Naturally Occurring Major and Minor Capsid Protein Variants of Human Papillomavirus 45 (HPV45): Differential Recognition by Cross-Neutralizing Antibodies Generated by HPV Vaccines

Abstract

cWe investigated naturally occurring variation within the major (L1) and minor (L2) capsid proteins of human papillomavirus genotype 45 (HPV45). Pseudoviruses (PsVs) representing HPV45 sublineages A1, A2, A3, B1, and B2 exhibited comparable particle-to-infectivity ratios and morphologies but demonstrated both increased (A2, A3, and B1) and decreased (B2) sensitivities to cross-neutralization by HPV vaccine antibodies compared to that of the A1 sublineage. Mutant PsVs identified HI loop residue 357 as being critical for conferring this differential sensitivity. The evolutionary mutation rate of the human papillomavirus (HPV) double-stranded DNA genome is low at ca. 2 ϫ 10 Ϫ8 base substitutions per site per year (1, 2), yet distinct genotypes and intragenotype variant lineages have arisen over time (3). HPV genotype 45 (HPV45) is closely related to HPV18 within the Alpha-7 species group and is associated with ca. 5% of cervical cancer cases worldwide (4, 5). Whole-genome sequence analysis of HPV45 strains has led to the delineation of distinct variant lineages (A and B) and sublineages (A1, A2, A3, B1, and B2) (3, 6, 7), with the possibility of a lineage C suggested from subgenomic sequences (8). Although firm data on their contribution to the risk of cervical disease progression are lacking, in part due to the low relative prevalences of individual lineages and sublineages in the population, current evidence does support some lineage-specific bias such that sublineage variant B2 (and possibly A3) appears to be overrepresented in patients with high-grade disease compared to controls (8-10). There may also be some geographical bias to the distribution of HPV45 sublineages (9). Intragenotypic variation occurs throughout the HPV genome, but the consequences of these polymorphisms on the functions of the resulting gene products are uncertain.The HPV structural genes encode the major (L1) and minor (L2) capsid proteins. The L1 protein multimerizes to form the nonenveloped icosahedral viral capsid (comprising 72 L1 pentameric capsomers) that mediates attachment to host cells (11), while the L2 protein is essential for viral infectivity (12). Structural alterations of the external surface topography of L1 can be conferred by minor sequence differences between genotypes (13), supporting observations that almost all neutralizing monoclonal antibodies (MAbs) that target these external surfaces are type specific (14-17). Nevertheless, functional antibody cross-reactivity is a common feature of sera from recipients of the Cervarix (bivalent) and Gardasil (quadrivalent) vaccines (18-22) and may be responsible for conferring HPV vaccine-induced cross-protection (23).It is reasonable to consider that lineage-specific variation in surface-exposed domains (7, 24, 25) may influence capsid recognition by HPV vaccine-derived antibodies. Single-cycle replication-incompetent pseudoviruses (PsVs) representing HPV16 L1, but not L2, variants (26) appear to exhibit little difference in their susceptibilities to type-specific antibodies eli...

Sensitivity of Human Papillomavirus (HPV) Lineage and Sublineage Variant Pseudoviruses to Neutralization by Nonavalent Vaccine Antibodies

“…HPV33 variants displayed a reduced (2- to 4-fold) sensitivity to type-specific nonavalent vaccine sera similar to that seen with cross-reactive bivalent and quadrivalent vaccine sera [9], suggesting that variant residues in the DE and FG loops alter capsid antigenicity to a range of antibody specificities. Natural variation in the HPV45 L1 capsid bestows an increased (A2, A3, B1) or reduced (B2) sensitivity to cross-reactive bivalent and quadrivalent vaccine antibodies [10]. In the present study, nonavalent vaccine antibodies demonstrated little (<2-fold) or no difference in the recognition of variants A2, A3, B1, and B2.…”

“…The biological consequences of HPV genome variants are unclear. Studies examining the potential impact of natural variation on L1 antigenicity have examined variants of HPV16 [6, 7], HPV31 [8], HPV33 [9], HPV45 [10], HPV52 [11], and HPV58 [12] and demonstrated, in some cases, variant-specific differences in sensitivity to monovalent, bivalent, and quadrivalent VLP immune sera, natural infection sera, and monoclonal antibodies (MAbs). Here, we evaluate the sensitivity of lineage and sublineage variants to neutralization by nonavalent HPV vaccine antibodies.…”

Phylogeny and In Silico Structure Analysis of Major Capsid Protein (L1) Human Papillomavirus 45 from Indonesian Isolates

“…On the surface of the capsid, there are 5 loops designated as BC, DE, EF, FG, and HI loop (Bisset et al, 2016). These surface exposed loops are known to be important for neutralizing antibody recognition, (Bisset et al, Buck et al, 2013) and sequence variation within the loops may affect efficiency of antibody neutralization (Godi et al, 2016;Guan J et al, 2015;Bisset et al, 2016). In this study, we have observed that the amino acid variation of HPV-45 L1 from Indonesian isolates are not showing major different in protein structure (Figure 2).…”

“…behaviours may distinct, for example, the difference in viral infectivity, persistence, antibody recognition and progression of cervical dysplasia to cervical cancer (de Oliviera et al, 2016;Bernard et al, 2005;Burk et al, 2013;Chen et al, 2014;Godi et al, 2016;Guan et al, 2015).…”

“…To date, it has been known that HPV-45 is classified into two major variants lineage A and B, and within this major lineage, the virus is grouped further into five variants of sub lineage A1, A2, A3, B1, and B2 (Guan et al, 2012). Some studies suggest that different HPV-45 variant may have been linked to different risk for cervical cancer development as well as protection from currently available HPV vaccine (Chen et al, 2014;Godi et al, 2016;Xi et al, 2014). Unlike HPV-16 and HPV-18, the geographic distribution of HPV-45 variant lineage varies around the world.…”