Expansion of restricted cellular immune responses to HIV-1 envelope by vaccination: IL-7 and IL-12 differentially augment cellular proliferative responses to HIV-1

Abstract

SUMMARYThe failure of immune effector mechanisms to control HIV-1 infection has important consequences for the human host. In a randomized cohort of HIV-infected patients, there was striking in vitro restriction of the proliferative response to HIV-1 envelope protein (Env), gp160; only 34% of patients recognized Env. Therapeutic vaccination with recombinant gp160 or gp120 (rgp160, rgp120) reversed the restriction in vitro, with Env recognition rising to 81%. Peripheral blood mononuclear cells (PBMC) from HIV-infected vaccine recipients, placebo recipients, and seronegative volunteers were cultured with exogenous IL-7 or IL-12 and either tetanus toxoid (TT) or gp160. IL-7 significantly augmented proliferative responses to TT and gp160, whereas IL-12 only affected proliferation to gp160. IL-7, but not IL-12, increased the number of HIV-infected placebo recipients who recognized rgp160. IL-12 had its greatest effect in the induction of rgp160-specific responses from seronegative individuals. The data suggest that these two cytokines have differential activity in the relief of restricted cellular immunity to Env; the predominant effect of IL-7 is in individuals who have been primed by exposure to antigen, while the effect of IL-12 is most evident in seronegative, unprimed individuals. Modification of restricted proliferative responses to Env by vaccination or cytokines in vitro suggests that strategies incorporating IL-7 or IL-12 as adjuvants may selectively boost cellular reactivity to HIV-1.

Cytokine and Chemokine Based Control of HIV Infection and Replication

“…In spite of its detrimental effects on HIV replication, IL-7 remains a potentially important cytokine for the immunologic reconstitution of HIV infected individuals given its ability to contribute to CTL development in synergy with IL-12 [213,214].…”

Bioterrorism Preparedness for Infectious Disease Proposal

“…All tests of significance will be at an alpha of 0.05. Previous research (see Table 1) suggests that following HAART, the group of seropositive individuals with HAD will have a mean (± SEM) percent M/Mφ activation of approximately 30 ± 6 and the group of cognitively normal seropositive individuals will have a mean percent M/Mφ activation of approximately 7 ± 2, a difference of 23 in mean percent M/Mφ activation (18). Based on these estimates, if we retain all 30 recruited individuals in these two groups, we will have a > 90% power to detect a significant difference in M/Mφ activation.…”

“…Dr. Kim's laboratory previously provided support for Nab evaluations of several products in HIV vaccine prime-boost studies [4][5][6], and his lab at Leahi has continued this practice, providing support for Nab analysis for an AACTG study on STI (A5170), and for a collaboration with Dr. M. Schnell at Thomas Jefferson University investigating a rhabdovirus prime/boost strategy designed to induce both cellular and humoral immune responses to HIV-1 envelope antigens [7]. Dr. S. Ratto-Kim has published extensively on T helper cell induction in HIV vaccines (therapeutic and prophylactic) [2,[8][9][10][11][12][13][14][15][16][17][18][19][20] and is an international leader in the analysis of epitope specific T helper cell responses to vaccination [12]. Drs.…”

“…Dr. Ratto-Kim assisted in the characterization of a novel dendritic cell based HIV vaccine [11]. The initial suggestions of the potential utility of IL-7 in HIV infection were posited in studies from this group [18]. Dr. Q. Yu who will be joining the HACRP program in Honolulu in Sept 2005 has studied the role of CD40 ligand (CD40L) and Ox40-ligation to activate and mature dendritic cells and enhance CD8+ T cell cytotoxic (CTL) response [21][22][23][24].…”

“…As previously explained, Drs Kim and Ratto-Kim have been involved in novel concepts in immunomodulatory therapy, including the use of CD3/CD28 expanded, non-specific T helper cells [3], a novel dendritic cell based HIV vaccine [11], and use of IL-7 [18] and rhabdovirus prime/boost strategy [7]. Dr. Q Yu has been involved in the role of CD40 ligand (CD40L) and Ox40-ligation to enhance CD8+ T cell cytotoxic responses [21][22][23][24].…”