The role of the microbiome in HPV-associated cervical cancer in women with HIV

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Cervical cancer remains an important cause of morbidity and mortality in women, in particular in HIV-infected women in low and middle-income countries (LMIC), such as South Africa. Testing for human papilloma virus (HPV), the etiological agent of cervical cancer has significantly improved screen-and-treat approaches at the point of care in LMIC. However, although persistence of high-risk HPV types is the primary cause of precancerous cervical intraepithelial neoplasia grade 2 and 3 (CIN2+) and invasive cervical carcinoma (ICC), its detection has a low positive predictive value, as only a small proportion of HPV+ women will progress to CIN or ICC. Therefore, there is a compelling need for “triaging” HPV-positive women, to reduce unnecessary treatment. Once precursor lesions are identified, they are treated by either ablative or excisional methods, depending on grade. Both of these methods have significant recurrence risk. Better predictors of high-risk recurrences at the time of treatment as well as potential markers for recurrence post-treatment are needed to drive down the incidence of cervical cancer. The key factors that promote cancer progression likely reside in the cervical environment, notably its local microbiome. Preliminary evidence suggests that increased bacterial diversity and the presence of Lactobacillus iners are associated with CIN2+. L. iners harbors a highly variable mobile genetic repertoire, containing methylases and toxins that may play a role in progression of cervical lesions. Elucidating which taxa or genes are predictive of disease state could enable the development of adjunct rapid diagnostics in HPV+ women. Here we propose to comprehensively study virus-microbiota-host interactions, specifically the interaction between HPV and lower genital tract commensal bacteria and fungi relevant to cervical cancer screening in HIV+ and HIV- women. Our group at Columbia University has a long- standing and highly-productive collaboration with the University of Cape Town, South Africa, with whom we have undertaken large clinical studies of cervical cancer prevention. We will leverage samples and clinical data already collected from two of these recent studies. In Aim 1, we will define whether the cervicovaginal bacterial and fungal communities distinguish between HPV-infected women who have or do not have CIN2+, stratified by HIV status. In Aim 2, we will test whether cervical microbial taxa at baseline, or changes in taxa over time, predict recurrence after ablative therapy at 6 or 12 months in women with HPV+/CIN2+. This will inform which patients require more monitoring, and guide the identification of potential “adjuvant” therapies to improve efficacy of screening programs by reducing recurrent disease after treatment. In Aim 3 we will apply metagenomics to identify microbial gene markers and structural genetic variants that predict cervical cancer treatment failure. Combined, our work will inform potential triage tests to reduce the number of women without cervical disease beginning treatment, increase the sensitivity for detecting women who are at high risk of treatment failure, and yield mechanistic insights to help guide the future development of adjunct therapeutics.