Acute Schistosoma mansoni infection increases susceptibility to systemic SHIV clade C infection in rhesus macaques after mucosal virus exposure

Abstract

Background: Individuals living in sub-Saharan Africa represent 10% of the world's population but almost 2/3 of all HIV-1/AIDS cases. The disproportionate HIV-1 infection rates in this region may be linked to helminthic parasite infections that affect many individuals in the developing world. However, the hypothesis that parasite infection increases an individual's susceptibility to HIV-1 has never been prospectively tested in a relevant in vivo model.

Methodology/principal findings: We measured whether pre-existing infection of rhesus monkeys with a parasitic worm would facilitate systemic infection after mucosal AIDS virus exposure. Two groups of animals, one consisting of normal monkeys and the other harboring Schistosoma mansoni, were challenged intrarectally with decreasing doses of R5-tropic clade C simian-human immunodeficiency virus (SHIV-C). Systemic infection occurred in parasitized monkeys at viral doses that remained sub-infectious in normal hosts. In fact, the 50% animal infectious (AID(50)) SHIV-C dose was 17-fold lower in parasitized animals compared to controls (P<0.001). Coinfected animals also had significantly higher peak viral RNA loads than controls (P<0.001), as well as increased viral replication in CD4(+) central memory cells (P = 0.03).

Conclusions/significance: Our data provide the first direct evidence that acute schistosomiasis significantly increases the risk of de novo AIDS virus acquisition, and the magnitude of the effect suggests that control of helminth infections may be a useful public health intervention to help decrease the spread of HIV-1.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1. Parasitologic and immunologic changes in rhesus macaques infected with Schistosoma mansoni.

(A) Eggs per gram feces in stool samples and percent eosinophils in blood from monkeys that were infected with S. mansoni; (B) IL-4 mRNA expression in PBMC of all S. mansoni-positive rhesus monkeys prior to exposure to SHIV-C. The ratios of IL-4 mRNA copies to mRNA copies of the housekeeping gene PDH are shown. Lines represent group medians. Statistical analysis of data in panel B was performed using the Wilcoxon rank-sum test.

Figure 2. Virology and T cell subsets of schistosome infected and control animals following exposure to SHIV-C.

(A) Peak vRNA loads (week 2 post-inoculation) and (B) longitudinal vRNA loads in coinfected and parasite-free monkeys. (C) CD4+ and (D) CD8+ T cells in coinfected and parasite-free monkeys. Lines in panel (A) represent group medians. For panels (B), (C) and (D), points represent group means and error bars represent standard deviations. Statistical analysis of data in panel A was performed using the Wilcoxon rank-sum test. Data in panels B–D were analyzed using repeated measures analysis and generalized estimating equations to compare the data over time for the two groups.

Figure 3. Differences in CD4+ T cell subsets and cell viral loads between animals with S. mansoni/SHIV-C coinfection and SHIV-C infection alone.

(A) Phenotyping strategy used to separate naïve, central memory (CM), effector memory (EM) and effector memory CD45RA+ (EMRA) T cell subsets. Percentages demonstrate T cell subsets for one of the coinfected monkeys. (B) CD4+ naïve, CM and EM in coinfected and parasite-free monkeys. (C) SHIV-C RNA detected in CD4+ naïve, CM, and EM T cells after sorting. For panels (B) and (C), group means and standard deviations are represented.