevated in schistosome-infected monkeys, consistent with previous in vitro, epidemiologic and primate model studies that suggest increased viral replication in schistosome-infected hosts or cells from persons with helminth infections 
. However, none of the earlier studies was able to address whether schistosome infection increased the likelihood of de novo
immunodeficiency virus infection in hosts harboring helminths. The increased susceptibility to mucosal immunodeficiency virus transmission we observed in schistosome-infected macaques, elevated viral replication in coinfected hosts, and accelerated loss of memory T cells all have profound public health implications for areas of the world where both parasitic worms and HIV-1 are endemic. Our data support the suggestion that better control of helminth infections may favorably impact efforts to reduce the spread of HIV/AIDS 
Our observations are consistent with the hypothesis that helminth infections increase a hosts' susceptibility to infection with immunodeficiency viruses and is associated with a Th2-type immunologic phenotype and increased viral replication within these cells 
. However, it is possible that any infection resulting in systemic immune activation or increased peripheral blood CD4+
T cell numbers () would have yielded similar results 
. Other data to support the hypothesis that Th2-type responses increase susceptibility to virus infection include the observation that PBMC from Kenyan schistosomiasis patients with HIV-1 coinfection produce decreased levels of IL-4 and IL-10 compared to patients with schistosomiasis alone. The magnitude of this effect correlates with the decrease in CD4+
T cells 
, suggesting that it is the CD4+
Th2 cells that are preferentially infected and killed by the virus. Alternatively, the shift to a predominant Th2-type response in schistosome-infected hosts may result in down-regulation of virus-controlling cytotoxic T lymphocytes 
. We will evaluate these possibilities more directly in future studies.
We also considered whether the biology of parasite egg excretion, combined with the rectal route of viral exposure, may have increased host susceptibility to virus. Fecal egg excretion in hosts infected with S. mansoni
or S. japonicum
increases the number of activated T cells associated with egg granulomas that are in close juxtaposition to the intestinal lining 
. Furthermore, the passage of eggs from mucosal tissue into the gut lumen may compromise the integrity of the epithelial lining, which in turn could lead to microbial translocation, release of immune-activating bacterial products into the bloodstream, and facilitate intrarectal SHIV-C transmission.
A limitation of our primate system is that we are only able to model the effect of the acute phase of schistosomiasis on susceptibility to viral transmission. This is because rhesus monkeys, while able to develop a fully patent infection, self cure their schistosomiasis at 20 to 25 weeks after exposure to cercariae 
. Thus, we were not able to assess whether animals exposed to immunodeficiency virus during the chronic, more immunologically regulated phase of schistosome infection similarly display increased susceptibility to viral transmission. If the increased susceptibility to viral infection is related to the shift towards a Th2-type immune response, the increase in susceptibility to virus may be more modest during chronic infections when the phenotypic shift is less dramatic. Nevertheless, in human hosts with chronic schistosomiasis, both the immunologic stimulation and Th2-type responses (e.g., eosinophilia) persist. In addition, surface levels of the chemokine coreceptors CCR5 and CXCR4 are elevated on CD4+
T cells and monocytes of persons with chronic schistosomiasis and decrease following praziquantel treatment 
Our data strengthen the hypothesis that helminth infection may be a risk factor for increased susceptibility to de novo HIV-1 infection and support control of schistosomiasis and perhaps other helminths in persons living in areas endemic for these parasites. In the absence of an effective AIDS vaccine, there are several other strategies that may help decrease the risk of HIV-1 transmission, including control of sexually transmitted diseases 
and male circumcision 
. Treatment of helminth infections is inexpensive, safe, and easily administered to large populations. In addition to the benefit of reducing host morbidity caused by the parasites, our data support control of helminths as a public health intervention for individuals at risk for acquiring HIV-1.