Faculty Bibliography

Male circumcision (MC) reduces penile high-risk human papillomavirus (HR-HPV) on the coronal sulcus and urethra. HR-HPV varies by anatomic site, and it is unknown whether MC decreases HR-HPV on the penile shaft. We assessed the efficacy of MC to reduce HR-HPV on the penile shaft and compared it to known efficacy of MC to reduce HR-HPV on the coronal sulcus. HIV-negative men randomized to receive immediate circumcision (intervention) or circumcision delayed for 24 months (control) were evaluated for HR-HPV at 12 months postenrollment using the Roche HPV Linear Array assay. Among swabs with detectable β-globin or HPV, year 1 HR-HPV prevalence on the coronal sulcus was 21.5% in the intervention arm and 36.3% in the control arm men [adjusted prevalence risk ratios (PRRs) = 0.57, 95% CI 0.39-0.84, p = 0.005]. On the shaft, year 1 HR-HPV prevalence was 15.5% in the intervention and 23.8% in the control arm (adjusted PRR = 0.66, 95% CI 0.39-1.12, p = 0.12). Efficacy of MC to reduce HR-HPV on the shaft was similar to efficacy on the coronal sulcus (p = 0.52). In a sensitivity analysis in which swabs without detectable β-globin or HPV were included as HPV negative, prevalence of HR-HPV on the shaft was lower in the intervention arm (7.8%) than control arm (13.6%; PRR 0.57, 95% CI 0.33-0.99, p < 0.05). HR-HPV was more frequently detected on the coronal sulcus than penile shaft among uncircumcised men (36.3% vs. 23.8%, respectively, p = 0.02) and circumcised men (21.5% vs. 15.5%, respectively, p = 0.24). MC reduced HR-HPV prevalence on both the coronal sulcus and shaft.

BACKGROUND:Male circumcision reduces the transmission of high-risk human papillomavirus (HPV) in HIV-uninfected men and their female partners. We assessed whether circumcision of HIV-infected men would reduce the transmission of high-risk HPV to their female partners. METHODS:Female partners of HIV-infected men (aged 15-49 years) in Rakai, Uganda, with CD4 counts of greater than 350 cells per mL who were randomly assigned to undergo circumcision immediately (intervention group) and after 24 months (control group) were assessed for infection with high-risk HPV. Randomisation was done in blocks of 20, stratified by community, with computer-generated random numbers. Laboratory technicians and female fieldworkers were masked to the circumcision status of male participants. The main outcome assessed in this study was the effects of circumcision of HIV-infected men on transmission of HPV to their female partners. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00124878. FINDINGS/RESULTS:474 men were assigned to the intervention group, 448 to the control group. 211 women were in consensual relationships with 193 men in the intervention group, and 171 women were in consensual unions with 155 men in the control group. High-risk HPV at the 2-year follow-up was prevalent in 88 female partners (55%) of 159 men in the intervention group and 68 (52%) of 131 female partners of men in the control group (prevalence risk ratio 1·07, 95% CI 0·86-1·32, p=0·64). Incidence of high-risk HPV over 2 years was 32·0 per 100 person-years in the female partners of men in the intervention group and 30·6 per 100 person-years in the female partners of men in the control group (incidence rate ratio 1·05, 0·77-1·43, p=0·78). No difference was noted in the clearance of genotype-specific high-risk HPV between the intervention group (196 [46%] of 424) and control group (167 [48%] of 347; rate ratio 0·96, 0·83-1·12; p=0·61). INTERPRETATION/CONCLUSIONS:Because circumcision of HIV-infected men did not affect transmission of high-risk HPV to their female partners, promotion of consistent safe sexual practices for HIV-infected men remains important. FUNDING/BACKGROUND:Bill & Melinda Gates Foundation and National Institutes of Health.

BACKGROUND:Randomised trials show that male circumcision reduces the prevalence and incidence of high-risk human papillomavirus (HPV) infection in men. We assessed the efficacy of male circumcision to reduce prevalence and incidence of high-risk HPV in female partners of circumcised men. METHODS:In two parallel but independent randomised controlled trials of male circumcision, we enrolled HIV-negative men and their female partners between 2003 and 2006, in Rakai, Uganda. With a computer-generated random number sequence in blocks of 20, men were assigned to undergo circumcision immediately (intervention) or after 24 months (control). HIV-uninfected female partners (648 of men from the intervention group, and 597 of men in the control group) were simultaneously enrolled and provided interview information and self-collected vaginal swabs at baseline, 12 months, and 24 months. Vaginal swabs were tested for high-risk HPV by Roche HPV Linear Array. Female HPV infection was a secondary endpoint of the trials, assessed as the prevalence of high-risk HPV infection 24 months after intervention and the incidence of new infections during the trial. Analysis was by intention-to-treat. An as-treated analysis was also done to account for study-group crossovers. The trials were registered, numbers NCT00425984 and NCT00124878. FINDINGS/RESULTS:During the trial, 18 men in the control group underwent circumcision elsewhere, and 31 in the intervention group did not undergo circumcision. At 24-month follow-up, data were available for 544 women in the intervention group and 488 in the control group; 151 (27·8%) women in the intervention group and 189 (38·7%) in the control group had high-risk HPV infection (prevalence risk ratio=0·72, 95% CI 0·60-0·85, p=0·001). During the trial, incidence of high-risk HPV infection in women was lower in the intervention group than in the control group (20·7 infections vs 26·9 infections per 100 person-years; incidence rate ratio=0·77, 0·63-0·93, p=0·008). INTERPRETATION/CONCLUSIONS:Our findings indicate that male circumcision should now be accepted as an efficacious intervention for reducing the prevalence and incidence of HPV infections in female partners. However, protection is only partial; the promotion of safe sex practices is also important. FUNDING/BACKGROUND:The Bill & Melinda Gates Foundation, National Institutes of Health, and Fogarty International Center.

INTRODUCTION/BACKGROUND:Microbial translocation has been implicated as a contributing factor to the heightened immune activation observed during HIV-1 disease progression. When examined in a longitudinal study of HIV-1 seroconverters in Rakai, Uganda, microbial translocation was not associated with HIV-1 disease progression. However, the role of general immune activation in HIV disease progression in this population was not fully examined. METHODS:Longitudinal serum samples of HIV-1 seroconverters in three HIV-1 disease progression groups [long-term nonprogressors (LTNP), standard progressors (SP), and rapid progressors (RP)] from Rakai, Uganda, were tested for levels of C-reactive protein (CRP), a marker for immune activation. RESULTS:CRP levels significantly increased in the SP group (P < 0.0001) but not in the RP group or the LTNP group. CRP levels during the first year post-HIV seroconversion in the RP group were significantly higher than those observed in the LTNP group (P < 0.05). For the entire population, CRP levels negatively correlated with lipopolysaccharide levels (P < 0.05) and were not associated with endotoxin antibody levels. CONCLUSIONS:This study suggests that in this population, increased immune activation is significantly associated with HIV-1 disease progression but not microbial translocation.

Organisms belonging to the genus Streptomyces produce numerous important secondary metabolites and undergo a sophisticated morphological differentiation program. In many instances these processes are under the control of gamma-butyrolactone (GBL) autoregulatory systems. Streptomyces acidiscabies strain 84.104 produces the secondary metabolite aromatic angucyclinone polyketide WS5995B. In order to explore the role of GBL regulatory circuitry in WS5995B production and morphogenesis in S. acidiscabies, a gene cluster encoding GBL autoregulatory signaling homologs was identified and characterized. Two GBL receptor homologs, sabR and sabS, were found flanking a GBL synthase homolog sabA. Strains carrying mutations in sabS produced elevated levels of WS5995B and displayed conditional morphological defects reminiscent of defects seen in Streptomyces bldA mutants. Notably, sabS possesses a TTA codon predicted to be recognized by tRNA(leu). sabA mutants produced higher levels of WS5995B than the wild-type strain but to a lesser extent than the levels of WS5995B seen in sabS mutants. Purified recombinant SabR and SabS were tested for their abilities to bind predicted AT-rich autoregulatory element (ARE) boxes within the sabRAS region. SabS did not bind any DNA sequences in this region, while SabR bound an ARE box in the region upstream of sabS. Quantitative reverse transcription-PCR analysis revealed higher levels of sabS transcript in sabR mutants than in the wild-type strain, suggesting that sabS expression is repressed by SabR. Based on these data, we propose that the S. acidiscabies sabRAS genes encode components of a signaling pathway which participates in the regulation of WS5995B production and morphogenesis.