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Obstetrics & Gynecology 2001;97:999-1004
© 2001 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Human Immunodeficiency Virus Type 1-Related Nucleic Acids and Papillomavirus DNA in Cervicovaginal Secretions of Immunodeficiency Virus-Infected Women

ARSENIO SPINILLO, MD, MAURIZIA DEBIAGGI, BSc, FRANCESCA ZARA, MD, ANTONELLA DE SANTOLO, MD, FRANCO POLATTI, MD and GAETANO FILICE, MD

From the Departments of Obstetrics and Gynecology, Microbiology and Infectious and Tropical Diseases, Policlinico S. Matteo, University of Pavia, Pavia, Italy.

Address reprint requests to: Arsenio Spinillo, MD Clinica Ostetrica e Ginecologica IRCCS Policlinico S. Matteo P. le Golgi 2 27100 Pavia Italy E-mail: spinillo{at}smatteo.pv.it


   Abstract
Top
Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To evaluate simultaneous human immunodeficiency virus (HIV)-related nucleic acids and human papillomavirus (HPV)-DNA in cervicovaginal secretions of HIV-seropositive women.

Methods: We collected 47 paired blood and cervicovaginal lavage samples from 124 known HIV-1–seropositive women. Proviral HIV-1 DNA, cell-associated, and cell-free HIV-1 RNA in cervicovaginal secretions were quantitatively evaluated by competitive polymerase chain reaction (PCR) and reverse transcription PCR. Polymerase chain reaction and subsequent restriction fragment length polymorphism analysis of PCR products were used to detect HPV types 6, 11, 16, 18, 31, 33, 35, and 56.

Results: Proviral HIV-1 DNA, cell-associated, and cell-free HIV-1 RNA were detected in 52.4% (65 of 124), 38.7% (48 of 124), and 33.9% (42 of 124) of lavage samples, respectively. Human papillomavirus-DNA in cervicovaginal secretions was detected in 64% (79 of 124) of participants. The rate of detection of HPV types of intermediate to high oncogenic risk was higher in HIV-positive women who tested positive for cell-associated (odds ratio [OR] 3.57, 95% confidence interval [CI] 1.17, 11.12) or cell-free (OR 4.63, 95% CI 1.42, 15.51) HIV-1 RNA in cervicovaginal secretions than their counterparts who tested negative. Logistic regression analysis showed that the association between HPV infection and the detection of HIV-1 RNA in cervicovaginal secretions persisted after adjustment for potential confounders such as CD4+ cell counts, HIV-1 RNA in plasma, use of antiretroviral drugs, vaginal infection, and regular condom use. In univariable and multivariable analysis, HPV-DNA detection was associated with amounts of cell-free and cell-associated HIV-1 RNA in cervicovaginal secretions ({chi}2 for trend 10.35, and 9.84, P = .001 and .002, respectively).

Conclusions: The rate of HPV detection in the genital tract of HIV-1–seropositive women is associated with the amount of cell-associated and cell-free HIV-1 RNA present in cervicovaginal secretions. The association does not appear to be attributable entirely to the effect of HIV-related immunodepression.

The association between human immunodeficiency virus (HIV)-1 infection and increasing rates of female lower genital tract neoplasia is well established.1 In addition to that, human papillomavirus (HPV) infection of the lower genital tract is more common among HIV-seropositive women than controls at all levels of immunosuppression.2 Cervical infection caused by HPV types of intermediate-to-high oncogenic potential (types 16, 18, 31, 33, 45) is responsible for 80% of high-grade squamous intraepithelial lesions (SIL) and subsequent cervical cancers.3 Over the last few years, several studies evaluated factors associated with HIV-related nucleic acids in cervicovaginal secretions.4–7 Although several systemic (HIV-1 RNA in plasma, severity of immunodepression) and local (cervical ectopy, vaginitis) factors influence presence and amount of HIV in genital secretions,5–7 there are no data on simultaneous presence of HIV and HPV in cervicovaginal secretions. The purpose of this study was to evaluate simultaneous HIV-related nucleic acids and HPV-DNA in cervicovaginal secretions in a cohort of known HIV-seropositive women.


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
 References
 
The study population comprised 124 known HIV-seropositive women seen at our department over a 2-year period (January 1998–December 1999) for periodic gynecologic screening of lower genital tract neoplasia. Subjects had abstained from unprotected sexual intercourse in the 3 days before their visits. A detailed questionnaire with information on demographic, sexual, and clinical data was administered to each participant. Clinical HIV staging was defined using the Centers for Disease Control and Prevention (CDC) classification system.8 Peripheral blood samples for estimating CD4+ lymphocyte cell counts and quantifying HIV-1 RNA in plasma were collected from subjects at the visits. After careful speculum examination, vaginal specimens were collected with sterile cotton swabs to diagnose infection by candida, trichomonas, or bacterial vaginosis. To evaluate candida infection, vaginal specimens were inoculated on Sabouraud’s dextrose agar containing gentamicin 40 g/mL. Cultures were incubated at 30C for 48–72 hours, then examined for growth. Isolated strains were identified using the germ tube test or auxanogram (API 20C Aux, API system, Montalieu-Vercieu, France). Vaginal specimens for trichomonas isolation were inoculated in a cysteinepeptoneliver maltose fresh medium, whereas diagnoses of bacterial vaginosis were made according to the criteria of Amsel et al.9

Cervicovaginal secretions for HIV-related nucleic acids and HPV-DNA identification were collected by gently rotating a Dacron swab within the posterior fornix, and by lavage after insertion of 10-mL or RPMI-1640 medium into the vagina, followed by aspiration of the suspension after allowing 1 minute for pooling. Swabs were used to detect cell-free HIV-1 RNA, whereas HIV-DNA and intracellular HIV-RNA transcripts together with HPV-DNA were detected from lavage samples. Upon arrival in the laboratory, and again afterwards, centrifugation samples were examined under the microscope to confirm absence of red blood cells and spermatozoa. The possible presence of blood contamination was further checked by using a routine screening test for hemoglobin detection (reactive strips, Bayer, multistic-10 visual). A detailed description of methods used to detect and quantify HIV-related nucleic acids from blood and cervicovaginal secretions has been reported elsewhere.10 The following substrates were analyzed using quantitative polymerase chain reaction (PCR) and reverse transcription PCR: 1) genomic HIV-1 RNA from plasma and cell-free cervicovaginal secretions, 2) virus-specific unspliced HIV-1 RNA transcripts from cervicovaginal cells, and 3) proviral HIV-1 DNA from nuclei of cervicovaginal cells. Qualitative analysis of specific RNA and DNA sequences was first done by PCR using the SK 426/431 pair of primers.11 RNA samples were reverse transcribed using 100 U of Moloney murine leukemia virus reverse transcriptase (RT, Gibco Life Technologies, Paisley, Scotland), 20 pmol of the SK 431 primer, 0.2 mM deoxynucleotide triphosphate, and 20 U of Rnasin (Gibco Life Technologies). DNA was subsequently amplified using 50 pmol of primers SK 462 and SK 431, 1.5 U of Taq-DNA polymerase (Perkin-Elmer Cetus, Emeryville, CA). Quantification of HIV-1 DNA and RNA was done with a competitive PCR and reverse transcription PCR as described by Menzo et al.12 Using this method, two similar RNA or DNA templates were reverse transcribed or amplified. The primer set (SK38/SK39) was specific for a highly conserved gag fragment of the HIV-1 genome, and the method has been useful in the quantitative analysis of HIV-1 genomic RNA from plasma, unspliced RNA transcript, and proviral DNA from peripheral blood mononuclear cells.13 For cervicovaginal samples, quantitative results were expressed as HIV-1 RNA transcripts and HIV-1 DNA copy number per 105 cells, and as HIV-1 RNA cell-free copy number per mL of cervicovaginal secretion. Swabs were incubated in a predefinite quantity of transport medium (1 mL), so it was possible to know the exact amount of cervicovaginal secretion present in each sample (usually 200–300 µL). Other authors4,7 measured HIV-RNA concentration directly in lavage samples. By using lavage samples, it is not possible to control for potential confounding of dilution. Under our experimental conditions, the lower limit of detection of the assay was two DNA or RNA copies/105 cells, 20 RNA copies/mL of cervicovaginal secretions, and 200 RNA copies/mL of plasma.

Human papillomavirus-DNA extraction procedures and PCR amplification were done on cervicovaginal secretions as described.14 Preliminary screening to determine overall prevalence of HPV infection was done with MY09/MY11 consensus primers. Human papillomavirus typing on positive samples was done with the "Multigen HPV" commercial kit (DiaTech, Jesi, Italy). In that assay, HPV-DNA is identified by the amplification of a 142–151 bp fragment of the L1 region by PCR and subsequent restriction fragment length polymorphism analysis of PCR products.15 The digestion pattern can yield HPV types 6, 11, 16, 18, 31, 33, 35, and 56. Mann-Whitney and Fisher exact tests were used to compare continuous and categoric data, respectively. A nonparametric approach (Spearman rank correlation coefficient) was used to analyze the association between levels of HIV-1 nucleic acids. Univariate associations between categoric variables were assessed by odds ratios (ORs) and 95% confidence intervals (CIs). Chisquare for trends was used to test trends on proportions.16 Logistic regression analysis was used to compute adjusted ORs and test for trend in multivariable models. This was not a randomized study, so we did not compute a preliminary sample. However, given a 55% rate of HPV infection among women who tested negative for cell-associated or cell-free HIV-RNA in cervicovaginal secretions, we had a 78% and 75% power to detect a minimum OR of 3 between groups.


   Results
Top
Abstract
 Materials and Methods
 Results
Discussion
 References
 
The mean age (± standard deviation [SD]) of the population studied was 31.9 ± 4.3 years, and the median time since first HIV-positive testing was 85 months (range 12–168). The rate of HIV-1 RNA detection in blood was 44.3% (95% CI 35.5, 53.5), (55 of 124). The prevalence of proviral HIV-DNA, HIV-RNA transcripts, and cell-free HIV-RNA in cervicovaginal secretions was 52.4% (95% CI 43.3, 61.5) (65 of 124), 38.7% (95% CI 30.4, 47.5) (48 of 124), and 33.9% (95% CI 25.6, 42.5) (42 of 124), respectively. Lavage samples that tested positive for cell-free HIV-1 RNA or HIV-1 RNA transcripts also were positive for proviral HIV-1 DNA. The median number of HIV-1 RNA genomes was 2000 copies/mL (range 50–60,000) in plasma samples and 250 copies/mL (range 20–3800) in cell-free cervicovaginal secretion samples. The median number of HIV-1 DNA copies and HIV-RNA specific transcripts per 105 cells was 50 (range 5–1500) and 26 (range 2–2000), respectively. Regarding the severity of HIV-related immunosuppression, 42 (33.9%) women were at stage C of HIV-disease (AIDS-defining conditions) and 39 (31.5%) had CD4+ cell counts less than 200 cells/mm3. The median number of CD4+ cell counts was 301 cell/mm3 (range 0–990). The presence of proviral HIV-1 DNA in cervicovaginal secretions correlated strongly with detection of HIV-1 RNA in plasma (41 of 55 versus 24 of 69, OR 5.49, 95% CI 2.35, 13.04, P < .001). Moreover, the rates of HIV-1 RNA transcripts and cell-free HIV-1 RNA in cervicovaginal secretions were more than fourfold higher among women who tested positive for HIV-1 RNA in plasma (32 of 55 versus 16 of 69, OR 4.61, 95% CI 1.99, 10.82, P < .001, and 28 of 55 versus 14 of 69, OR 4.07, 95% CI 1.73, 9.73, P = .001, respectively) than negative controls. The HIV-1 RNA viral load in plasma highly correlated with the amounts of HIV-1 DNA (Spearman Rho = 0.387, P < .001), HIV-1 RNA transcripts (Spearman Rho = 0.31, P = .018), and cell-free HIV-1 RNA (Spearman Rho = 0.34, P = .001) in cervicovaginal secretions.

Distribution of HPV-DNA types detected is reported in Table 1Go. The overall prevalence of HPV infection was 63.7% (95% CI 55, 71.8) (79 of 124). Table 2Go reports the association between sociodemographic and clinical variables and HPV detection. Regular condom use was associated with a 70% reduction in likelihood of HPV infection. At the time of the study, only three women were taking hormonal contraceptives. The rate of HPV infection was obviously related to severity of cytologically diagnosed squamous intraepithelial lesions (SIL) ({chi}2 for trend 9.39, P = .002) and severity of HIV-related immunodepression expressed by a decreasing number of CD4+ cells ({chi}2 for trend 6.54, P = .011). The rate of cervical SIL increased from 45% (27 of 60) among women at stage A of HIV-disease to 68.2% (15 of 22) and 76.2% (32 of 42), for women at stages B and C, respectively ({chi}2 for trend 10.36, P = .001). Prevalence of SIL was 50% (14 of 28) among women with CD4 cell counts above 500 mm3, 47.4% (27 of 57) and 84.6% (33 of 39) among women with CD4+ cell counts between 200 and 500, and less than 200/mm3, respectively ({chi}2 for trend 9.73, P = .002).


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  		Table 1. HPV-DNA Typing
 

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  		Table 2. Sociodemographic and Clinical Variables Associated With HPV Infection
 
Forty-nine of 63 women (77.8%) with genital infections (trichomonas, candida, or bacterial vaginosis) had symptoms of vulvovaginal irritation (pruritus, burning, dyspareunia) or leukorrhea. Vaginal infection was more frequent among women who tested positive for HIV-1 RNA transcripts (30 of 48 versus 33 of 76, OR 2.17, 95% CI 1.0, 4.88) or cell-free HIV-1 RNA (29 of 42 versus 34 of 82, OR 3.15, 95% CI 1.34, 7.50) in cervicovaginal secretions compared with negative subjects.

The detection of HIV-1 RNA in blood did not influence the likelihood of HPV infection. Among 28 women with plasmatic HIV-1 RNA viral loads above the median (2000 copies/mL), the prevalence of HPV infection was 75% (21 of 28) opposed to 62.3% of nonviremic controls (OR 1.81, 95% CI 0.62, 5.47). At the time of the study, 104 women (83.9%) had been receiving stable antiretroviral therapy for at least 3 months. Nucleoside analogues (zidovudine plus lamivudine or didanosine) were the only antiretroviral drugs used by 61 subjects (49.2%). Nucleoside analogues plus indinavir was the anti-HIV treatment for the remaining 43 women (34.7%).

Table 3Go shows the relationships between HPV infection and the detection of HIV-related nucleic acids in cervicovaginal secretions. Human papillomavirus-DNA of intermediate to high oncogenic risk was detected more frequently among women positive for HIV-1 RNA transcripts or cell-free HIV-1 RNA in their secretions than negative subjects. Table 4Go reports univariable and multivariable analyses of relationships between HPV infection and the HIV-related nucleic acids loads in cervicovaginal secretions. The HIV-1 viral load in cervicovaginal secretions was categorized into three groups according to median copy number of HIV-1 related nucleic acids. Overall prevalence of HPV infection correlated positively with the loads of HIV-1 RNA transcripts ({chi}2 for trend 9.84, P = .002) and cell-free HIV-1 RNA ({chi}2 for trend 10.35, P = .001) in cervicovaginal secretions. Association between HPV infection and cell-associated or cell-free HIV-1 RNA in cervicovaginal secretions was studied by logistic regression analysis. We constructed three logistic models including detection of HIV-related nucleic acids, CD4+ cell counts, vaginal infection (yes, no), HIV viremia (yes, no), regular condom use (yes, no), antiretroviral treatment (yes, no) as explanatory variables, and HPV infection as outcome variable. The results of this analysis confirmed that likelihood of HPV infection was more than three times higher among subjects who tested positive for cell-associated or cell-free HIV-1 RNA in cervicovaginal secretions than negative counterparts. Also, multivariable analysis of trend showed that increasing quantities of cell-associated (P for trend = .011) or cell-free (P for trend = .002) HIV-1 RNA in cervicovaginal secretions were associated with increased rates of overall HPV infections.


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  		Table 3. HIV-1–Related Nucleic Acids and HPV-DNA in Lavage Samples
 

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  		Table 4. HPV Infection According to Amount of HIV-Related Nucleic Acids
 

   Discussion
Top
Abstract
 Materials and Methods
 Results
 Discussion
References
 
Prevalence of HIV genital shedding in our study was similar to that reported by other authors who used different assays.4–7 Human immunodeficiency virus-DNA in cervicovaginal secretions identify infected cells but not the presence of the virus, so we also evaluated cell-associated and cell-free HIV-RNA, which are markers for in vivo viral replication. To reduce the likelihood of blood contamination, some authors17 have suggested that in studies of HIV shedding in the female genital tract, lavages are better than swabbing. For that reason, we used cervicovaginal lavages, whereas vaginal swabbing was used only to detect cell-free HIV-1 RNA. Prevalence of plasma HIV-1 RNA detection in our population was lower than reported in other investigations.4,7 Prevalence of women on stable antiretroviral treatment was greater in our study than others,4–7 and the rate of plasma HIV-1 RNA detection was similar to that reported in other Italian investigations.18 As with other investigators, we found that presence and amounts of HIV-1–related nucleic acids in cervicovaginal secretions were highly correlated with detection of HIV-1 RNA in plasma.4,5,7 However, as in the other investigations,5–7 between 20 and 35% of women without detectable HIV-1 RNA in plasma were positive for proviral HIV-1 DNA or HIV-1 RNA in cervicovaginal secretions. Those findings suggest that the processes that regulate HIV-1 dynamics in cervicovaginal secretions are different from those that regulate the virus in the blood.5,7,17 Analogous to studies in male semen, it is believed that local infection by different HIV-1 phenotypes or a different response to antiretroviral treatment could be responsible for compartmentalization of HIV-1 infection in the female genital tract.5,19 Human papillomavirus infection and lower genital tract neoplasia are common problems among HIV-seropositive women.1 Several authors1,2 reported that severity of HIV-related immunodepression is associated with increased incidence of SIL and HPV infection. Our cross-sectional data further confirm these findings. Prevalence of HPV infection in our study was similar to that reported by other investigators of our geographic area.20 We are not aware of other studies that evaluated simultaneous HIV-related nucleic acids and HPV infection in cervicovaginal secretions. Recently, Luque et al21 evaluated the relationship between the HIV-1 viral load in plasma and HPV genital infection. They found that prevalence of HPV infection correlated strongly with HIV-1 plasma levels. We were not able to show a crude relationship between HIV-1 RNA in plasma and HPV infection; however, HPV types of intermediate-to-high oncogenic risk were detected more frequently among women actively shedding HIV-1 RNA in cervicovaginal secretions than negative controls. Subsequent analysis using quantitative data suggested strongly that the rate of HPV infection increases among women with high HIV-1 viral loads in cervicovaginal secretions. Some studies22,23 suggested that markers of advanced HIV disease such as CD4 cell counts or HIV-RNA plasmatic levels are associated with increased risk of HPV infection and SIL. However, there are several data that indicated that the relationship between HIV and HPV is more complex. At least among women with low numbers of sexual partners, HPV and HIV-1 are independent risk factors for cervical neoplasia.23 Human immunodeficiency virus infection is associated with an increased transcriptional activity of early HPV genes such as E7.24 In vitro studies25 have shown that HIV-1 activates integrated HPV-18 and induces synthesis of the L1 capsid protein. In addition, HIV-1 related genes are able to interact with HPV-16 E6, modifying the cell-cycle of cervical cancer cells.26 In our study, the relationship between HPV infection and HIV-1 genital shedding persisted after adjustment for confounders that described severity of HIV-related immunosuppression or antiretroviral drugs. In vitro studies and, indirectly, our findings suggest that the association between HIV and HPV in cervicovaginal lavages could be caused in part by a direct or cytokine-mediated action of HIV, in addition to HIV-related immunodepression. Future studies aimed at simultaneous quantitation of HIV and HPV viral copies in cervicovaginal secretions could further clarify the relationship between the two infections.


   Footnotes
 
PII S0029-7844(00)01130-9

Received September 18, 2000. Received in revised form December 6, 2000. Accepted January 12, 2001.


   References
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 Materials and Methods
 Results
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 References
 
1. Palefsky JM, Minkoff H, Kalish LA, Levine A, Sacks HS, Garcia P, et al. Cervicovaginal human papillomavirus infection in human immunodeficiency virus1 (HIV)-positive and high-risk HIV-negative women. J Natl Cancer Inst 1999;91:226–36.[Abstract/Free Full Text]

2. Sun X, Ellerbrock TV, Lungu O, Chiasson MA, Bush TJ, Wright TC. Human papillomavirus infection in human immunodeficiency virus-seropositive women. Obstet Gynecol 1995;85:680–6.[Abstract]

3. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, et al. Prevalence of human papillomavirus in cervical cancer: A worldwide perspective. J Natl Cancer Inst 1995;85:796–802.

4. Cu-Uvin S, Caliendo AM, Reinert S, Chang A, Juliano-Remollino C, Flanigan TP, et al. Effect of highly active antiretroviral therapy in cervicovaginal HIV-1 RNA. AIDS 2000;10:415–21.

5. Iversen AKN, Larsen AR, Jensen T, Fugger L, Balsler U, Wahl S, et al. Distinct determinants of human immunodeficiency virus type 1 RNA and DNA loads in vaginal and cervical secretions. J Infect Dis 1998;177:1214–20.[Medline]

6. Rasheed S, Zhiliang L, Xu D, Kovacs A. Presence of cell-free human immunodeficiency virus in cervicovaginal secretions is independent of viral load in the blood of human immunodeficiency virus-infected women. Am J Obstet Gynecol 1996;175:122–30.[Medline]

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12. Menzo S, Bagnarelli P, Giaca M, Manzin A, Varaldo PE, Clementi M. Absolute quantitation of viremia in human immunodeficiency virus infection by competitive reverse transcription and polymerase chain reaction. J Clin Microbiol 1992;30:1752–7.[Abstract/Free Full Text]

13. Bagnarelli P, Valenza A, Menzo S, Manzin A, Scalise G, Varaldo PE, et al. Dynamics of molecular parameters of human immunodeficiency virus type 1 activity in vivo. J Virol 1994;68:2495–502.[Abstract/Free Full Text]

14. Manos MM, Tying Y, Wright DK, Lewis AJ, Broker TR, Wolinsky SM. Use of polymerase chain reaction amplification for the detection of genital human papillomavirus. Cancer Cells 1989;7:209–14.

15. Tyng Y, Manos MM. Detection and typing of genital human papillomaviruses. In: Innis MA, Gelfand DH, Sninsky JJ, White TJ, eds. PCR protocols: A guide to methods and applications. San Diego: Academic Press, 1990:356–67.

16. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22: 719–48.

17. Ghys PD, Fransen K, Diallo MO, Ettiegne-Traore V, Coulibaly IM, Yeboue KM, et al. The associations between cervicovaginal HIV shedding, sexually transmitted diseases and immunosuppression in female sex workers in Abidjan, Cote d’Ivoire. AIDS 1997;12:F85–93.

18. Re MC, Ramazzotti E, Manfredi R, Furlini G, Vignoli M, Maldini C, et al. Viral load trend in HIV-1 seropositive patients with different CD4 cell counts before starting HAART. J Clin Virol 2000;17:5–11.[Medline]

19. Coombs RW, Speck CE, Hughes JP, Lee W, Sampoleo R, Ross SO, et al. Association between culturable human immunodeficiency virus type 1 in semen and HIV-1 RNA levels in semen and blood: Evidence for compartmentalization of HIV-1 between semen and blood. J Infect Dis 1998;177:320–30.[Medline]

20. Uberti-Foppa C, Origoni M, Maillard M, Ferrari D, Ciuffreda D, Mastrorilli E, et al. Evaluation of the detection of human papillo-mavirus genotypes in cervical specimens by hybrid capture as screening for precancerous lesions in HIV-positive women. J Med Virol 1998;56:133–7.[Medline]

21. Luque AE, Demeter LM, Reichman RC. Association of human papillomavirus infection and disease with magnitude of human immunodeficiency virus type 1 (HIV-1) RNA plasma level among women with HIV-1 infection. J Infect Dis 1999;179:1405–9.[Medline]

22. Massad LS, Riester KA, Anastos KM, Fruchter RG, Palefsky JM, Burk RD, et al. Prevalence and predictors of squamous cell abnormalities in Papanicolau smears from women infected with HIV-1. Women’s Interagency HIV Study Group. J Acquir Immune Defic Syndr 1999;21:33–41.

23. Vernon SD, Unger ER, Piper MA, Severin ST, Wiktor SZ, Ghys PD, et al. HIV and human papillomavirus as independent risk factors for cervical neoplasia in women with high or low numbers of sex partners. Sex Transm Infect 1999;75:258–60.[Abstract]

24. Arany I, Tyring SK. Systemic immunosuppression by HIV influences HPV transcription and thus local immune responses in condyloma acuminatum. Int J STD AIDS 1998;5:268–71.

25. Dolei A, Curreli S, Marongiu P, Pirangieli A, Gomes E, Bucci M, et al. Human immunodeficiency virus infection in vitro activates naturally integrated human papillomavirus type 18 and induces synthesis of the L1 capsid protein. J Gen Virol 1999;80:2937–44.[Abstract/Free Full Text]

26. Toy EP, Rodriguez-Rodriguez L, McCance D, Ludlow J, Planelles V. Induction of cell-cycle arrest in cervical cancer cells by the human immunodeficiency virus type 1 viral protein R. Obstet Gynecol 2000;95:141–6.[Abstract/Free Full Text]




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