IL-15 and HIV infection: lessons for immunotherapy and vaccination.

IL-15 is a pleiotropic and multifunctional cytokine that has a diverse array of distinct biological effects in the body. It plays a crucial role in host defense from viral and non-viral intracellular pathogens. The cytokine is essential for the development and differentiation of NK cells and for homeostatic expansion of CD8+ memory T cells, NKT cells and certain subsets of intestinal intra-epithelial lymphocytes (iIEL). It acts as a survival factor and inhibits spontaneous apoptosis in T, B and NK cells by increasing expression of different anti-apoptotic proteins. Several studies have shown that IL-15 production is compromised in HIV-infected AIDS patients and exogenous IL-15 drastically enhances functions of immune cells from these patients. Considering these distinct immune enhancing effects, relative safety in animal models, and minimal effects on HIV replication, IL-15 may represent a better cytokine for immune reconstitution in these patients. Furthermore, IL-15 may also act as a better adjuvant in eliciting antiviral immunity in anti-HIV vaccine strategies.

Peripheral blood cytotoxic gammadelta T lymphocytes from patients with human immunodeficiency virus type 1 infection and AIDS lyse uninfected CD4+ T cells, and their cytocidal potential correlates with viral load.

Progression of human immunodeficiency virus type 1 (HIV-1) infection in humans is marked by declining CD4+-T-cell counts and increasing virus load (VL). Cytotoxic T lymphocytes (CTL) play an important role in the lysis of HIV-infected cells, especially during the early phase of asymptomatic infection. CTL responses in the later phase of disease progression may not be as effective since progressors with lower CD4+-T-cell counts have consistently higher VL despite having elevated CTL counts. We hypothesized that, apart from antiviral effects, some CTL might also contribute to AIDS pathogenesis by depleting CD4+ T cells and that this CTL activity may correlate with the VL in AIDS patients. Therefore, a cross-sectional study of 31 HIV-1-infected patients at various clinical stages was carried out. Purified CTL from these donors as well as HIV-seronegative controls were used as effectors against different human cell targets by using standard 51Cr release cytolytic assays. A direct correlation between VL and CTL-mediated, major histocompatibility complex (MHC)-unrestricted lysis of primary CD4+-T-cell, CEM.NKR, and K562 targets was observed. CD4+-T-cell counts and duration of infection also correlated with MHC-unrestricted cytolytic activity. Our data clearly show that gammadelta CTL are abnormally expanded in the peripheral blood of HIV-infected patients and that the Vdelta1 subset of gammadelta T cells is the main effector population responsible for this type of cytolysis. The present data suggest that gammadelta CTL can contribute to the depletion of bystander CD4+ T cells in HIV-infected patients as a parallel mechanism to HIV-associated immunopathogenesis and hence expedite AIDS progression.