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Mucosal-associated invariant T (MAIT) cells play an important role in mucosal homeostasis. MAIT cells recognize microbial small molecules presented by the major histocompatibility complex class Ib molecule MR1. MAIT cells are absent in germ-free mice, and the mechanisms by which microbiota control MAIT cell development are unknown (see the Perspective by Oh and Unutmaz). Legoux et al. show that, in mice, development of MAIT cells within the thymus is governed by the bacterial product 5-(2-oxopropylideneamino)-6- d -ribitylaminouracil, which rapidly traffics from the mucosa to the thymus, where it is captured by MR1 and presented to developing MAIT cells. Constantinides et al. report that MAIT cell induction only occurs during a limited, early-life window and requires exposure to defined microbes that produce riboflavin derivatives. Continual interactions between MAIT cells and commensals in the skin modulates tissue repair functions. Together, these papers highlight how the microbiota can direct immune cell development and subsequent function at mucosal sites by secreting compounds that act like self-antigens. Science , this issue p. 494 , p. eaax6624 ; see also p. 419 In neonatal mice, microbial small molecules presented in the thymus drive the expansion of mucosal-associated invariant T cells. How early-life colonization and subsequent exposure to the microbiota affect long-term tissue immunity remains poorly understood. Here, we show that the development of mucosal-associated invariant T (MAIT) cells relies on a specific temporal window, after which MAIT cell development is permanently impaired. This imprinting depends on early-life exposure to defined microbes that synthesize riboflavin-derived antigens. In adults, cutaneous MAIT cells are a dominant population of interleukin-17A (IL-17A)–producing lymphocytes, which display a distinct transcriptional signature and can subsequently respond to skin commensals in an IL-1–, IL-18–, and antigen-dependent manner. Consequently, local activation of cutaneous MAIT cells promotes wound healing. Together, our work uncovers a privileged interaction between defined members of the microbiota and MAIT cells, which sequentially controls both tissue-imprinting and subsequent responses to injury.

Background. Because many human papillomavirus (HPV) infections are transient, rates of transmission may be miscalculated if the interval between testing spans several months. We examined rates of concordance and transmission in heterosexual couples over short intervals. Methods. Twenty-five adult couples were enrolled and sampled for HPV DNA from the genitals, hand, and mouth 5 times over a 6-week period, including 24 hours after sexual intercourse and after 48 hours of abstinence. Concordance and transmission patterns were described. Results. Concordance between the couple's genital sites ranged from 64% to 95% for at least 1 HPV type. The highest rates of concordance were observed 24 hours after sexual intercourse. A similar peak in concordance was not seen between genital and nongenital anatomic sites. Transmission rates for female genital to male genital ranged from 26.8 to 187.5 per 100 person-months and for male genital to female genital from 14.5 to 100 per 100 person-months. Conclusions. High rates of concordance shortly after intercourse suggest that some DNA detections in the genital area are contaminants from a partner and not established PHV infections. Female-to-male transmission appeared more common than male-to-female transmission.

Background. Anal cancer is more common in women than in men, yet little is known about the natural history of human papillomavirus (HPV) in women. The objective was to examine the natural history of anal HPV in heterosexual women. Methods. Young women participating in an HPV cohort study were seen at 4-month intervals for cervical and anal HPV testing. Time to clearance was estimated using the Kaplan-Meier approach; risks for persistence were assessed using Cox regression models. Results. Seventy-five women (mean age, 23.5 ± 4.1 years) who tested positive for anal HPV were followed for a mean of 84.5 ± 44.9 months. By 3 years, 82.5% of anal non-16 high-risk (HR) HPV, 82.6% of low-risk (LR) HPV, and 76.2% of HPV-16 infections had cleared. By 3 years, only 36.4% of women had become negative for all HPV types. In the multivariable model, concurrent cervical HPV-16 (P < .001), weekly alcohol use (P = .015), anal touching during sex (P = .045), recent anal sex (P = .04), and no condom use during anal sex (P = .04) were associated with HPV-16 persistence. Greater number of new sex partners (P = .024) and condom use during vaginal sex (P = .003) were associated with clearance. Similar associations were found for clearance in all HR-HPV infections. Only concomitant cervical HPV was associated with non-16 HR-HPV persistence. Conclusions. The majority of anal HPV infections cleared within 3 years. HPV-16 infections were slower to clear than other HR-HPV infections, consistent with its role in anal cancer. Specific sexual behaviors were associated with persistence, suggesting that education and behavioral interventions may decrease persistence.

CD8 T-cell responses were examined in subjects with incident (new following negative visits) or prevalent (lasting ≥ 4 months) human papillomavirus type 16 (HPV16) or human papillomavirus (HPV18) infection. The groups were chosen from a cohort of women being followed every 4 months with cervical cytology and HPV-DNA testing. Enzyme-linked immunospot (ELISPOT) assay was performed at enrollment (time zero) and one year later. At time zero, 1 (6%) of 17 subjects with incident HPV 16/18 infections had positive ELISPOT results which increased to 6 (35%) at one year. For the subjects with prevalent HPV 16/18 infections, the ELISPOT results were similar at time zero (2 (15%) of 15 subjects positive) and at one year (3 (20%)). While all of the 11 women with prevalent HPV16 infection showed clearance one year later, unexpectedly only 1 (25%) of 4 women with prevalent HPV18 infection demonstrated clearance one year later (P=.009).

Background. The purpose of this study was to examine the rate of and risks for cervical human papillomavirus type 16 (HPV16) redetection in women with documented or suspected HPV16 infection. Methods. A convenience sample of women aged 13-21 years were seen at 4-month intervals for HPV DNA testing and cytology. Serum samples were obtained at baseline and annually. Results. A total of 1543 women entered the study. Of the 295 women with detection of HPV 16 DNA and subsequent clearance, 18.1% had HPV 16 redetected by 8.5 years (88% cleared this second detection by 3 years). Of the 247 women who had antibodies to HPV16 and were HPV16 DNA negative at baseline, 15.3% had HPV16 redetected by year 5. Risks for redetection included douching, current use of medroxyprogesterone, reporting >1 sex partner or having a new sex partner, and having a sexually transmitted infection. Development of cervical intraepithelial neoplasia 2/3 was rare in women with redetection, except for those with prevalent HPV 16 infection. Conclusions. Reappearance of HPV 16 DNA was observed in 18% of women. Most are associated with sexual exposure and appear benign. Interpretation of the studies is more complex in women with prevalent infections as it appears that this small subset reflects women with persistence already present at entry.

Cell-mediated immune responses have been thought to be important in the control of human papillomavirus (HPV) infections. We examined cell-mediated immune responses to HPV-16 E6 and E7 in the peripheral blood using interferon gamma (IFN-γ) enzyme-linked immunospot assay (Cellular Technology Ltd, Cleveland, Ohio) in women with HPV-16 infection who showed clearance and compared these women to women with HPV-16 persistence. Women participating in a longitudinal study of cervical HPV were recruited once cervical HPV-16 infection was detected by polymerase chain reaction. Four groups of women were examined: (1) persistent, (2) intermittent, (3) transient, and (4) cleared. Ninety-six samples from 55 women were compared. Comparing IFN-γ enzyme-linked immunospot to the HPV-16 clearance of 10 women with recent persistence, none had response to either E6 or E7; of 24 women with recent clearance, 14 had E6 and 8 had E7 response. Women with intermittent persistence behaved similarly to the clearance group than recent persistors: 50% were positive to E6 and 20% to E7. In summary, anti-E6 responses seem critical in the immediate control of HPV, and in some women, an immune tolerance eventually develops if HPV is not eliminated soon after infection.

Background. High rates of persistence of human papillomavirus (HPV) infection have been reported for adult women with human immunodeficiency virus (HIV) infection. Although most women are first infected with HPV during adolescence, persistence of specific HPV types has not been carefully examined among HIV-infected adolescents. The objective of this study was to examine the rates of and risk factors for persistence of HPV types among HIV-infected and -uninfected adolescent girls. Methods. This is a prospective cohort study of female adolescents, aged 13–18 years, participating in the Reaching for Excellence in Adolescent Care and Health project, a national study of HIV-infected and -uninfected adolescents. The main outcome measured was type-specific loss of initial HPV DNA detected. Loss of HPV DNA was defined for the following categories of HPV DNA types: low risk, which included types 6, 11, 42, 44, 54, 40, 13, 32, 62, 72, 2, 57, and 55; and high risk, which included types 16-like (16, 31, 33, 35, 52, 58, and 67), 18-like (18, 39, 45, 59, 68, 70, 26, 69, and 51), and 56-like (56, 53, and 66). Results. Prevalent or incident HPV infection was detected in 334 girls. When type-specific loss of HPV was examined, HIV-uninfected girls had a shorter mean time to loss of initial infection than did HIV-infected girls (403 days vs. 689 days, respectively; P<.0001). By means of multivariate analysis, CD4 immunosuppression and the presence of multiple HPV-type subgroups were found to be associated with persistence of HPV. Conclusion. Since persistence of high-risk HPV types has been strongly linked with the development of invasive cancer, the prolonged persistence of HPV observed among HIV-infected adolescents who are relatively healthy underscores the importance of prevention of HPV infection in this group.

Background. Vulnerability of younger women to human papillomavirus 16 (HPV16) infection has been attributed to the predominance of ectocervical columnar epithelia in this age group. However, squamous metaplastic tissue may be more influential. We examined the extent of ectopy and metaplastic activity as risks for HPV16 acquisition in a prospective cohort. Methods. Participants were HPV16 negative at the first two visits. Follow-up occurred every 4 months. Ectopy was quantitatively measured on colpophotographs. We calculated metaplastic rate as the difference in ectopy between visits. Cox proportional hazards models were constructed, adjusting for several covariates. Results. Analyses included 198 women (mean baseline age 17 years) for 1734 visits. Mean follow-up was 4.4 years. Incident HPV16 was detected in 36 (18%) women. Metaplastic rate between the two visits before HPV16 detection was significantly associated with incident infection (hazard ratio [HR], 1.17; confidence interval [CI], 1.02—1.33; P = .02). However, ectopy was not significant, whether measured before or concurrent to HPV16 detection (HR range, 0.99—1.00; CI range, .97—1.02; P range, .47—.65). Conclusions. Dynamic metaplasia rather than the sheer extent of ectopy appears to increase risk for incident HPV16 in healthy young women. This in vivo observation is consistent with the HPV life cycle, during which host cell replication and differentiation supports viral replication.

BackgroundBeta (β) and gamma (γ) human papillomavirus (HPV) are commonly found on the skin. Few of the β types are associated with nonmelanoma skin cancer. Little is known about transmission patterns of these HPV, specifically in the anogenital (AG) areas. The primary objective of this study was to examine the AG concordance and transmission of β and γHPV types between heterosexual couples.MethodsArchival samples from a previously published study examining concordance of alpha HPV types between couples were tested for β and γHPV. Hand, mouth, and genital samples were obtained 5 times over a 6-week period.ResultsOf the 21 couples examined, β and γHPV were detected in AG sites in 67% and 30% of men, respectively, and 41% and 25% of women. Positive concordance for β and γHPV was 27% and 20%, respectively, which was greater than the observed concordance between noncouples (10% for βHPV and 4% for γHPV). Transmission rate of βHPV between AG areas was 15.9 (95% confidence interval [CI], 3.3–46.5) per 100 person months for men-to-women at risk and for γHPV was 6.6 (95% CI, .2–36.7). Risks for women-to-men were similar.ConclusionsBeta and γHPV are common in the AG area, and data suggest that they can be sexually transmitted.

In contrast to high rates of oral HPV found in HIV-infected adults, only 2% of 209 perinatally HIV-infected youth had oral HPV. This rate was similar in HIV exposed but uninfected youth. No association was found with sexual activity; however, low CD4 counts were associated with oral HPV.