γδ T Cell Immune Manipulation during Chronic Phase of Simian HIV Infection Confers Immunological Benefits

V gamma 2V delta 2 T cells, a major human gamma delta T cell subset, recognize the phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) produced by mycobacteria and some opportunistic pathogens, and they contribute to innate/adaptive/homeostatic and anticancer immunity. As initial efforts to explore V gamma 2V delta 2 T cell-based therapeutics against HIV/AIDS-associated bacterial/protozoal infections and neoplasms, we investigated whether a well-defined HMBPP/IL-2 therapeutic regimen could overcome HIV-mediated immune suppression to massively expand polyfunctional V gamma 2V delta 2 T cells, and whether such activation/expansion could impact AIDS pathogenesis in simian HIV (SHIV)-infected Chinese rhesus macaques. While HMBPP/IL-2 coadministration during acute or chronic phase of SHIV infection induced massive activation/expansion of V gamma 2V delta 2 T cells, the consequences of such activation/expansions were different between these two treatment settings. HMBPP/IL-2 cotreatment during acute SHIV infection did not prevent the increases in peak and set-point viral loads or the accelerated disease progression seen with IL-2 treatment alone. In contrast, HMBPP/IL-2 cotreatment during chronic infection did not exacerbate disease, and more importantly it could confer immunological benefits. Surprisingly, although viral antigenic loads were not increased upon HMBPP/IL-2 cotreatment during chronic SHIV infection, HMBPP activation of V gamma 2V delta 2 T cells boosted HIV Env-specific Ab titers. Such increases in Abs were sustained for > 170 days and were immediately preceded by increased production of IFN-gamma, TNF-alpha, IL-4, and IL-10 during peak expansion of V gamma 2V delta 2 T cells displaying memory phenotypes, as well as the short-term increased effector function of V gamma 2V delta 2 T cells and CD4(+) and CD8+ alpha beta T cells producing antimicrobial cytokines. Thus, HMBPP/V gamma 2V delta 2T cell-based intervention may potentially be useful for combating neoplasms and HMBPP-producing opportunistic pathogens in chronically HIV-infected individuals. The Journal of Immunology, 2009, 183: 5407-5417.