Objective: The development of drugs that can be used as topical microbicides is currently recognized as a priority area of research. Design: A preclinical evaluation of the potential effectiveness of TMC120, a non-nucleoside reverse transcriptase inhibitor (NNRTI), as a topical microbicide to prevent vaginal HIV-1 transmission in a humanized severe combined immunodeficient (hu-SCID) mouse model. Methods: Reconstituted mice received an intravaginal application of a TMC120-containing gel 20 min prior to a non-invasive vaginal challenge with cell-associated HIV. The possible cytotoxic effect of TMC120-containing-gel on lymphocytes was assessed and their in vivo migration was followed using fluorescently labelled human lymphocytes. Systemic infection was monitored by p24 antigen detection in culture supernatant from cocultured intraperitoneal cells using antigen capture enzyme-linked immunosorbent assay test and by the presence of integrated proviral HIV-1 DNA in DNA extracted from spleen cells. In vivo migration of labelled lymphocytes was examined by analysis of cells isolated from regional lymph nodes. Results: In this model, systemic infection was successfully inhibited by the presence of TMC120-containing gel at vaginal level. The in vivo migration of human lymphocytes from the vagina to regional lymph nodes, following the deposition of TMC120-containing gel, excluded the possibility that inhibition of systemic infection was a result of NNRTI toxicity. Conclusions: Vaginal transmission of HIV was successfully prevented by the application of a gel formulation containing TMC120. This is the first evidence of the in vivo effectiveness of a microbicide preparation containing an NNRTI against cell-associated HIV.

Accumulating evidence indicates that the human intestinal microbiota can contribute to the etiology of colorectal cancer. Triggering factors, including inflammation and bacterial infections, may favor the shift of the gut microbiota from a mutualistic to a pro-carcinogenic configuration. In this context, certain bacterial pathogens can exert a pro-tumoral activity by producing enzymatically-active protein toxins that either directly induce host cell DNA damage or interfere with essential host cell signaling pathways involved in cell proliferation, apoptosis, and inflammation. This review is focused on those toxins that, by mimicking carcinogens and cancer promoters, could represent a paradigm for bacterially induced carcinogenesis.

To develop an animal model of vaginal transmission of HIV-1 for the evaluation of vaginal microbicides. Vaginal infection was performed in SCID mice reconstituted with 4 × 107 human peripheral blood lymphocytes (hu-PBL) by non-invasive vaginal administration. The hu-PBL were previously infected in vitro with a non-syncytium (NSI) strain of HIV-1 (SF162) (hu-PBL-SCID). Lymphocyte migration in vivo was examined using fluorescently labelled human lymphocytes. The percentage of CD4 T cells, plasma viral load and p24 antigen were evaluated using fluorescent activated cell sorting (FACS), the Amplicor HIV-1 monitor kit and enzyme-linked immunosorbent assay, respectively. Polymerase chain reaction (PCR) analysis was performed on DNA extracted from spleen and lymph nodes. For in vivo migration of labelled lymphocytes, the mice were sacrified after 4, 24 and 48 h; vaginae and local lymph nodes were removed, snap frozen with OCT, sectioned and examined by fluorescent microscopy and FACS. HIV transmission was established using virus-infected cells inoculated vaginally, as shown by FACS, HIV viral load, p24 and PCR results. Labelled cells were easily located within the vaginal tissues after 4 h. However, few or no cells could be identified after 24 or 48 h at the vaginal level, whereas labelled cells could be detected at the level of regional lymph nodes. Because of its simplicity and practical features compared with other animal models, the vaginal HIV-infected hu-SCID mouse model may prove useful to test the activity of compounds against cell-associated HIV and, possibly, other sexually transmitted diseases.

To evaluate the impact of different modalities of infant feeding on HIV transmission in children in a prevention of mother-to-child transmission (PMTCT) program in an urban hospital in Uganda. HIV-infected pregnant women in the PMTCT program at St Francis Hospital Nsambya, Kampala were offered the chance to participate in the study. Short-course antiretroviral regimens were provided and formula feeding offered free of charge for women choosing not to breastfeed. Mother–infant pairs were followed until 6 months postpartum. HIV status in children was assessed at week 6 and month 6. For the analyses, mother–infant pairs were classified into three groups according to the mode of infant feeding: exclusive formula feeding (EFF), exclusive breastfeeding (EBF) and mixed feeding (MF). A total of 306 children were enrolled. Transmission rates were 8.9% at week 6 (3.4% in the EFF group, 11.2% in the EBF group, 17.1% in the MF group) and 12.0% at month 6 (3.7% in the EFF group, 16.0% in the EBF group, and 20.4% in the MF group). The EBF and MF groups were associated with a significantly higher risk of HIV transmission than the EFF group. No significant risk difference was observed between the EBF and the MF groups. HIV transmission rates were significantly lower in formula-fed infants in comparison with both exclusively breastfed and mixed-fed infants. Transmission through breastfeeding seems to occur mainly in the first weeks after delivery.