Maria Alice G Gonçalves

Human papillomavirus types among women infected with HIV: a meta-analysis

Background:HIV-positive women have a high prevalence of human papillomavirus (HPV) infection and are infected with a broader range of HPV types than HIV-negative women. It is not known to what extent these different types are associated with high-grade squamous intraepithelial lesions (HSIL) and cancer. Methods:Meta-analysis of HPV type-specific prevalence among HIV-positive women, stratified by geographical region and by cervical cytology: normal, atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesions (ASCUS/LSIL) or HSIL. Results:In 20 studies, 5578 HIV-positive women were identified, largely from North America but also Africa, Asia, Europe and South/Central America. For 3230 with no cytological abnormalities, prevalence was 36.3% for any HPV and 11.9% for multiple HPV types. The six most common high-risk HPV types were 16 (4.5%), 58 (3.6%), 18 (3.1%), 52 (2.8%), 31 (2.0%) and 33 (2.0%). HPV16 was also the most common type in 2053 HIV-positive women with ASCUS/LSIL and 295 with HSIL. Those with HSIL were significantly less likely to be infected with HPV16 (odds ratio, 0.6; 95% confidence interval, 0.4–0.7) than the general female population with HSIL. In contrast, HIV-positive women with HSIL were significantly more likely to be infected with HPV types 11, 18, 33, 51, 52, 53, 58 and 61, and with multiple HPV types. Conclusions:The proportion of HIV-positive women with HPV16 rose with increasing severity of cervical lesions. Nevertheless, HPV16 remained underrepresented in HIV-positive women with HSIL, who showed a higher proportion of other HPV types and multiple types compared with the general female population with HSIL.

Relationship between human papillomavirus (HPV) genotyping and genital neoplasia in HIV-positive patients of Santos City Sao Paulo Brazil.

Among HIV-positive women, infection with multiple human papillomavirus (HPV) types is known to be more frequent and persistent, as well as a greater prevalence of high-grade genital lesions. This study aims to characterize, for the first time in Brazil, HPV presence and types among HIV-positive women of a high-risk population for genital intraepithelial neoplasia (GIN) development. A non-anonymous, voluntary, cross-sectional epidemiological survey was conducted, from June 1996 to April 1997, among 141 HIV-positive women followed at the Center of Reference in AIDS (CRAIDS). They were submitted to gynaecological examination, cytological screening and biopsies whenever necessary, for GIN and HPV DNA detection through polymerase chain reaction (PCR) technique. Positive HPV DNA were found in 80.8% patients. Two or more HPV types were detected in 45% of the samples. The most frequent HPV types detected were 16, 18 (30.5%); 61, 53 (24.4%), and non-identified types (18.7%). According to the oncogenic potential, 34.8% were considered of high-risk types. Among these HIV-positive patients, a great variety of HPV types, including high-risk types, was found in anogenital environment, as well as among young women, a great prevalence of high-grade genital lesions. Thus, it should strengthen the need for a periodical careful gynaecological examination among those women.

HLA-G polymorphisms in women with squamous intraepithelial lesions harboring human papillomavirus

Human papillomavirus (HPV) infection is etiologically associated with low- (LSIL) and high-grade squamous intraepithelial lesions (HSIL) and with cervical cancer. The progression or regression of the lesions may depend, among other factors, on the host heritable immune response. Because human leukocyte antigen (HLA)-G molecules are involved in the modulation of innate and adaptive immune responses, and because no previous studies have evaluated HLA-G polymorphism in patients with SIL, we conducted a study to assess the association between HLA-G polymorphisms and cervical lesions harboring HPV infection. Cervico-vaginal scrapings and blood samples were collected from 125 women with SIL (68 LSIL and 57 HSIL) and from 94 healthy women without HPV infection and cytological abnormalities. HPV type and HLA-G polymorphisms in exons 2, 3 and 8 (14 bp insertion/deletion) were evaluated by PCR methodology, and digested with restriction endonucleases. The Genepop software and the EM and PHASE algorithms were used for statistical analysis. A significant protective association was observed between the presence of the G*0103 allele and SIL and between the G0101/G0104 genotype and HSIL in the group of patients compared to control. The presence of the G0104/+14 bp and G0104/−14 bp haplotypes conferred susceptibility to SIL compared to control. In addition, patients possessing the G0104/+14 bp haplotype and harboring HPV-16 and -18 co-infections were particularly associated with HSIL. These findings suggest that HLA-G polymorphisms may be associated with HPV infection and SIL, consequently representing a profile of predisposition to cervical cancer.

Immunohistochemical Expression of p16INK4a and bcl-2 According to HPV Type and to the Progression of Cervical Squamous Intraepithelial Lesions

Inactivation of the cell cycle inhibitor gene p16MTS1 seems to be involved in human papillomavirus (HPV)-related carcinogenesis because E6 and E7 oncoproteins may impair p16INK4a and, indirectly, bcl-2 functions. In this study, we analyzed the role of immunohistochemical expression of p16INK4a and bcl-2 in HPV-infected cervical biopsies as prognostic markers of the progression of squamous intraepithelial lesion (SIL). Sixty-five cervical biopsies were stratified into two subgroups according to the second biopsy: 27 of them maintained a low-grade (LG)-SIL diagnosis, and 38 progressed from LG-SIL to high-grade (HG)-SIL. p16INK4a and bcl-2 quantitative expression levels were measured by the immunoperoxidase method. PCR-DNA techniques were used to detect and type HPV. The Wilcoxon and Fisher exact tests were employed for the statistical analysis. In the group with an LG-SIL diagnosis at the second biopsy, no significant associations were found between p16INK4a and bcl-2 expression and presence of HPV16/18. In the group that progressed to HG-SIL, a significant association was observed between p16INK4a overexpression and HPV16/18 presence (p=0.021), but none with bcl-2 levels. It is concluded that immunohistochemical bcl-2 expression may not be useful for predicting the progression of HPV-related SIL. In contrast, p16INK4a overexpression seemed to be associated with HPV 16 and 18, suggesting that it may be a good marker for predicting SIL progression.

Immune cellular response to HPV: current concepts

Although cellular immunity is essential for the elimination of human papillomavirus (HPV), the mechanisms involved are still poorly understood. We summarize the main mechanisms involved in cellular immune response to infections caused by HPV. Immunotherapies for HPV-related cancers require the disruption of T-cell response control mechanisms, associated with the stimulation of the Th1 cytokine response.

Classical and non-classical HLA molecules and p16INK4a expression in precursors lesions and invasive cervical cancer

OBJECTIVES Viruses and tumour cells may regulate the expression of HLA molecules on the cell surface to escape immune system surveillance. Absence of classical HLA class I molecules may impair the action of specific cytotoxic cells, whereas non-classical HLA class I molecules may regulate innate and adaptive immune cells. We assess here the possible associations between classical/non-classical class I HLA and p16(INK4a) molecule expression in cervical biopsies of women infected with HPV, stratified according to grade of the lesion and HPV type. STUDY DESIGN Cervical biopsies (N=74) presenting cervical intraepithelial neoplasia grade 1 (CIN1) (n=31), CIN2-3 (n=19), and invasive cancer (n=14) were evaluated alongside 10 normal cervical specimens. RESULTS HLA-A/B/C/G staining was observed in the early stages of HPV infection. A significant association was detected between HLA-A/B/C staining and HPV16/18 infection (OR=0.12, 95%CI: 0.0163-0.7899; p=0.04). HLA-E expression increased with the progression of the lesion (chi(2)-test for trend=4.01; p=0.05), and a significant association was found between HLA-E staining and HPV16/18 infection (OR=11.25, 95%CI: 2.324-54.465; p=0.003). Irrespective of the grade of the lesion, HLA-A/B/C staining and p16(INK4a) presented a good concordance (Kappa: 0.67). CONCLUSIONS HLA-E overexpression seemed to be associated with invasive cancer and HPV16/18 infection.

HPV type infection in different anogenital sites among HIV-positive Brazilian women

ObjectivesTo evaluate the prevalence of human papillomavirus (HPV) types, and risk factors for HPV positivity across cervix, vagina and anus, we conducted a study among 138 women with human immunodeficiency virus (HIV).GoalCompare the prevalence of different HPV types and the risk factors for HPV positivity in three sites.ResultsThe most frequently detected HPV types in all sites were, in decreasing order, HPV16, 53, 18, 61 and 81. Agreement between the cervix and vagina was good (kappa 0.60 – 0.80) for HPV16 and 53 and excellent (Kappa > 0.80) for HPV18 and 61. HPV positivity was inversely associated with age for all combinations including the anal site.ConclusionIn HIV positive women, HPV18 is the most spread HPV type found in combinations of anal and genital sites. The relationship of anal to genital infection has implications for the development of anal malignancies. Thus, the efficacy of the current HPV vaccine may be considered not only for the cervix, but also for prevention of HPV18 anal infection among immunossuppressed individuals.

Expression of the Classical and Nonclassical HLA Molecules in Breast Cancer.

Considering that downregulation of HLA expression could represent a potential mechanism for breast carcinogenesis and metastasis, the aim of the present study was to use immunohistochemical methods to analyze the expression of HLA-Ia, HLA-DR, HLA-DQ, HLA-E, and HLA-G in invasive ductal carcinoma (IDC) of the breast and to relate this HLA profile to anatomopathological parameters. Fifty-two IDC from breast biopsies were stratified according to histological differentiation (well, moderately, and poorly differentiated) and to the presence of metastases in axillary lymph nodes. The expression of HLA molecules was assessed by immunohistochemistry, using a computer-assisted system. Overall, 31 (59.6%) out of the 52 IDC breast biopsies exhibited high expression of HLA-G, but only 14 (26.9%) showed high expression of HLA-E. A large number (41, 78.8%) of the biopsies showed low expression of HLA-Ia, while 45 (86.5%) showed high expression of HLA-DQ and 36 (69.2%) underexpressed HLA-DR. Moreover, 24 (41.2%) of 52 biopsies had both low HLA-Ia expression and high HLA-G expression, while 11 (21.2%) had low HLA-Ia expression and high HLA-E expression. These results suggest that, by different mechanisms, the downregulation of HLA-Ia, HLA-E, and HLA-DR and the upregulation of HLA-G and HLA-DQ are associated with immune response evasion and breast cancer aggressiveness.

A pilot case-control association study of cytokine polymorphisms in Brazilian women presenting with HPV-related cervical lesions

OBJECTIVE AND STUDY DESIGN A case-control study was conducted on 42 Brazilian women presenting with human papilloma virus (HPV) infection and cervical lesion and 87 HPV-negative women to evaluate single nucleotide polymorphisms observed in TNF-alpha, TGF-beta, IL-10, IL-6, and IFN-gamma genes. RESULTS AND CONCLUSION No significant association was observed on the cytokine polymorphisms analyzed in this series. Larger studies using cytokine polymorphisms may be useful for providing further information regarding their influence or not in HPV-related cervical lesions.

Risk factors associated with genital warts in HIV-positive Brazilian women.

Aims and Background In Brazil, the female population has been increasingly infected with human immunodeficiency virus (HIV), and uterine cervix carcinoma now represents the second highest cause of mortality. Although HIV infection among women is associated with an increased prevalence of cervical cancer precursors, the co-infection with human papillomavirus (HPV) is considered to be a necessary but not sufficient factor to induce genital lesions. This study was conducted to identify risk factors associated with the history of genital warts among HIV-positive women. Methods A comparative cross-sectional evaluation was applied to 141 HIV-positive women. All patients were submitted to colposcopy, smear cytology, directed biopsy, and HPV-DNA detection. The chi-square, Fishers exact test, and the odds ratio (OR, 95%; confidence interval, CI) were used to evaluate associations between history of genital warts and risk factors. Results A history of genital warts presented associations with: a) age at first sexual intercourse ≤17 years (OR, 0.42; CI, 0.16-1.11); b) history of genital warts in sex partners (OR, 11.39; CI, 4.21–30.76), especially with recurrent episodes (OR, 6.60; CI, 2.69–16.12); c) drug addiction (OR, 2.38; CI, 1.09–5.19), especially in crack users (OR, 5.34; CI, 1.64–17.41); d) cervical HPV infection (OR, 2.75; CI 1.09–6.90); e) cervical infection caused by only one HPV type (OR, 2.77; CI 1.06–7.20); f) perianal HPV infection (OR, 2.30; CI, 0.70–7.56), associated with negative results for undetermined risk HPV (OR, 8.41; P = 0.04); and g) no antiretroviral therapy (OR, 3.41; P = 0.07). Conclusions Evaluation of behavioral risk factors associated with a genital wart history is an important tool to prevent and reduce persistent HPV infection, and consequently genital cancer precursors in HIV infected women.