Rhonda Meys and colleagues at Chelsea and Westminster Hospital have conducted the first study to examine the relationship between persistent warts, HPV infection and tissue type in HIV-positive people1.
The investigators found that in HIV-positive people specific HLA class I tissue types are associated with persistent HPV infection and there are particular HPV genotypes that are more commonly seen.
The study looked at individuals who have a history of persistent cutaneous or genital warts and examined the HPV serotypes found in wart biopsies as well as their class I and class II HLA types. The study recruited patients of northern European descent in three groups: 1) HIV-positive people with HPV disease (>6 months history of persistent warts); 2) HIV-positive people with no history of HPV disease; 3) HIV-negative individuals with HPV disease (>6 months history of persistent warts).
All HIV-positive people in the study were male, had been on ART for more than 1 year and had viral loads below 50 copies/mL for more than 6 months. In contrast 29% of the HIV-negative individuals with HPV disease were female.
In total 137 individuals were recruited to the study of which 49 were HIV+/HPV+ cases, 46 were HIV+/HPV- cases and 42 were HIV-/HPV+ cases. All individuals were HLA typed and their HPV genotypes were determined by PCR from biopsies of wart tissue. HPV has 120 genotypes that are divided up amongst five different genera: alpha-papillomavirus; mu-papillomavirus; nu-papillomavirus; gamma-papillomavirus; and beta-papillomavirus. Different genera of HPV tend to infect either cutaneous dry skin or genitalia. Therefore primers were designed to detect cutaneous wart-associated HPV or genital wart-associated HPV.
Primers for cutaneous HPV included the following 23 genotypes 1, 2, 3, 4, 7, 10, 27, 28, 29, 40, 41, 43, 48, 50, 57, 60, 63, 65, 77, 88, 91, 94 and 95. Primers for genital HPV included 25 genotypes 6, 11, 16, 18, 31, 33, 34, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 70 and 74. Furthermore the following 25 beta-papillomaviruses were detected with a separate set of primers 5, 8, 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, 36, 37, 38, 47, 49, 75, 76, 80, 92, 93, and 96.
Of all the individuals with HPV infection, 86% of HIV-positive individuals and 69% of HIV-negative individuals had a history of cutaneous warts, 39% of HIV-positive individuals and 45% of HIV-negative individuals had a history of genital warts and 24% of HIV-positive individuals and 14% of HIV-negative individuals had a history of both. Three individuals in each group also had a history or penis or anal cancer.
HLA-B*44 was the main tissue type allele of significant difference in this study. HLA-B*44 is present in approximately 32% or a comparable blood donor population, but was found to be present in the genotypes of 47% of HIV+/HPV+ cases and only 17% of the HIV+/HPV- control cases (p=0.004, p-corrected=0.54). In the HIV-/HPV+ group HLA-B*44 was found at a frequency of 33%, similar to the general population. Subtype analysis revealed that HLA-B*44:02 was the predominant allele in this group and was present in 38% of HIV+/HPV+ cases and only 7% of HIV+/HPV- control cases (p=0.0006, p-corrected=0.04), while it is present in the genotypes of 19% of a comparable blood donor population (p=0.0006, p-corrected=0.43).
HLA-C*05 was also present in the genotypes of HIV+/HPV+ individuals at a significantly increased frequency of 33% compared to 9% of HIV+/HPV- controls (p=0.009, p-corrected=0.59). 37% of HIV+/HPV+ individuals carried both HLA-B*44 and HLA-C*05 compared to 7% of HIV+/HPV- controls (p=0.001, p-corrected=0.07). No differences were found between the groups in the proportion of subject who were homozygous for one or more HLA alleles.
Analysis of HPV genotype was conducted on wart biopsies from 30 HIV+/HPV- individuals and 36 HIV-/HPV+ individuals. In 29% of biopsied warts, more than one HPV genotype was identified, showing that mixed in HPV infection was common. Multiple beta-papillomavirus HPVs were detected in wart biopsies from 60% of HIV-positive individuals compared with 38% in warts from HIV-negative individuals (p=0.03).
The number of different types of beta-papillomavirus HPVs was also greater in HIV-positive people who had a median of 3 (IQR 0.3-8) compared with HIV-negative people who had a median of 1 (IQR 0-2), (p=0.002). HPV 7 was present in cutaneous warts from 8% of HIV-positive individuals, but not present at all in HIV-negative individuals (p=0.04).
In contrast HPV 2 was more frequent in cutaneous warts of HIV-negative people, where it was identified in 30 % of the group, compared to 3% of HIV-positive people (p=0.002). There was no difference between HIV-positive and negative people in the frequency of HPV genotypes associated with genital warts, though the number of warts examined was small.
The authors suggest that the differences in HLA-type between groups suggest an effect of HLA class I on predisposition to HPV, while evidence in the literature suggests more of a role for HLA class II.2 This is one of few reports that identify HLA class I as potentially important in susceptibility to HPV. This is the first study to examine HLA-associations with HPV infection in HIV-positive patients. The authors also note that the effect of HLA class I maybe indirect, as it is known to play a significant role in HIV infection.
Importantly, this study highlights the possibility that the relatively rare HPV 7 may be an important pathogen in HIV-positive people.
- Rhonda M et al. HLA immunogenotype determines persistent human papillomavirus virus infection in HIV-infected patients receiving antiretroviral treatment. J Inf Dis 2016.
- Madkan VK et al. The oncogenic potential of human papillomaviruses: a review on the role of host genetics and environmental cofactors. Br J Dermatol 2007 157 228-41.