HLA Immunogenotype Determines Persistent Human Papillomavirus Virus Infection in HIV-Infected Patients Receiving Antiretroviral Treatment

Meys, Rhonda; Purdie, Karin J.; Koning, Maurits N.C. de; Quint, Koen D.; Little, Ann‐Margaret; Baker, F.A.; Francis, N.; Asboe, David; Hawkins, David; Marsh, Steven G.E.; Harwood, Catherine A.; Gotch, Frances; Bunker, C.B.

doi:10.1093/infdis/jiw038

Cited by 8 publications

(8 citation statements)

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“…Although associations between HPV infection and Human Leukocyte Antigen (HLA) genotypes have previously been described 6, the relationship between HIV/HPV co-infection, class II HLA and cervical cancer development has not been reported 7. It is also unclear what the immune mechanism would be 8.…”

Section: Introductionmentioning

confidence: 99%

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Human Leukocyte Antigen (HLA) Class II -DRB1 and -DQB1 Alleles and the Association with Cervical Cancer in HIV/HPV Co-Infected Women in South Africa

et al. 2019

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Background: A subset of women who are co-infected with Human Immunodeficiency Virus type 1 (HIV) and Human papillomavirus (HPV), progress rapidly to invasive cervical cancer regardless of antiretroviral therapy (ART) or immune status. We posit that HIV/HPV co-infection along with specific host HLA II -DRB1 and -DQB1 alleles play a major role in cervical cancer development. Methodology: We conducted a hospital-based genetic susceptibility case-control study in Cape Town, South Africa. We recruited 256 women of the same race, from which a total of 624 HLA-DRB1 and -DQB1 class II genotypes were studied. We characterized HLA II candidate genes using PCR based, Luminex intermediate resolution genotyping and confirmed significant associated genotypes at four-digit resolution by high resolution gel typing. We analyzed 160 alleles from cancer, 64 alleles from pre-cancer and 400 alleles from healthy control women. Whole blood was used for HIV antibody test and HLA II typing. Cervical tumor tissue biopsies were used for HPV genotyping. Tests were statistically significant if p<0.05. Results: Women who were co-infected with HIV/HPV had advanced cervical disease compared to women who were HIV negative. HLA class II -DQB1*03:01 and -DQB1*06:02 alleles were associated with cervical cancer in HIV/HPV co-infected women (p=0.001 and p<0.0001, respectively) while HLA class II -DRB1*13:01 and -DQB1*03:19 were rare or absent in women with cervical disease when compared to the control population (p=0.012 and 0.011, respectively). Conclusion: We describe associations between HLA class II genotypes with cervical cancer, or likely protection from cervical cancer disease in HIV/HPV co-infected South African women. Identifying mechanisms that give rise to this likely protective HLA association will provide insight into development of immune-based prevention measures.

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Section: Introductionmentioning

confidence: 99%

“…The etiology of cervical cancer has been related to certain high-risk HLA class II genes 15. Polymorphisms in HLA-DRB1 and -DQB1 genes are hypothesized to play a role in carcinogenesis of cervical cancer 6. Despite considerable scientific interest, findings of different published studies have been inconsistent 10,16,17.…”

Section: Introductionmentioning

confidence: 99%

Human Leukocyte Antigen (HLA) Class II -DRB1 and -DQB1 Alleles and the Association with Cervical Cancer in HIV/HPV Co-Infected Women in South Africa

et al. 2019

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“…In a previous study (13), we described an association, or likely protection from cervical cancer in HIV-1/HPV co-infected South African women, with certain HLA II genotypes. Furthermore, a study carried out by Meys et al (42) reported that specific HLA immunogenotypes can determine the persistence of HPV infection in HIV-1 infected patients even during antiretroviral treatment. The presence of HIV-1/HPV co-infection in combination with specific HLA II genotypes or a haplotype may increase or decrease the risk of cervical disease development.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Cervical Tumor Biopsies for Chromosomal Loss of Heterozygosity (LOH) and Microsatellite Instability (MSI) at the HLA II Locus in HIV-1/HPV Co-infected Women

et al. 2019

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Background: A subgroup of women who are co-infected with human immunodeficiency virus type 1 (HIV-1) and human papillomavirus (HPV) progress rapidly to cervical disease regardless of high CD4 counts. Chromosomal loss of heterozygosity (LOH) and microsatellite instability (MSI) are early frequent genetic alterations occurring in solid tumors. Loss of an allele or part of a chromosome can have multiple functional effects on immune response genes, oncogenes, DNA damage-repair genes, and tumor-suppressor genes. To characterize the genetic alterations that may influence rapid tumor progression in some HIV-1-positive women, the extent of LOH and MSI at the HLA II locus on chromosome 6p in cervical tumor biopsy DNA samples with regard to HIV-1/HPV co-infection in South African women was investigated.Methods: A total of 164 women with cervical disease were recruited for this study, of which 74 were HIV-1-positive and 90 were HIV-1-seronegative. DNA from cervical tumors and matched buccal swabs were used for analyses. Six fluorescently-labeled oligonucleotide primer pairs in a multiplex PCR amplification were used to study LOH and MSI. Pearson chi-squared test for homogeneity of proportions using an exact p value, a two-proportion Z-score test, ROC curves and a logistic regression model were used for statistical analyses. All p-values were corrected for false discovery rate (FDR) using the Benjamini-Hochberg test and the adjusted p-values (q-values) were reported. All tests were significant when both p and q < 0.05.Results: Tumor DNA from HIV-1/HPV co-infected women demonstrated a higher frequency of LOH/MSI at the HLA II locus on chromosome 6p21.21 than tumor DNA from HIV-1-seronegative women (D6S2447, 74.2 vs. 42.6%; p = 0.001, q = 0.003), D6S2881 at 6p21.31 (78.3 vs. 42.9%; p = 0.002, q = 0.004), D6S2666 at 6p21.32 (79 vs. 57.1%; p = 0.035, q = 0.052), and D6S2746, at 6p21.33 (64.3 vs. 29.4%; p < 0.001, q < 0.001), respectively.Conclusions: HPV infection alone can induce LOH/MSI at the HLA II locus in cervical tumor DNA, whereas HIV-1 co-infection exacerbates it, suggesting that this may accelerate cervical disease progression in a subgroup of HIV-1-positive women.

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“…It has been argued that, despite underlying immunodeficiency and immune reconstitution, the existing cervical carcinogenesis process in HIV/HPV co-infected women is further influenced by host molecular genetic factors, which vary between individuals (18,23,24) (Figure 1). It has also been suggested that the rate of cervical disease progression and likely protection may depend on host immunogenetic variations (25)(26)(27)(28)(29).…”

Section: Ivyspring International Publishermentioning

confidence: 99%

Impact of Host Molecular Genetic Variations and HIV/HPV Co-infection on Cervical Cancer Progression: A Systematic review

Chambuso¹,

Gray²,

Kaambo³

et al. 2018

Oncomedicine

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Only a small subset of women who are co-infected with Human Immunodeficiency Virus sub-type 1 (HIV) and persistence oncogenic Human papillomavirus (HPV), progress rapidly to invasive cervical cancer by mechanisms that are currently poorly understood. The use of Highly Active Antiretroviral Therapy (HAART), with ensuing immune reconstitution of CD4 T-cells, does not appear to prevent rapidly progressing cervical carcinogenesis. Therefore, to better understand the cervical cancer pathogenesis in HIV/HPV co-infected women, this review focuses on identifying host molecular genetic variations and genetic alterations in cervical cancer progression that may play a role in disease progression. This is an important aspect for individualised genomic profiling and targeted molecular prevention in order to improve the management of the disease in this sub-population.

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HLA Immunogenotype Determines Persistent Human Papillomavirus Virus Infection in HIV-Infected Patients Receiving Antiretroviral Treatment

Cited by 8 publications

References 46 publications

Human Leukocyte Antigen (HLA) Class II -DRB1 and -DQB1 Alleles and the Association with Cervical Cancer in HIV/HPV Co-Infected Women in South Africa

Human Leukocyte Antigen (HLA) Class II -DRB1 and -DQB1 Alleles and the Association with Cervical Cancer in HIV/HPV Co-Infected Women in South Africa

Investigation of Cervical Tumor Biopsies for Chromosomal Loss of Heterozygosity (LOH) and Microsatellite Instability (MSI) at the HLA II Locus in HIV-1/HPV Co-infected Women

Impact of Host Molecular Genetic Variations and HIV/HPV Co-infection on Cervical Cancer Progression: A Systematic review

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