SummaryUnderstanding the initial events in the establishment of vaginal human immunodeficiency virus type-1 (HIV-1) entry and infection has been hampered by the lack of appropriate experimental models. Here, we show in an ex vivo human organ culture system that upon contact in situ, HIV-1 rapidly penetrated both intraepithelial vaginal Langerhans and CD4+ T cells. HIV-1 entered CD4+ T cells almost exclusively by CD4 and CCR5 receptor-mediated direct fusion, without requiring passage from Langerhans cells, and overt productive infection ensued. By contrast, HIV-1 entered CD1a+ Langerhans cells primarily by endocytosis, by means of multiple receptors, and virions persisted intact within the cytoplasm for several days. Our findings shed light on the very earliest steps of mucosal HIV infection in vivo and may guide the design of effective strategies to block local transmission and prevent HIV-1 spread.

Treatment of early-stage cervical and endometrial cancer has been associated with significant sexual difficulties in at least half of women following hysterectomy. Despite the fact that women report such sexual side effects to be the most distressing aspect of their cancer treatment, evidence-based treatments for Female Sexual Arousal Disorder (FSAD), the most common sexual symptom in this group, do not exist. We developed and pilot tested a brief, three session psychoeducational intervention (PED) targeting FSAD in 22 women with early-stage gynecologic cancer. The PED consisted of three, 1-h sessions that combined elements of cognitive and behavioral therapy with education and mindfulness training. Women completed questionnaires and had a physiological measurement of genital arousal at pre- and post-PED (sessions 1 and 4) and participated in a semi-structured interview (session 4) during which their feedback on the PED was elicited. There was a significant positive effect of the PED on sexual desire, arousal, orgasm, satisfaction, sexual distress, depression, and overall well-being, and a trend towards significantly improved physiological genital arousal and perceived genital arousal. Qualitative feedback indicated that the PED materials were very user-friendly, clear, and helpful. In particular, women reported the mindfulness component to be most helpful. These findings suggest that a brief 3-session PED can significantly improve aspects of sexual response, mood, and quality of life in gynecologic cancer patients, and has implications for establishing the components of a psychological treatment program for FSAD.

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The objective of our study was to estimate the age-specific incidence and lifetime risk of surgically managed pelvic organ prolapse (POP) and urinary incontinence (UI). Women aged 20 and older who underwent primary surgical management of POP or UI in 1993 were identified from the database of a health maintenance organization using ICD-9 codes and confirmed through chart abstraction. From a population of 147,719 women, 135 were identified who underwent prolapse surgery only, 82 incontinence only, and 34 surgery for both conditions. From the age-specific incidence, we estimated the lifetime risk of undergoing an operation by age 80 to be 11.8%. Our findings agree with a previous estimate that approximately 11% of women will undergo surgery for POP or UI by age 80. POP and UI appear to be common problems, undoubtedly affecting an even larger proportion of the women than suggested by this high cumulative incidence of surgery.

Although implied by other models, proof that Langerhans cells (LCs) in the human vagina participate in dissemination of infectious human immunodeficiency virus type 1 (HIV-1) has been lacking. Here, we show that LCs migrate from HIV-1-exposed vaginal epithelia and pass infectious virus to CD4 + T cells without being productively infected themselves, and we point to a pathway that might enable HIV-1 to avoid degradation in vaginal LCs. Transport by migratory LCs to local lymphatics in a nonproductive but infectious form may aid HIV-1 in evasion of topical microbicides that target its intracellular productive life cycle.

BackgroundFunctional analysis of mononuclear leukocytes in the female genital mucosa is essential for understanding the immunologic effects of HIV vaccines and microbicides at the site of HIV exposure. However, the best female genital tract sampling technique is unclear.Methods and FindingsWe enrolled women from four sites in Africa and the US to compare three genital leukocyte sampling methods: cervicovaginal lavages (CVL), endocervical cytobrushes, and ectocervical biopsies. Absolute yields of mononuclear leukocyte subpopulations were determined by flow cytometric bead-based cell counting. Of the non-invasive sampling types, two combined sequential cytobrushes yielded significantly more viable mononuclear leukocytes than a CVL (p<0.0001). In a subsequent comparison, two cytobrushes yielded as many leukocytes (∼10,000) as one biopsy, with macrophages/monocytes being more prominent in cytobrushes and T lymphocytes in biopsies. Sample yields were consistent between sites. In a subgroup analysis, we observed significant reproducibility between replicate same-day biopsies (r = 0.89, p = 0.0123). Visible red blood cells in cytobrushes increased leukocyte yields more than three-fold (p = 0.0078), but did not change their subpopulation profile, indicating that these leukocytes were still largely derived from the mucosa and not peripheral blood. We also confirmed that many CD4+ T cells in the female genital tract express the α4β7 integrin, an HIV envelope-binding mucosal homing receptor.ConclusionsCVL sampling recovered the lowest number of viable mononuclear leukocytes. Two cervical cytobrushes yielded comparable total numbers of viable leukocytes to one biopsy, but cytobrushes and biopsies were biased toward macrophages and T lymphocytes, respectively. Our study also established the feasibility of obtaining consistent flow cytometric analyses of isolated genital cells from four study sites in the US and Africa. These data represent an important step towards implementing mucosal cell sampling in international clinical trials of HIV prevention.

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