IL27 is a newly described cytokine related to IL12 which is produced by activated macrophages and DCs and which induces differentiation of naïve T cells. Fakruddin and colleagues showed that IL27 potently inhibits HIV replication in CD4+ T cells (and macrophages) at the level of transcription but post reverse transcription. Interestingly this is not observed with the related cytokine IL23. These observations raise the possibility of using IL27 in immunomodulatory therapy for HIV.

How HIV infection is established and regulated in resting, naïve T cells is not understood. Such infection is more apparent within the lymph node compared to the periphery and data from Sharon Lewin’s laboratory supported a role for homeostatic chemokines CCL19 and 21 in permitting infection of these cells. Treatment of resting T cells with CCL19/21 for 3d prior to HIV-1 infection in vitro enhanced HIV replication without overt activation of these cells as assessed by a panel of activation and proliferation markers. A high level of viral integration was also detected. These data suggest that these chemokines may be important in the development of latent reservoirs of virus in resting T cells within the lymph node.

The brain is an anatomical sanctuary site and major reservoir for HIV which is established early in infection. Nicole Webster explored the role of monocyte subsets in establishing this reservoir. Using a blood brain barrier model consisting of HUVECS and an underlying astrocyte seeded on either side of collagen-coated transwells, it was shown that monocytes from HIV patients transmigrated towards a gradient of CXCL3 to a significantly greater extent than control monocytes. CD16+ monocytes (a minor subset expanded in HIV+ patients with dementia) also expressed more receptor for CXCL3 on their surface. Together with data from the same laboratory showing that the CD16+ monocyte subset is preferentially infected with HIV, these data suggest a role for CD16+ monocytes in establishing reservoirs of HIV in the brain.

Identification of latently-infected cells is an important step in evaluating strategies for their elimination. Berro et al used a proteomic approach to compare expression of membrane proteins on latently infected and uninfected T cell lines. Seventeen proteins were identified as being differentially expressed providing potential markers to identify these cells. Notably, latently-infected cells upregulated several anti-apoptotic proteins. Drugs which target these proteins induced apoptosis in latently-infected cells to a greater extent than uninfected cells suggesting that they protect cells from infection-induced apoptosis. Targetting the differential sensitivity of latently-infected cells may be beneficial in eliminating reservoirs.

Combination chemotherapy using three or more drugs has been established to be essential for HIV treatment, and will undoubtedly be the standard for gene therapy as well. In an exciting plenary talk earlier in this confeerence, John Rossi described the potential use of a lentiviral vector combining three separate strategies for HIV gene therapy. The Triple-R vector contains a short hairpin RNA which targets tat/rev, a TAR decoy and a CCR5 ribozyme. In the presentation by R.Akkina, experiments were described in which the Triple–R vector was transduced into human CD34+ progenitor cells which were expanded in vitro, challenged with HIV-1 NL4.3 and subsequently used to populate hu thy/liv SCID mice. Triple-R was able to transduce human progenitor cells without affecting their subsequent maturation into T cells and macrophages. Triple-R blocked HIV replication in the transduced cells in vitro.  These data show promise for the use of such vectors in planned human clinical trials.