Nature is full of diversity, which can both elucidate interesting biology or obscure it. In the case of human disease rare pathologies or uncommon variants are often overlooked in order to maximize the number of people benefiting from research. However, when scientists are able to study uncommon biology nature’s diversity can be leveraged for our understanding. This is the case for human papilloma virus (HPV). There are hundreds of HPV strains, yet a very small subset is known to cause cervical carcinomas. In fact, in the USA 70% of HPV positive cervical cancers are caused by HPV16 or HPV18 strains. Due to this overwhelming majority, most research to date has focused on HPV16 and HPV18 resulting in a number of highly effective vaccines. With these clinical successes, the question remains – which non-HPV16/18 strains contribute to developing cervical carcinoma in the other 20% of patients? The HPV Research Group (a collaborative effort amongst Fred Hutch and University of Washington Laboratories) has begun to answer this question, and understand why these variant strains are also oncogenic. A recent clinical study published in the International Journal of Cancer analyzed the type-specific viral load of non-HPV16/18 strains from pre-cancerous cervical lesions to determine the risk factor associated with each HPV type progressing to stage two or three cervical intraepithelial neoplasia (CIN2/3) the precursor to cervical cancer. These data revealed that the risk of HPV positive patients being diagnosed with CIN2/3 correlated with viral load for HPV strains evolutionarily similar to HPV16.
Image provided by de Villiersa et al., Virology, 2004 - link below
Women were enrolled for this clinical study if routine pap smears contained cells with mildly abnormal appearance referred to as ‘atypical squamous cells of undetermined significance’ (ASC-US) or ‘Low-grade squamous intraepithelial lesion’ (LSIL). Essentially, these pap smears do not indicate CIN or cervical cancer, but are not entirely normal, so increased observation is necessary. Participants were examined every six months for two years, this included detection of HPV and cervical neoplasia. This specific analysis included only participants who were positive for one or more of the nine strains most similar to HPV16 and HPV18. These two groups are referred to as species 7 (HPV18, 39, 45, 59, and 68) and species 9 (HPV16, 31, 33, 35, 52, and 58). Approximately 3000 women with pap smears classified as ASC-US or LSIL were positive for these HPV strains, and within the two years of observation 565 participants presented with CIN2/3, the precursor to cervical cancer.
Image provided by the National Cancer Institute
This study focused on two major factors, the viral load at the first time a participant was HPV positive and if a patient presented CIN2/3. Measuring these key factors there was a clear trend that if a participant exhibited CIN2/3 on her first HPV positive examination, viral loads were very high. While such findings are biologically useful they do not contribute to diagnostic or prognostic measures. For this purpose researchers determined the risk factor of developing CIN2/3 based on the HPV strain and size of viral load from the first positive cervical swab. This analysis revealed that higher viral loads of the species 9 viruses increased risk of developing CIN2/3. Species 9 viruses include HPV16, for which this same association was previously reported.
While major successes have been reported in preventing cervical cancer caused by HPV16 and HPV18, it is important that doctors and researchers continue these efforts into related, but unique strains. Expanding our understanding and the therapeutic toolbox to include other species 7 and 9 HPVs will likely help in achieving eradication like has been observed for small pox or poliovirus. These results from the HPV Research Group emphasize that making research collaborative only increases the productivity of science and increases its value to human health.
Xi LF, Schiffman M, Ke Y, Hughes JP, Galloway DA, He Z, Hulbert A, Winer RL, Koutsky LA, Kiviat NB. 2017. Type-Dependent Association between Risk of Cervical Intraepithelial Neoplasia and Viral Load of Oncogenic Human Papillomavirus Types Other than Types 16 and 18. Int J Cancer.
Funding for this research was provided by the National Cancer Institute (NIH).
de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. 2004. Classification of papillomaviruses. Virology. 324(1);17-27