Abstract
Cervical cancer is one of the most common gynecological cancers in the world but in India, it is the top most cancer among women. Persistent infection with high-risk human papillomaviruses (HR-HPVs) is the most important risk factor. The sequence variation(s) in the most common HR-HPV i.e. HPV type 16 leads to altered biological functions with possible clinical significance in the different geographical locations. Sixteen major variants (V1-V16) in full length L1 gene of HPV-16 were identified following analysis of 250 prospectively collected cervical cancer tissue biopsies and their effect on immunogenicity was studied. The effect of these major variations on the epitopes were predicted by in silico methods and the immunogenicity of variants and respective reference DNA vaccine constructs were evaluated by administration of prepared DNA vaccine constructs in female BALB/c mice to evaluate antibody titer. In the present study, L500F (V16) variation showed a significant ~2.7 fold (p < 0.002) increase in antibody titer, whereas T379P (V8) showed ~0.4 fold (p < 0.328) decrease after final injection. These results showed a promising roadmap for the development of DNA based vaccine and for the generation of effective response, though there is a need to study more prevalent variants of HPV in the Indian population.
Highlights
It was observed that variations V3, V12 and V13 were observed in all HPV 16 positive samples (100%), which correspond to amino acid change from histidine to aspartate at position H228D, an insertion of serine residue at 448 and deletion of aspartate residue at 465 position respectively (Table 1)
Persistent infection with high risk Human Papillomavirus (HR-HPV) is associated with precancerous lesions with the ultimate development of CaCx and HPV 16 infection is highly prevalent in India[23]
It has been reported from various studies that gene variant T350G of HPV-16 was found to display more efficient degradation of Bax and strong binding to E6 binding protein
Summary
In India, HPV-16 alone contribute to > 90% of the cancer of uterine cervix[7,8,9] This could be due to HPV intratype variants, which may have different biological and pathological consequences with respect to disease progression[10]. Alteration in one or more amino acid within the L1 protein of HPV-16 could represent a conformational change in the protein and could affect the conformation of epitopes relevant for viral neutralization[15]. It is, imperative to understand the geographical variants of HPV for better targeting the vaccines against it. The previous studies have reported mainly the variations in L1, the major capsid protein of HPV-16 genome, whereas the present study reports here the effect of Indian major variants of L1 on the epitope change (in-silico) as well as on potential immunogenicity in-vivo (BALB/c mice)
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