Role of human papillomavirus (HPV) variants and host genetic susceptibility in cervical carcinogenesis

Cervical carcinoma continues to be one of the leading causes of cancer-related mortality among women worldwide, disproportionately striking developing regions, including India. High-risk persistent HPV infection has long been recognized as the central etiological factor in cervical carcinogenesis; however, not all infected women end up with malignancy, indicating the role of viral genomic variation and host genetic susceptibility. High-risk HPV variants, primarily comprising lineage clusters of HPV16 and HPV18, exhibit differential oncogenic potential due to mutations in the E6/E7 oncogenes and the LCR, which is responsible for viral persistence, the efficiency of p53/pRb degradation, immune evasion, and epithelial cell transformation. Genetic polymorphisms in the host regulate the natural history of infection and cervical cancer risk. Variants of HLA class I/II alleles influence antigen presentation and Single nucleotide polymorphism in immune regulatory cytokine genes (IL-10, TNF-α, IFN-γ), TP53 codon 72 (Arg/Pro), DNA repair and metabolic genes (XRCC1, MTHFR), and detoxification gene null genotypes (GSTM1, GSTT1) modulate viral persistence, oxidative DNA damage response, and oncogenic progression. Advancements such as next-generation sequencing and immunogenetics, which identify the relationship between HPV variants and host immune genes that modulate disease susceptibility, vaccine responsiveness, and progression patterns across various genetic backgrounds. This review systematically integrates molecular mechanisms of HPV variant-induced oncogenesis and host genetic susceptibility with emphasis on population-based variability in addition to evidence culled from meta-analyses and GWAS data for immune regulation, DNA repair, as well as host single nucleotide polymorphisms in different populations and its implications for personalized prevention measures, screening, and vaccine response.