HIV This Week

Wilkinson J, Cunningham AL. Mucosal transmission of HIV-1: first stop dendritic cells. Curr Drug Targets 2006;7:1563-69.

Worldwide the heterosexual route is the prevalent mode of transmission of HIV, increasing the demand for measures that block the sexual (penile-vaginal) spread of HIV infection. Vaccines designed to prevent mucosal transmission of HIV should be considered a component of vaccine strategies against HIV (in addition to cytotoxic T cells required for clearance and to prevent viral dissemination) and include antibodies, which are capable of blocking HIV entry at mucosal epithelial barriers, and prevent initial infection of target cells in the mucosa. However, in the interim and in the absence of an effective vaccine, the development of microbicides, topical preparations that block the early steps of HIV infection and transmission, may represent a more viable alternative to condom use in many HIV infected regions of the world, especially by empowering women. To date there has been some success with antiviral antibodies applied as a microbicide capable of preventing SIV infection in macaques and there have been reports of vaccines capable of preventing intravaginal and intrarectal inoculated SIV. However, for such success in humans a much greater understanding of the mechanisms involved in the very early stages of mucosal transmission in HIV infection is required. These may lead to additional strategies to inactivate or inhibit viral uptake and replication before a potentially life threatening acute infection develops. Such measures will lead to the development of effective microbicides and vaccines that will diminish the global spread of HIV.

Editors’ note: The role of dendritic cells in transferring HIV to CD4 and other target cells for HIV needs further study, whether for vaccines or microbicide development.

Liu J, Roederer M. Differential susceptibility of leukocyte subsets to cytotoxic T cell killing: implications for HIV immunopathogenesis. Cytometry A. 2007 Jan 2 [Epub ahead of print].

Cytotoxic T lymphocytes (CTL) are crucial for the host defence against viral infection. In many cases, this anti-viral immune response contributes to host pathogenesis, through inflammation and tissue destruction. Few studies have explored the relative susceptibility of infected cells to CTL killing, and the range of cell types that may be effectively killed by CTLs in vivo, both of which are key to understanding both immune control of infection and immune-related pathogenesis. Liu and Roederer developed and optimized a highly sensitive method to quantify the relative susceptibility of leukocyte subsets to CTL-mediated killing. Maximal sensitivity was achieved by uniquely measuring cell death occurring during the assay culture. The authors found that leukocyte subsets have a wide range of susceptibility to antigen-specific CTL-mediated lysis. Generally, T cells were more susceptible than B or natural killer (NK) cells, with CD4-T cells being more susceptible than CD8-T cells. In all lymphocyte lineages, susceptibility was greater for more differentiated subsets compared with their naive counterparts; however, for dendritic cells, immature cells are more susceptible than mature cells. Liu and Roederer focused on the susceptibility of T cell subsets, and found that naive cells are far more resistant than memory cells, and in particular, CCR5+ or HLA-DR+ memory cells are highly susceptible to CTL-mediated killing. The authors conclude that the results provide an explanation for the observation that certain subsets of CD4-T cells are ablated during chronic HIV infection, and indicate which subsets are most likely to contain the persistent viral reservoir.