Dense Genotyping of Immune-Related Loci Identifies Variants Associated with Clearance of HPV among HIV-Positive Women in the HIV Epidemiology Research Study (HERS)

Abstract

Persistent high-risk human papillomavirus (HR-HPV) is a necessary and causal factor of cervical cancer. Most women naturally clear HPV infections; however, the biological mechanisms related to HPV pathogenesis have not been clearly elucidated. Host genetic factors that specifically regulate immune response could play an important role. All HIV-positive women in the HIV Epidemiology Research Study (HERS) with a HR-HPV infection and at least one follow-up biannual visit were included in the study. Cervicovaginal lavage samples were tested for HPV using type-specific HPV hybridization assays. Type-specific HPV clearance was defined as two consecutive HPV-negative tests after a positive test. DNA from participants was genotyped for 196,524 variants within 186 known immune related loci using the custom ImmunoChip microarray. To assess the influence of each single-nucleotide polymorphism (SNP) with HR-HPV clearance, the Cox proportional hazards model with the Wei-Lin-Weissfeld approach was used, adjusting for CD4+ count, low risk HPV (LR-HPV) co-infection, and relevant confounders. Three analytical models were performed: race-specific (African Americans (n = 258), European Americans (n = 87), Hispanics (n = 55), race-adjusted combined analysis, and meta-analysis of pooled independent race-specific analyses. Women were followed for a median time of 1,617 days. Overall, three SNPs (rs1112085, rs11102637, and rs12030900) in the MAGI-3 gene and one SNP (rs8031627) in the SMAD3 gene were associated with HR-HPV clearance (p<10−6). A variant (rs1633038) in HLA-G were also significantly associated in African American. Results from this study support associations of immune-related genes, having potential biological mechanism, with differential cervical HR-HPV infection outcomes.

HPV Infection and Cervical Abnormalities in HIV Positive Women in Different Regions of Brazil, a Middle-Income Country

“…HPV infection is an important STD and is considered the most prevalent in the world and the main factor in the genesis of SCC (Shrestha et al, 2010;Smith-McCune et al, 2010). HPV-DNA is present in 99.7% of all SCC (Sudenga et al, 2014); HPV-16 and HPV-18 are the genotypes most frequently associated with this type of cancer (McKenzie et al, 2010;Firnhaber et al, 2011). The majority of HPV infected patients are able to clear the infection naturally, and only a small proportion will progress to SCC (Sudenga et al, 2014).…”

“…HPV-DNA is present in 99.7% of all SCC (Sudenga et al, 2014); HPV-16 and HPV-18 are the genotypes most frequently associated with this type of cancer (McKenzie et al, 2010;Firnhaber et al, 2011). The majority of HPV infected patients are able to clear the infection naturally, and only a small proportion will progress to SCC (Sudenga et al, 2014). The most important protective immune mechanism is the suppression or elimination of the HPV virus and the immune response mediated by cells within 1-2 years of exposure (Rosa et al, 2008).…”

“…The most important protective immune mechanism is the suppression or elimination of the HPV virus and the immune response mediated by cells within 1-2 years of exposure (Rosa et al, 2008). A persistent infection of the HR-HPV genotypes is considered the most important factor for the development of cervical lesions and progression to SCC; however, it is not a sufficient cause (Sudenga et al, 2014). There are other factors that can contribute to the emergence and progression of the lesion, for example, high viral load, number of pregnancies, use of oral contraceptives, smoking, immunosuppression, other STD infections and genetic predisposition (Rosa et al, 2008).…”

“…Its incidence varies between different regions, and it is well established that it is higher in developing countries than in developed countries (Ferlay et al, 2010;Sudenga et al, 2014). The estimated unadjusted SCC incidence rate in 2014 was 15.3/100,000 women in Brazil; it is the third most prevalent non-melanoma cancer among women in Brazil, with differences around all territories.…”

Cancer prevention in HIV-infected populations

“…Quantitative defects in perforin granule release by CD8+ T cells in HPV/HIV co-infected patients may further contribute to pathogenesis 81 . Polymorphisms in human genes that code for proteins targeted by E6 and E7 or those associated with IL-2 and IL-7 signaling are host factors that may further modulate HPV clearance 82,83 .…”