Objective Factors governing events between exposure of male genital mucosa surfaces and the establishment of infection are poorly understood. Furthermore, little is known about the safety and efficacy of microbicides on male genital mucosa. Design Here we present a novel penile tissue explant model to characterise the mechanisms of HIV-1 infection of male genital tissue and evaluate candidate microbicides. Methods Mucosal explant culture conditions were determined for glans, urethra and foreskin obtained from gender reassignment and circumcision. Density and distribution of CD4+ and CD1a+ cells were visualized by microscopy. In vitro HIV-1 infection was determined by measuring p24 release, while microbicide biocompatibility and efficacy were assessed by measurement of tissue viability, cytokine expression and p24 production. Results Cultured glans and foreskin showed comparable epithelial thickness but some differences in CD4+ and CD1a+ cell density. All tissue sites examined (foreskin, glans, meatus, urethra) were equally susceptible to R5 HIV-1 infection, which was productively disseminated by migratory cells emigrating from tissue. In contrast, X4 HIV-1 failed to infect mucosal tissue and dissemination by migratory cells was less efficient. The three candidate microbicides PMPA, PRO 2000 and Cyanovirin-N, showed good tissue compatibility and efficient prevention of HIV-1 infection, causing only minor changes in tissue cytokine profile. Conclusion The described model provides a useful model to study the determinants of HIV-1 infection of male genital tissue and is likely to be an important tool for the future development of microbicide candidates and concepts.

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The decrease in HIV acquisition after circumcision suggests a role for the foreskin in HIV transmission. However, the mechanism leading to protection remains undefined. Using tissue explant cultures we found that Langerhans cells (LCs) in foreskin alter their cellular protein expression in response to external stimuli. Furthermore, we observe that upon treatment with TNF-α, tissue-resident LCs became activated and that stimulatory cytokines can specifically cause an influx of CD4+ T-cells into the epithelial layer. Importantly, both of these changes are significant in the inner, but not outer, foreskin. In addition, we find that LCs in the inner foreskin have increased ability to sample environmental proteins. These results suggest differences in permeability between the inner and outer foreskin and indicate that HIV target cells in the inner foreskin have increased interaction with external factors. This increased responsiveness and sampling provides novel insights into the underlying mechanism of how circumcision can decrease HIV transmission.

Induction of the ␣1,3-fucosyltransferase FucT-VII in T lymphocytes is crucial for selectin ligand formation, but the signaling and transcriptional pathways that govern FucT-VII expression are unknown. Here, using a novel, highly phorbol myristate acetate (

We measured the microbial community structure of genital ulcers in women. Swabs from clinically detected ulcers were tested for HSV-2 and Treponema pallidum by polymerase chain reaction (PCR). HSV-2 and T. pallidum were detected by serum antibody testing. Microbial community structure was characterized by high-throughput 16 s rRNA gene amplicon sequencing. Multiple group testing and Elastic net and Lasso regressions identified taxa associated with differences in factors of interest. Among 49 ulcer specimens from 49 HSV-2 seropositive women, by PCR HSV-2 was recovered from 28 (57%) specimens and T. pallidum from none; one woman showed serologic evidence of syphilis. Overall, 63% of women were HIV-positive and 49% had an uncircumcised male sex partner. By both multiple group testing and regression, Porphyromonas (FDR p-value = 0.02), Prevotella (FDR p-value = 0.03), Anaerococcus (FDR p-value = 0.07), and Dialister (FDR p-value = 0.09) were detected at higher relative abundance in HSV-2 PCR-positive than negative ulcers. The presence of HSV-2 in a lesion was associated with presumed bacterial agents of Bacterial vaginosis. Differences in bacterial communities may contribute to HSV-2 ulcer pathogenesis, severity, or prolonged healing. If these results are confirmed, future studies may consider the influence of BV treatment on women’s GUD and HSV-2 incidence and recurrence.

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Every year the Cancer Research Institute from University of California at Irvine organizes the West Coast Retrovirus Meeting where participants have a chance to discuss the latest progress in understanding the pathology of retroviruses. The 12 th meeting was held at the Hyatt Regency Suites in Palm Springs, California from October 6 th to October 9 th 2005, with the major focus on human immunodeficiency virus (HIV) pathogenesis. Philippe Gallay from The Scripps Research Institute and Thomas J. Hope from Northwestern University organized the meeting, which covered all the steps involved in the lifecycle of retroviruses with an emphasis on virus:host interactions. The trend in research appeared to be on the restriction of viral infection, both by the endogenous, cellular restriction factors, as well as by the potential antimicrobial compounds of known or unknown mechanisms. Additionally, new stories on the inevitable feedback from the host immune system were presented as well. HIV still represents a challenge that an army of motivated people has been working on for over 20 years. And yet, the field has not reached the plateau in knowledge nor enthusiasm, which was proven again in October 2005 in Palm Springs. Review Viral EntryJohn Young of the Salk Institute began this session by describing work his lab has recently completed in understanding cellular requirements for replication of Murine Leukemia Virus (MLV) [1]. Through use of chemically mutagenized CHO cells, they identified five clones that became resistant to MLV infection. Additional studies revealed this restriction was specific to the MLV core. After confirming the virus was blocked prior to integration, the clones were separated into two phenotypes, those which blocked reverse transcription early and those which allowed reverse transcription and nuclear entry, but prevented viral integration. Young and colleagues are currently identifying cellular factors involved in the latter phenotype. While the exact identities of these cellular factors were not revealed, Young shared that they believe one is an enzyme and the other a putative transcription factor. Pankaj Kumar from Lorraine Albritton's lab at the University of Tennessee continued this theme by examining cellular factors involved in Moloney MLV entry. Previous work found that the exposure of MLV to proteases enhanced the viral infectivity and certain cell lines, including XC cells, innately possessed proteases that could facilitate MLV infection. The group decided to focus on cathepsins, since expression of these cellular proteases is induced under these conditions. They found a broad spectrum cathepsin inhibitor as well as a cathepsin B-specific inhibitor reduced Moloney MLV infectivity. Additionally,