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1.  Characterization of three novel human papillomavirus types isolated from oral rinse samples of healthy individuals 
Despite the strong evidence of HPV infection as the etiological agent in a subset of oral cancer, oral α-HPV detection is rare in healthy individuals, and little is known of the existing of novel HPV types in oral cavity.
We determined whether novel HPV types can be isolated from oral rinse samples collected from healthy individuals.
Study design
We performed rolling circle amplification (RCA) coupled with degenerated PCR assay on 48 oral rinse samples to amplify novel HPV types. Full length HPV DNA was cloned using long range PCR. Quantitative type specific Taqman assays were used to determine the prevalence of novel HPV types in 158 archived oral tissue samples.
We were able to isolate four novel human papillomavirus types. Full length HPV DNA was cloned for three of the four novel HPV types. All four HPV types belong to the genus Gammapapillomavirus (γ-PV), where HPV 171 is most closely related to HPV 169, showing 88% similarity; HPV 172 is most closely related to HPV 156, showing 70% similarity; HPV 173 is most closely related to HPV 4, showing 73% similarity; oral sample lavage (OSL) 37 is most closely related to HPV 144, showing 69% similarity. Finally, we showed that HPV 173 was rarely present in oral tissues (2/158), HPV 172 was only detected in normal oral tissues (25/76), and HPV 171 was more prevalent in malignant oral tissues (17/82 vs 10/76, p=0.21).
Novel γ-HPV types are present in oral cavity of healthy individuals.
PMCID: PMC3898882  PMID: 24268765
HPV; oral lavage; oral squamous cell carcinoma
2.  Behavioral, Biological, and Demographic Risk and Protective Factors for New HIV Infections among Youth, Rakai, Uganda 
Prevalence of HIV infection is considerable among youth, although data on risk factors for new (incident) infections is limited. We examined incidence of HIV infection and risk and protective factors among youth in rural Uganda, including the role of gender and social transitions.
Participants were sexually experienced youth (15–24 years-old) enrolled in the Rakai Community Cohort Study,1999–2008 (n=6741). Poisson regression with robust standard errors was used to estimate incident rate ratios (IRR) and 95% confidence intervals (CI) of incident HIV infection.
HIV incidence was greater among young women than young men (14.1 vs. 8.3 per 1000 person-years, respectively); this gender disparity was greater among teens (14.9 vs. 3.6). Beyond behavioral (multiple partners and concurrency) and biological factors (sexually transmitted infection (STI) symptoms), social transitions such as marriage and staying in school influenced HIV risk. In multivariate analyses among women, HIV incidence was associated with living in a trading village [adjusted IRR (aIRR) = 1.48; 95% CI: 1.04 to 2.11], being a student (aIRR = 0.22; 95% CI: 0.07 to 0.72), current marriage (aIRR = 0.55; 95% CI: 0.37 to 0.81), former marriage (aIRR = 1.73; 95% CI: 1.01 to 2.96), having multiple partners, and sexually transmitted infection symptoms. Among men, new infections were associated with former marriage (aIRR = 5.57; 95% CI: 2.51 to 12.36), genital ulceration (aIRR = 3.56; 95% CI: 1.97 to 6.41), and alcohol use (aIRR = 2.08; 95% CI: 1.15 to 3.77).
During the third decade of the HIV epidemic in Uganda, HIV incidence remains considerable among youth, with young women particularly at risk. The risk for new infections was strongly shaped by social transitions such as leaving school, entrance into marriage, and marital dissolution; the impact of marriage was different for young men than women.
PMCID: PMC4131841  PMID: 23535293
Youth; Uganda; HIV; Incidence; Risk Factors; Education
3.  Abstinence Promotion Under PEPFAR: The Shifting Focus of HIV Prevention For Youth 
Global public health  2013;8(1):1-12.
Abstinence-until-marriage (AUM) – strongly supported by religious conservatives in the U.S. - became a key element of initial HIV prevention efforts under the President’s Emergency Plan for AIDS Relief (PEPFAR). AUM programs have demonstrated limited efficacy in changing behaviors, promoted medically inaccurate information, and withheld life-saving information about risk reduction. A focus on AUM also undermined national efforts in Africa to create integrated youth HIV prevention programs. PEPFAR prevention efforts after 2008 shifted to science-based programming, however vestiges of AUM remain. Primary prevention programs within PEPFAR are essential and nations must be able to design HIV prevention based on local needs and prevention science.
PMCID: PMC3984004  PMID: 23327516
HIV; PEPFAR; Abstinence; Youth; Prevention
4.  Serum Antibody Response Following Genital α9 Human Papillomavirus Infection in Young Men 
The Journal of Infectious Diseases  2011;204(2):209-216.
Background. Although the prevalence of human papillomavirus (HPV) genital infection is similarly high in males and females, seroprevalence is lower in males. This study assessed rates and determinants of seroconversion after detection of genital HPV infection in young men.
Methods. We investigated HPV type-specific seroconversion in a cohort of heterosexual male university students who had an α9 HPV type (HPV-16, -31, -33, -35, -52, -58, or -67) detected in the genital tract (n = 156). HPV DNA and antibodies were detected and typed using liquid bead-based multiplex assays. We calculated seroconversion using Kaplan–Meier survival analysis. Cox proportional hazards models with generalized estimating equations were used to examine associations with seroconversion.
Results. Within 24 months of detecting genital HPV infection, type-specific seroconversion ranged from 4% for HPV–52 to 36% for HPV-31. HPV-16 seroconversion at 24 months was 13% (95% confidence interval [CI], 7%–25%). Among incident HPV infections, ever cigarette smoking and infection site(s) (shaft/scrotum and glans/urine vs shaft/scrotum or glans/urine only) were positively associated with type-specific seroconversion.
Conclusions. For each of the α9 HPV types, type-specific seroconversion within 24 months was observed in 36% or less of infected men. Seroconversion might be related to cigarette smoking and genital site(s) infected.
PMCID: PMC3114468  PMID: 21673030
5.  Viral Load in the Natural History of Human Papillomavirus Type 16 Infection: A Nested Case–control Study 
The Journal of Infectious Diseases  2011;203(10):1425-1433.
Background. Viral load may influence the course of human papillomavirus type 16 (HPV-16) infection.
Methods. This case-control study was nested within the 2-year Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous Intraepithelial Lesion Triage Study, in which women were followed semiannually for HPV and cervical intraepithelial neoplasia (CIN). Case patients (n = 62) were women diagnosed with CIN3 following HPV-16–positive detection at a follow-up visit. HPV-16–positive controls (n = 152) without CIN2 or CIN3 were matched to cases based on the follow-up visit in which viral load was measured. Real-time polymerase chain reaction was used for HPV-16 DNA quantification.
Results. The risk of CIN3 increased with increasing HPV-16 DNA load at the follow-up visit (odds ratio, 1.63; 95% confidence interval, 1.33–1.99 per 1 log10 unit increase); the association was not affected by whether HPV-16 was present at enrollment. When HPV-16 was present at both enrollment and follow-up, viral load remained high among cases (P = .77) but decreased substantially among controls (P = .004). Among women with HPV-16 found initially during follow-up, viral load in the first HPV-16–positive sample was associated with short-term persistence; load was higher in those with infection, compared with those without infection, 1 visit after the initial positivity (P = .001).
Conclusions. Viral load of newly detected infections and changes in viral load predict persistence and progression of HPV-16 infections.
PMCID: PMC3080901  PMID: 21415020
6.  Human Papillomavirus Type 16 Variants in Paired Enrollment and Follow-up Cervical Samples: Implications for a Proper Understanding of Type-Specific Persistent Infections 
The Journal of Infectious Diseases  2010;202(11):1667-1670.
Prospective studies of the persistence of human papilloma-virus (HPV) variants are rare and typically small. We sequenced HPV-16 variants in longitudinal pairs of specimens from 86 women enrolled in the ASCUS-LSIL Triage Study. A change of variants was identified in 4 women (4.7% [95% confidence interval, 1.3%-11.5%]). Among women with intervening HPV results (n = 60), a variant switch occurred in 2 of 11 who had evidence of intervening negativity for HPV-16, compared with 1 of 49 who consistently tested positive (P = .11). These results suggest the possibility that rare misclassification of transient infections as persistent infections occurs in natural history studies of type-specific HPV infections.
PMCID: PMC3107552  PMID: 20977339
7.  Baseline human papillomavirus type 16 and 18 DNA load and persistence of the type-specific infection during a 2-year follow-up 
The Journal of infectious diseases  2009;200(11):1789-1797.
Studies of viral load-related persistence of human papillomavirus (HPV) infection are rare, with inconsistent results reported.
Study subjects were 741 and 289 women who were positive for HPV16 and HPV18, respectively, at enrollment into in the ASCUS-LSIL Triage Study and who returned one or more times for HPV testing during a biannual 2-year follow-up. Baseline HPV16 and HPV18 copies per nanogram of cellular DNA were measured by real-time polymerase chain reaction.
Women with, compared to without, persistent infection at month 6 had higher viral load at enrollment (P<0.001 for HPV16; P=0.01 for HPV18). The association of per 1 log10-unit increase in viral load with the first 6-month persistence of HPV16 or HPV18 was statistically significant among women with multiple types at enrollment (OR=1.53, 95% CI, 1.29–1.82 for HPV16; OR=1.35, 95% CI, 1.09–1.68 for HPV18) but not among those with mono-type infections (test for interaction between viral load and coinfection: P=0.002 for HPV16; P=0.34 for HPV18). Among women who continued to be positive at month 6, 12, or 18, persisting for another 6 months was unrelated to baseline viral load.
Higher viral load of prevalent HPV16 or HPV18 infection was associated with short- but not long-term persistence.
PMCID: PMC2783915  PMID: 19848609
Human Papillomavirus; Viral Load; Persistence
8.  Relationship between cigarette smoking and human papillomavirus type 16 and 18 DNA load 
Although cigarette smoking has been associated with increased human papillomavirus (HPV) detection, its impact on HPV DNA load is unknown.
Study subjects were women who were positive for HPV16 and/or HPV18 at enrollment into the ASCUS-LSIL Triage Study. Assessments of exposure to smoke and sexual behavior were based on self-report. Viral genome copies per nanogram of cellular DNA were measured by multiplex real-time polymerase chain reaction. Linear or logistic regression models were used to assess the relationship between cigarette smoking and baseline viral load.
Of 1,050 women (752 with HPV16, 258 with HPV18, and 40 with both HPV16 and HPV18), 452 (43.0%) were current smokers and 101 (9.6%) were former smokers at enrollment. Baseline viral load was statistically significantly greater for current, compared to never, smokers (P = 0.03 for HPV16; P = 0.02 for HPV18), but not for former smokers. Among current smokers, neither HPV16 nor HPV18 DNA load appeared to vary appreciably by age of smoking initiation, smoking intensity or smoking duration. Results remained similar, when the analysis of smoking-related HPV16 DNA load was restricted to women without detectable cervical abnormality.
Higher baseline HPV16 and HPV18 DNA load was associated with status as a current but not former smoker. A lack of dose-response relationship between cigarette smoking and viral load may indicate a low threshold for the effect of smoking on HPV DNA load.
PMCID: PMC2920639  PMID: 19959700
Human Papillomavirus; Viral Load; cigarette smoking
9.  Identification of Recombinant Human Papillomavirus Type 16 Variants 
Virology  2009;394(1):8-11.
Intratypic diversity of human papillomavirus (HPV) genome is generally characterized by point mutation, insertion, and/or deletion. Using PCR-based cloning and sequencing, we detected concurrent infection with 8 HPV16 variants in a woman enrolled in the ASCUS-LSIL Triage Study. The European variant was the major variant; each of the seven minor variants had partial DNA sequences identical to the European variant and another part identical to the African-2 variant. At a follow-up visit, only an HPV16 African-2 variant was detected. Results from the present study suggest presence of intratypic recombination of HPV genome in natural infection.
PMCID: PMC2769496  PMID: 19758676
human papillomavirus; recombination; variant
10.  Human Papillomavirus Types 16 and 18 DNA Load in Relation to Coexistence of Other Types, Particularly Those in the Same Species 
Infection with multiple human papillomavirus (HPV) types is common. However, it is unknown whether viral DNA load is related to the coexistence of other types.
Study subjects were 802 and 303 women who were positive for HPV16 and HPV18, respectively, at enrollment into the Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous Intraepithelial Lesion Triage Study. HPV16 and HPV18 E7 copies per nanogram of cellular DNA in cervical swab samples were measured by real-time polymerase chain reaction in triplicate.
Concurrent coinfection was common in this population of women with minor cervical lesions; multiple HPV types were detected in 573 (71.4%) of 802 HPV16-positive women and 227 (74.9%) of 303 HPV18-positive women. The adjusted odds ratio associating coinfection with per 1 log unit increase in HPV16 DNA load was 0.78 (95% confidence interval (CI), 0.68-0.89); it was 0.64 (95% CI, 0.52-0.79) for a similar analysis of HPV18 DNA load. Women with, compared to without, coinfection of A9 species possessed a significantly lower HPV16 DNA load (p < 0.001) whereas women with, compared to without, coinfection of A7 species types possessed a significantly lower HPV18 DNA load (p = 0.001). A trend of decrease in HPV16 DNA load with increasing number of the coexisting non-HPV16 A9 species types was statistically significant (p for trend = 0.001).
Coinfection with other types was associated with lower HPV16 and HPV18 DNA load. The extent of reduction was correlated to phylogenetic distance of the coexisting types to HPV16 and HPV18, respectively.
PMCID: PMC2745080  PMID: 19690188
Human Papillomavirus; Viral Load; Coinfection
11.  Age of Diagnosis of Squamous Cell Cervical Carcinoma and Early Sexual Experience 
Given the established links between young age at first intercourse (AFI), number of sex partners, high-risk human papillomavirus infection, and squamous cell cervical cancer (SCC), we hypothesized that women diagnosed with SCC at younger ages would be more likely to report young AFI than women diagnosed later in life.
We performed a population-based investigation among invasive SCC cases who were diagnosed between 1986 and 2004, were 22 to 53 years old, and lived in the metropolitan Seattle-Puget Sound region (n=333). Using multivariate linear regression, we estimated coefficients and 95% confidence intervals (CI) to assess the association between age at SCC diagnosis and AFI (<15, 15–18, ≥19) and number of sex partners before age 20 (0, 1, 2–4, 5–14, 15+), accounting for birth year and other factors. Interactions were assessed using the likelihood ratio test.
The interval between AFI and SCC diagnosis ranged from 4 to 35 years. In a multivariate model, compared to SCC cases reporting AFI≥19, the mean age of diagnosis was 3.1 years younger for SCC cases reporting AFI<15 (CI: −5.8, −0.5) and 2.6 years younger for SCC cases reporting AFI 15–18 years (CI: −4.6, −0.6). Although number of sex partners before age 20 was associated with age at SCC diagnosis in a crude analysis, the association was not independent of AFI. However, in the AFI≥19 and AFI<15 groups, differences in effect were seen by number of sex partners before age 20 (p for interaction=0.08), with the association remaining strong and significant only in the AFI<15 group that had 2 or more partners before age 20 (coefficient: −4.2, CI: −6.3, −2.1).
Among younger and middle-aged women with SCC, early age of diagnosis was associated with early AFI, though the effect appeared to be modified by number of sex partners before age 20.
PMCID: PMC2667560  PMID: 19318437
Cervical Carcinoma; Sexual Initiation; Age
12.  Risk factors for Barrett’s esophagus among patients with gastroesophageal reflux disease: A community clinic-based case-control study 
To measure the relative risks of Barrett’s esophagus (BE) associated with demographic factors, measures of adiposity and smoking among patients with gastroesophageal reflux disease (GERD).
Patients newly diagnosed with specialized intestinal metaplasia (SIM) (n=197) were compared to patients with GERD (n= 418) in a community clinic-based case-control study. Case sub-groups included those with any visible columnar epithelium (VBE) (n=97), and those with a long segment (=2cm) of columnar epithelium (LSBE) (n=54).
Risks increased with older age (adjusted odds ratio (aOR) per decade for SIM=1.3, 95% confidence interval (CI)= 1.1–1.5; VBE aOR=1.4, CI=1.1–1.6; LSBE aOR=1.5, CI=1.2–1.9), male gender (SIM aOR=1.5, CI=1.1–2.2; VBE aOR=2.7, CI=1.6–4.5; LSBE aOR=3.9, CI=1.9–8.1) and possibly Asian race. Increased risk of BE in particular was observed with high waist-to-hip ratio (WHR, male high: =0.9, female high: =0.8) (SIM aOR=1.3, CI=0.9–2.1; VBE aOR=1.9, CI=1.0–3.5; LSBE aOR=4.1, CI=1.5–11.4). These associations were independent of body mass index (BMI) for the VBE and LSBE case groups but not for SIM which was the only case group in which BMI was a significant risk factor. Ever smoking cigarettes increased risk similarly for all case groups (SIM aOR=1.8, CI=1.2–2.6; VBE aOR=1.6, CI=1.0–2.6; LSBE aOR=2.6, CI=1.3–4.9), although dose response relationship was not detected for duration or intensity of smoking.
Older age, male gender and history of smoking increased risk of SIM and BE among GERD patients independent of other risk factors for BE. Central adiposity was most strongly related to risk of VBE and LSBE. These results may be useful in development of risk profiles for screening GERD patients.
PMCID: PMC2714477  PMID: 19319131
Barrett’s esophagus; body mass index (BMI); gastroesophageal reflux disease (GERD); epidemiology; obesity

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