HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

Abstract

Human papillomavirus (HPV) infection is the most important risk factor for development of cervical carcinoma. Carriers of certain HLA class II alleles, e.g., DRB1*1501 and DQB1*0602, are more prone to HPV 16 infection and cervical carcinoma, whereas other alleles, e.g., DRB1*1301 and DQB1*0603, render carriers less susceptible to the disease. In our study comprising 484 cases and 601 controls, we examine the effect of HLA class II alleles on viral load of the oncogenic types HPV 18/45 and HPV 31 and risk of developing cervical carcinoma in situ. We find that carriers of the commonly reported protective DRB1*1301 and DQB1*0603 alleles have lower HPV 18/45 load compared to noncarriers and a lower risk of developing HPV 18/45-positive cervical carcinoma. This provides further evidence that the HLA class II-mediated immune response to HPV is important for controlling viral load and outcome of an infection. ' 2005 Wiley-Liss, Inc.Key words: HLA; human papillomavirus; viral load; cervical carcinoma HPV is the major etiologic risk factor for cervical carcinoma and is found in the majority of cervical tumors. Although infection with oncogenic forms of HPV are common among young women, less than 1% of those infected develop cervical carcinoma. [1][2][3] Both the length of the infection and a high viral load several years before diagnosis have been shown to increase the risk of developing cervical dysplasia and carcinoma in situ (CIS). [4][5][6] Certain HLA class II alleles, such as DRB1*1501 and DQB1*0602, have been shown to increase the risk for cervical carcinoma, most strongly in HPV 16-positive carcinomas. [7][8][9][10][11][12][13] We have previously shown that the increased carcinoma risk primarily depends on that the alleles render carriers more susceptible to HPV16 infections. 12 In addition, carriers of these HLA susceptibility alleles had higher HPV 16 load in their cervical smears compared to HPV 16-positive noncarriers. A plausible hypothesis is that HLA is involved in the cellular immunity against HPV. Also, HLA alleles making carriers more susceptible to HPV infections are likely to be less efficient in triggering immunity and inducing viral clearance. As a consequence, carriers of susceptibility alleles harbor higher HPV load than carriers of more efficient alleles. The relation between viral load and carcinoma development has been most extensively studied for HPV 16, presumably because it is the most prevalent HPV type in cervical tumors throughout most of the world. 1 We have previously examined the effect of HPV 18/45 and HPV 31 viral load on the risk for cervical CIS. 14 Our results showed that higher viral load of HPV 18/45 or HPV 31 increases the risk of CIS, although the risk magnitude is less than that observed for HPV 16. Therefore, it is possible that HLA alleles could influence carcinoma development by affecting viral load also for other HPV types besides HPV 16.A meta analysis demonstrated a protective effect of the DRB1*1301 and DQB1*0603 alleles against development of cervical carcinoma in 18 ...

Determination of viral load thresholds in cervical scrapings to rule out CIN 3 in HPV 16, 18, 31 and 33‐positive women with normal cytology

“…This finds support by the observation that HPV 16 and 18/45 positive carriers of commonly reported protective human histocompatibility leukocyte antigen class II (HLA II) alleles displayed lower viral loads together with short term HPV infections and a decreased risk of cervical carcinoma in situ. 25,26 Although our findings for non-HPV 16 types are in line with some studies, 11 it contradicts others. 12 Variables such as differences in methods to preselect hrHPV positive women 6 and sample size may have contributed to inconsistent data for non-HPV 16 types.…”

Genetic susceptibility to cervical squamous cell carcinoma is associated with HLA-DPB1 polymorphisms in Taiwanese women

“…We found a decreased risk of CSCC in association with the HLA-DPB1*05:01 allele and +550 G/G genotype and G allele and an increased risk in association with the +550 A allele. When the analysis was restricted to the subgroup of women with HPV-16 positive CSCC, the association of HLA-DPB1*05:01 allele still existed and the DPB1 Certain HLA class II alleles have been reported to influence cervical cancer development by affecting the interactions between host immune response and HPV infection [23][24][25][26]. The DRB1 and DQB1 loci therefore have been thoroughly investigated in several cervical cancer association studies [5].…”

Associations of human leukocyte antigen class II genotypes with human papillomavirus 18 infection and cervical intraepithelial neoplasia risk

“…A Swedish study reported that DRB1*1301 and DQB1*0603 carriers had a lower HPV18 of 45 titer in comparison to noncarriers. 17 Cohort studies in Brazil and Canada showed inconsistent findings for the association between HLA class II genes and persistent infection. 19,20 In these studies, the average age of participants was 20 to 30 years.…”

“…A Swedish nested case-control study reported associations between certain HLA class II genotypes and viral load of specific oncogenic HPV types. 17,18 A Brazilian community-based cohort study showed that specific HLA class II haplotypes increased the risk of HPV persistence. 19 However, a Canadian cohort study of female university students found no associations between specific HLA class II alleles and risk of HPV persistence.…”