Here we showed the results of end-point titrations of an identical SHIV-C stock as a function of the challenge route (i.v. versus i.r.) and the presence or absence of parasites in Chinese-origin RM. Together, our data showed: 1) the difference in AID50-i.v. for parasite-positive vs. parasite-free RM was 3.3-fold, which was not statistically significant; 2) in contrast, the difference in AID50-i.r. for parasite-positive vs. parasite-free RM was 17-fold (P<0.001) with very similar numbers of RM per experimental group; and 3) peak viral RNA loads differed only among i.r. challenged but not i.v. challenged groups of schistosome positive vs. parasite-free RM.
The fact that the 3.3-fold difference in AID50-i.v. was not statistically significant, whereas the difference for the AID50-i.r. was, needs to be interpreted with caution given the constraints of our study. Primate studies with their inherently high costs limit the numbers of experimental animals that can be enrolled. Much larger group sizes than we were able to use may find that parasitized hosts challenged intravenously develop systemic infection at statistically significantly lower viral inocula compared to parasite-free hosts. Our current data would predict that such a difference would be smaller than that for the mucosal virus challenge.
Overall, our data indicate that the increased host susceptibility to the R5 SHIV-C is predominantly due to parasite-induced changes at the mucosal level. We postulate that host factors of the mucosal innate and adaptive immune systems will be implicated. The nature of our virus challenge study mandated not disturbing the mucosa for tissue sampling. Future studies should seek to identify the exact mechanism(s) involved in mucosally-mediated upregulation of host susceptibility to an R5 AIDS virus in the presence of acute S. mansoni infection.
The increased susceptibility of S. mansoni
-infected monkeys to i.r. viral exposure may be related to the passage of eggs from the bloodstream, where the adult worms reside, to the lumen of the gut. Egg excretion in schistosome-infected hosts is dependent on cellular immune responses 
and is thought to be facilitated by the granulomatous response to parasite eggs 
. As a result, schistosomiasis is associated with increased numbers of activated T cells in the intestinal mucosa, along with disruption of the epithelial cell layer integrity as eggs exit the tissue. However, this does not necessarily result in bacterial translocation and transmission. Although a recent study in humans demonstrated an overall increased level of lipopolysaccharides (LPS) in the plasma of parasite-infected Kenyan individuals compared to uninfected controls, no differences were seen when LPS levels were compared between individuals with active egg excretion compared to those without 
. Similarly, we found no evidence of elevated LPS levels in the plasma of schistosome-infected RM in a previous study (unpublished data).
In S. haematobium
infections, adult worms live in the blood vessels surrounding the bladder instead of the intestine. Eggs are excreted into the bladder and pass out of the host in the urine. However, the worms can reside in other areas of the urogenital vasculature and eggs often become lodged in other nearby organs, especially in women, and can cause female urogenital schistosomiasis (FUS). The latter is associated with “sandy patches” (yellow, grainy areas), neovascularization, and contact bleeding of the cervix and vaginal wall as a result of the inflammation in response to the eggs. In studies in Zimbabwe and Tanzania, FUS was associated with a 2.7 to 4-fold higher risk of HIV-1 acquisition 
. Furthermore, the scarring of the cervix and vaginal wall caused by FUS may increase a woman's risk for HIV-1 infection throughout life if she does not receive treatment at a young age 
. This has led to suggestions that treatment of schistosomiasis could be a low-cost intervention to reduce transmission of HIV-1 in areas of sub-Saharan Africa where this parasite is endemic.
While our primate model studies have focused on the role of parasites in facilitating lentiviral acquisition, other investigators have examined the role of parasites on HIV-1 disease progression. Parasitic worms elevate viral loads and exacerbate destruction of CD4 cells in chronic AIDS virus infection. Both studies in experimental animals 
and intent-to-treat studies in people with either schistosomiasis 
or soil-transmitted helminthes 
showed elevated viral replication in groups with active parasitic infections compared to control groups that were never infected with schistosomes or that had received treatment for their worms.
Helminth infections in pregnant women, with associated higher viral loads, may also increase the risk of mothers transmitting HIV-1 infections to their infants 
. The majority of maternal HIV-1 transmissions are thought to occur intrapartum via mucosal exposure of the fetus 
. It is possible that parasite infection of the mother increases the HIV-1 burden in cervico-vaginal secretions, thereby increasing the risk of passing the virus to the infant.
Our current study, together with previous reports, clearly suggests that schistosomiasis increases the risk of immunodeficiency virus acquisition predominantly at the mucosal level. While the conclusions of our earlier intrarectal challenge study are not directly applicable to other routes of HIV-1 exposure among humans, our primate model data provide a proof of concept that alterations in the mucosal environment enhance HIV-1 transmission in schistosome-infected hosts. Our conclusions are also consistent with studies showing FUS as a risk factor for HIV-1 infection and the greater role of heterosexual transmission of HIV-1 in sub-Saharan Africa than in more industrialized countries that do not have endemic schistosomiasis. Thus, treatment for parasitic infections in populations at high risk for HIV-1 acquisition could represent a cost-effective approach to slow the spread of HIV-1. Furthermore, treatment of parasites in individuals with HIV-1 coinfection could lower viral RNA loads, which in turn would decrease the infectivity of such persons and slow their HIV-1 disease progression.