In this issue, Bennetts et al.1 provide a timely review of the association of “low-risk” α-mucosal human papillomaviruses (HPVs) with cancer and the acquisition of HIV. The use of the terms “low and high oncogenic risk” or “low-and high-risk” (LR and HR) HPV became commonplace in the late 1980s. Around that time, the Bethesda system for reporting cytology and histology was introduced, defining the concepts of low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions precancer lesions, and such a dual classification system encompassing both HPV virology and disease seemed intuitive and was subsequently reinforced by phylogenetics. New mucosal HPV types continue to be described and their phylogenetic classification has continued to evolve.2 Within the genus α-papillomavirus, 5 species are entirely composed of what are thought to be LR viruses. These are species α1 (HPV types and 42), α3 (HPV types 61, 62, 72, 81, 83, 84, 86, 87, 89, 102, 114), α4 (HPV types 2, 27, and 57), α8 (HPV types 7, 40, 43, and 91), and α10 (HPV types 6, 11, 13, 44, and 74). Nevertheless, one HPV type that has previously thought to be LR in its pathologic associations is found within an HR species, namely, HPV70 (α7). Thus, phylogenetic characteristics may not solely predict LR/HR status, and the essential criterion for such classification is the disease association or phenotype of the HPV type in question. In terms of clinical disease caused by LR viruses, HPV6 and HPV11 overwhelmingly predominate by virtue of the frequency of anogenital warts in populations worldwide; recognized clinical lesions caused by other LR types are infrequent. Anogenital warts cause significant loss of quality-adjusted life-years and health care costs3 which are nowadays recognized as important in determining HPV vaccine implementation decisions.4 Whereas HPV6 and HPV11 are normally associated with purely benign disease, they can much more rarely be associated with various malignancies, including Buschke-Lowenstein tumors and occasionally other anogenital malignancies.
Bennetts et al. review both prospective and case-control studies of participants with genital warts and observe that these do suggest an increased risk for the subsequent development of anogenital malignancy. They discuss the possible reasons for such an association and suggest that LR-HPV genotypes may not have a direct role in cancer etiology. Of note, Guimerà et al.5 recently investigated the putative direct causative role of HPV LR genotypes in anogenital malignancy in an elegant study using laser capture microdissection and polymerase chain reaction (PCR) methodology. From a global study of 13,328 anogenital carcinomas, they identified 10,055 pathological samples which were HPV positive. Within that sample set, there were 225 lesions (2.2%) where LR genotypes were found, with 57 (25.2%) of those lesions containing a single LR type. Genotypes were identified by whole-tissue PCR using SPF10-LiPA25. In 43 (93.5%) of 46 available single LR type–associated carcinomas, multiple PCR assays confirmed sole detection of either HPV6, HPV11, HPV42, HPV44, or HPV70 DNA. Of these 46 anogenital carcinomas, 46% were cervical, 2% vaginal, 11% vulval, 9% anal, and 33% penile. In 75% (n = 32) of these, LR-HPV DNA was confirmed in tumor cells by laser capture microdissection. In 2 cases, including 1 adenocarcinoma, viral DNA was only found outside the tumor. All anogenital tumors with confirmed HPV6/11 showed a characteristic pattern of papillary, warty or warty-basaloid histology with patchy or negative p16 expression. HPV6-associated cervical tumors occurred at a low median age. HPV42 and 70 were associated with histologically typical squamous cell carcinomas showing diffuse p16 staining, as seen in HR HPV-related malignancies. HPV44 was found in one case. Guimerà et al. propose that their data support the causal involvement of LR-HPVs in carcinogenesis less than 2% of anogenital malignancies with 2 distinct clinicopathological patterns, related to the different respective abilities of the E6/E7 gene products of HPV types 6/11 and 42/70 in binding of p53 and pRb. Low-risk HPVs are also occasionally described in laryngeal cancer, and in a recent series of 92 lesions, 3 single detections of HPV11, HPV42, and HPV70 were described.6
In addition to this direct role of LR-HPVs in a small percentage of anogenital malignancies, there are a number of factors associated with LR-HPV infection that may increase cancer risk indirectly. These include demographic risk factors,7,8 smoking,1 and other sexually transmitted diseases such as Chlamydia trachomatis.9 human papillomavirus infection, both LR and HR, is associated with quite profound immunosuppressive changes within the HPV lesion itself which should be considered within this context.10 Human papillomavirus directly induces down-regulation of interferon signaling within persistent lesions,11 which in turn increases the likelihood of further HPV coinfection of those target sites.12 Thus, an LR infection increases the likelihood of a further HR infection at that site, which is likely to be another indirect factor in the apparent increased cancer risk associated with LR infections.1
There is a “flip side” to this “HPV immunological coin” which also comes into play. Most HPV lesions regress spontaneously, and the evidence suggests that such regression is mediated by CD8 T cells13 accompanied by CD4 T cells and innate effector cells. A landmark study of spontaneously regressing genital warts highlighted the dramatic immunological activation and cellular infiltration seen during such resolution.14 Bennetts et al. review the evidence linking increased acquisition of HIV infection with HPV infection, which could be mediated through such HPV resolution–associated CD4 T-cell activation events. Proof of the hypothesis could be derived through an HPV vaccine randomized controlled trial, but the temporal window of opportunity to conduct such a randomized controlled trial is narrowing. If the hypothesis was correct, it would be an extremely important observation and add large weight to the rationale for universal HPV vaccination. Bennetts et al. have highlighted important aspects of LR-HPV infection which are not always considered, including within cost-effectiveness analyses of HPV6/11 vaccine implementation. But we are in the fortunate position of looking forward to significant declines in HPV6/11-associated disease in the future through increasing population coverage of HPV vaccines.
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