Short Communication Human Papillomavirus Capsid Antibody Response to Natural Infection and Risk of Subsequent HPV Infection in HIV-Positive and HIV-Negative Women Raphael P. Viscidi, 1 Brad Snyder, 3 Susan Cu-Uvin, 4 Joseph W. Hogan, 3 Barbara Clayman, 1 Robert S. Klein, 5 Jack Sobel, 6 and Keerti V. Shah 2 1 Johns Hopkins University School of Medicine and 2 School of Public Health, Baltimore, Maryland; 3 Center for Statistical Sciences, Department of Community Health and 4 The Miriam Hospital, Brown University, Providence, Rhode Island; 5 Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York; and 6 Harper Hospital, Detroit, Michigan Abstract The association between seropositivity to virus-like particles (VLP) of human papillomavirus (HPV) types 16, 18, 31, 35, or 45 and subsequent cervical HPV infection was examined in 829 women with HIV and 413 risk-matched HIV-negative women. We found no statistically significant differences between HPV-seropositive and HPV-seronegative women in the risk of a new infection with the homologous HPV type, with the exception of a reduced risk of HPV 45 infections 4.5 years beyond the baseline serology measurement in HIV- positive women [hazard ratio, 0.21; 95% confidence interval (CI), 0.05-0.89]. Among HIV-negative women, HPV seropo- sitivity was not associated with a statistically significant reduced risk of infections with related viruses in the HPV 16, HPV 18, or ‘‘other’’ HPV groups. Among HIV-positive women, HPV seropositivity was associated with a slightly increased risk of infection with group-related viruses, but the differences were only statistically significant for infec- tion with HPV 16 group viruses (hazard ratio, 1.6; 95% CI, 1.1-2.3) in HPV 18-seropositive women and for infections with ‘‘other’’ HPV group viruses in HPV 31-seropositive women (hazard ratio, 1.45; 95% CI, 1.0-2.0). The lack of a protective immune effect from natural infection is most likely due to the low level of antibody elicited by natural HPV infection and/or the potential for reactivation of HPV, especially in HIV-positive women. (Cancer Epidemiol Bio- markers Prev 2005;14(1):283 – 8) Introduction Human papillomavirus (HPV) is the most common sexually transmitted viral infection in the world. An estimated 60% of sexually active women will become infected with a genital HPV in their lifetime (1– 3). In the majority of women, the infection is asymptomatic and cleared within weeks to months (4, 5). More than 40 HPV types infect the genital tract. Whether the antibody response to one type of HPV confers protection against subsequent infection with the same or related types is unknown. For many viruses, the presence of serum neutralizing antibodies is a correlate of immune protection (6). HPV cannot be cultivated in tissue culture; therefore, true neutralization assays are not available. Surro- gate neutralization assays with the use infectious pseudovi- rions have been developed but these methods are insensitive and inefficient for large-scale epidemiologic studies (7). Capsid proteins of HPV produced in insect cells self-assemble into virus-like particles (VLP; ref. 8). VLPs have many immunologic features of native virions including display of type-specific, surface-exposed neutralizing epitopes (8), and are suitable reagents for use in enzyme immunoassays (9). Among recipients of an HPV 16 L1 VLP vaccine, for example, the serum antibody titer measured by VLP-based enzyme immunoassay was highly correlated with the neutralizing antibody titer, thereby indicating the VLP-based enzyme immunoassay can serve as a surrogate marker for neutralizing antibodies (10). Compared with HIV-negative women, HIV-infected women have a higher prevalence of cervical HPV infection (11) and are at increased risk of acquiring new HPV infections (12). Whether prior HPV type-specific immune status influences the risk of HPV infection in HIV-positive women is unknown. The HIV Epidemiology Research Study (HERS) is a large prospective cohort study of HIV-positive and risk- matched HIV-negative women recruited at multiple sites around the United States (13). The women in HERS have had HPV DNA measurements at approximately 6-month intervals for up to 6 years, providing a wealth of data on detection of type-specific HPV infection. To assess whether anti-VLP antibodies are a marker of immune protection, we examined measures of baseline serum antibodies to VLPs of HPV types 16, 18, 31, 35, and 45 in 829 HIV-positive and 413 HIV-negative women enrolled in HERS and analyzed the association of seropositivity with risk of detection of HPV DNA during follow-up. Methods Study Population. The study population was drawn from HERS. These women were recruited at four sites: Baltimore, MD; Bronx, NY; Detroit, MI; and Providence, RI. The cohort characteristics, recruitment methods, and protocols of the Received 3/30/04; revised 7/16/04; accepted 8/6/04. Grant support: NIH grants AI-42058 (R.P. Viscidi) and R01-AI-50505 (J.W. Hogan), the Lifespan/Tufts/Brown Center for AIDS Research (NIH grant P30-AI-42853), and Centers for Disease Control and Prevention (contracts U64/CCU106795, U64/CCU206798, U64/ CCU306802, and U64/CCU506831). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Raphael P. Viscidi, Johns Hopkins Hospital, Blalock Room 1105, 600 North Wolfe Street, Baltimore, MD 21287. Phone: 410-614-1494; Fax: 410-955-3723. E-mail: rviscid1@jhem.jhmi.edu Copyright D 2005 American Association for Cancer Research. 283 Cancer Epidemiol Biomarkers Prev 2005;14(1). 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