Effect of Schistosomiasis Mansoni on HIV Susceptibility and Female Genital Immunology

Effect of Schistosomiasis Mansoni and Its Treatment on HIV Susceptibility and Female Genital Immunology

The aim of this study is to assess the impact of Schistosoma mansoni infection and its treatment on genital immunology and HIV susceptibility in Ugandan women.

Schistosomiasis mansoni is a water-borne disease caused by helminth Schistosoma mansoni (S. mansoni), in which adult worms deposit eggs in mesenteric blood vessels. Schistomiasis prevalence in the fishing communities in East Africa, and particularly in the Lake Victoria region, exceeds 60% and there is overlap in this region with a high prevalence of HIV (29%). A recent epidemiological study found an association between S. mansoni and HIV infection in adult women residing near Lake Victoria in Tanzania. Furthermore, in primate studies S. mansoni infection was shown to increase susceptibility to SIV infection after rectal (but not intravenous) challenge, implying that S. mansoni might increase HIV susceptibility by altering local mucosal (gut) immunology. While S. mansoni does not directly infect the genital tract, we hypothesize that the inflammation it causes in the gut may be associated with mucosal inflammation at other sites through activation of common mucosal homing integrins such as a4b7. Therefore in this study we propose to explore whether S. mansoni increases inflammation and/or HIV susceptibility in the endocervix of adult women. HIV-uninfected adult women from Entebbe, Uganda will be screened for schistosomiasis using a commercial CCA rapid test kit, and infected women who fulfill the study eligibility criteria will be recruited into the study. Kato-Katz microscopy analysis will be performed to assess egg shedding at baseline. Additionally, urine microscopy will be done to screen for Schistosoma hematobium (which can directly involve the genital mucosa). Schistosomiasis treatment will be provided to all participants according to Ugandan clinical guidelines. Endocervical cytobrush, vaginal SoftCup and blood samples will be collected at three time points; at baseline and 4 and 8 weeks after schistosomiasis treatment, at the same stage of the menstrual cycle. Using an ex vivo HIV entry assay and mucosal cytokine and microbiome analyses we will quantify the effect of S. mansoni and its treatment on cervical HIV susceptibility and genital inflammation.

Schistosomiasis mansoni, HIV susceptibility, Genital immunology, Mucosal immunology, HIV entry assay, Adult women

Participants will be HIV-uninfected women with asymptomatic Schistosoma mansoni infection; the study will examine the impact of standard praziquantel therapy (40 mg/kg po single dose) on genital immunology and HIV susceptibility.

Change in the percentage of endocervical CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis.

The percentage of endocervical CD4+ T cells per cytobrush infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.

Change in the number of endocervical CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis.

The number of endocervical CD4+ T cells per cytobrush infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.

Change in the percentage of blood CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis.

The percentage of blood CD4+ T cells infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.

Surface expression of CCR5, CD69, CD38, HLA-DR, a4b7, CCR7 and CD45RA by endocervical and blood CD4 T will be assessed using flow cytometry.

A predefined genital inflammation score based on genital levels of pro-inflammatory cytokines and chemokines [as per Arnold K et al, Muc Immunol, 2015] will be assessed.

The cervico-vaginal microbiome will be assessed by 16s rRNA sequencing before and after schistosomiasis therapy.

Change in the percentage of endocervical CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis.

The percentage of endocervical CD4+ T cells per cytobrush infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.

Change in the number of endocervical CD4+ T cells susceptible to HIV pseudovirus entry after treatment of schistosomiasis.

The number of endocervical CD4+ T cells per cytobrush infected ex vivo by an HIV pseudovirus construct, as quantified by flow cytometry.

Inclusion Criteria: Positive (score above "trace") on a urine CCA rapid test Willing to be treated with praziquantel Willing to give informed consent, and answer short questionnaires on economic status, and sexual risk behavior. Willing to comply with the requirements of the protocol HIV and classical STI (see below) negative Exclusion Criteria: HIV infected Malaria infected Pregnant. Irregular menstrual cycle, or actively menstruating at the time of genital sampling. Tested positive for classical STIs (syphilis, gonorrhea, chlamydia, Trichomonas vaginalis) or having genital ulcers Prior hysterectomy Deemed by physician to be unlikely to complete study protocol.

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