Background Prevention of rectal HIV transmission is a high priority goal

Background Prevention of rectal HIV transmission is a high priority goal for vaccines and topical microbicides because a large portion of HIV transmissions occurs rectally. distal stomach and demonstrates in general terms that the colon and rectum are immunologically unique anatomical storage compartments. Greater manifestation of CCR5 on rectal macrophages suggests that the most distal sections of the stomach may be especially vulnerable to HIV contamination. Our findings also emphasize that caution should be exercised when extrapolating data obtained from colon tissues to the rectum. Introduction HIV contamination frequently occurs through anal intercourse, in both men having sex with men and in women,1C7 so the distal stomach is usually an important target organ for achieving HIV control through topical microbicides or vaccination. The design of effective prevention strategies depends on knowing where HIV penetrates the stomach mucosa and establishes contamination most successfully and what the target cell composition is usually at that site. In the macaque model, SIV penetration through the rectal mucosa, followed by quick dissemination to local lymphatic tissues, has been shown.8 In humans, however, it remains unclear which anatomical sections of the distal stomach (anal canal, rectum or sigmoid colon) are most vulnerable to infection upon luminal contact with HIV. A recent study showed that surrogates of cell-free and cell-associated HIV (99mTc labeled sulfur colloid particles and 111In-oxine labeled autologous leukocytes, respectively) launched into the rectum through simulated intercourse reached their highest concentrations 10C20 cm from the anus, where the 1361030-48-9 IC50 rectum transitions into the sigmoid colon.9 The event of HIV infection in humans cannot be directly observed but in general depends highly on the likelihood of virion penetration into the mucosa and the local availability of susceptible target cells.10 For the colon, target cell availability has been relatively well established: T cells tend to express CCR5 and be highly susceptible to HIV,11C20 while macrophages express little to no CCR5 and are mostly resistant.21C25. Myeloid dendritic cells (DCs) and epithelial 1361030-48-9 IC50 cells were shown to enhance contamination by disseminating HIV to T cells in the colon.26C28 In contrast to the colon, less is known about target cell density and cell-virus interactions within the rectum. The rectum contains many CCR5+ T cells,29 but macrophages and DCs have not been analyzed at this site. Thus, whether immunological variance – and potentially differences in HIV susceptibility – exists between the colon and the rectum remains unexplored. A better understanding of the rectal mucosa could be important for the design of rectal microbicide gels to prevent anal HIV transmission. 1361030-48-9 IC50 Moreover, as intestinal immune responses to HIV vaccination are currently assessed in the colon, the extent to which colon biopsies are fully associate of the rectum needs to be resolved. In this study, we required advantage of the unique opportunity of having biopsies available from both the rectum (taken 4 cm proximal to the pectinate collection in the anal canal) and colon (~30 cm) of 29 healthy men who were enrolled in an exploratory follow-up study of a phase 2B HIV vaccine trial (Step Study).30, 31 This allowed us to compare with high statistical Rabbit Polyclonal to SAR1B reliability the complete and relative densities of the three main potential 1361030-48-9 IC50 target cell populations for HIV contamination – T cells, macrophages and DCs – as well as their CCR5 manifestation levels in the rectum and colon. Our results.