Innate and Adaptive Mucosal Immunity in Protection against HIV Infection

Abstract

The appalling toll on the populations of developing countries as a result of the HIV epidemic shows no signs of abatement. While costly drug therapies are effective in developed nations, the sheer scale of the epidemic elsewhere makes the need for a vaccine an ever more urgent goal. The prevalent DNA prime-viral boost strategy aims to elicit cytotoxic lymphocytes (CTL) against HIV, but this approach is undermined by the rapid mutation of HIV, which thereby escapes CTL control. Alloimmunity has been found to be protective in vertical transmission from infected mothers to their babies, in alloimmunization of women with their partners’ mononuclear cells, and in monkeys immunized with SIV grown in human T-cells. Vaginal mucosal immunization, as a result of unprotected sex with a regular partner, induced in vitro protection against HIV infection, and this was confirmed in macaques. The second type of natural protection is found in persons with the homozygous Δ32 CCR5 mutation, a 32-base-pair deletion of the CCR5 gene, which results in a lack of cell-surface expression of CCR5, which is associated with an increase in CC chemokines and the development of CCR5 antibodies. These two ‘experiments of nature’ have been used to develop vaccine strategies—first, in vaginal immunization of macaques with CCR5 peptides, in addition to HIV envelope (env) and SIV core (gag) antigens, all of which were linked to the 70-kD heat-shock protein (HSP70); and second, in mucosal allo-immunization of macaques, which also gave rise to in vitro protection from infection. Immunization with this vaccine elicited serum and vaginal IgG and IgA antibodies, IFNγ- and IL-12-producing cells, and increased concentrations of CCL-3 and CCL-4. Vaginal challenge with a simian immunodeficiency virus engineered to carry a human envelope protein (SHIV 89.6) showed significant clearance of SHIV in the immunized macaques. This platform strategy will now be developed to activate the co-stimulatory pathways with the aim of enhancing the primary allogeneic and CCR5-directed responses which are involved in natural protection against HIV infection. Abbreviations: IFN-γ, gamma interferon; IL-12, interleukin 12; MIP-1 α,β, Macrophage inflammatory protein-1; RANTES, Regulated on activation normal T-cell expressed and secreted; SDF-1, stromal-derived factor 1; SIV, simian immunodeficiency virus; and SHIV, engineered SIV carrying a human envelope protein.