Gamma/Delta T-Cell Functional Responses Differ after Pathogenic Human Immunodeficiency Virus and Nonpathogenic Simian Immunodeficiency Virus Infections

Following human immunodeficiency virus (HIV) infection, progression to AIDS is typically associated with increased viral replication and generalized immune dysregulation that is manifested in a variety of malignancies or opportunistic infections. Immune dysfunction occurs in numerous immunologic cells, including CD4+ T cells (22, 30), CD8+ T cells (27, 29), B cells (16, 25, 45), macrophages (10), natural killer cells (50), and gamma/delta (γδ) T cells (13, 32, 39). In humans, γδ T cells comprise a minor subset (1 to 5% on average) of circulating T cells but may represent as much as 50% of the T cells present within the mucosa-associated lymphoid tissue (6). γδ T cells play an important role in the recognition of microbial pathogens and can influence adaptive immune responses by the production of both Th1 and Th2 cytokines (15). There are two main γδ T-cell subsets that express either the first variable region (Vδ1) or the second variable region (Vδ2) of the delta locus from the T-cell receptor (TCR) (19, 24). The Vδ1+ γδ T cells are found predominately at mucosal sites and can respond to nonclassical major histocompatibility complex molecules expressed on stressed cells, while Vδ2+ γδ T cells are predominately in the peripheral circulation and respond to nonpeptide phosphoantigens (19, 20). γδ T cells are influenced by HIV infection as evidenced by a phenotypic switch from predominately Vδ2 before infection to predominately Vδ1 within the peripheral blood of HIV-positive (HIV+) patients (2). In addition, a decrease in the number of effector (CD27− CD45RA−) γδ T cells was observed in immunocompromised patients (18) and in simian immunodeficiency virus (SIV)-infected rhesus macaques (53). Previous studies suggest this may be due to the induction of cellular anergy (32, 33, 39, 42) or the ability of γδ T cells to migrate in response to proinflammatory chemokines (43) and kill cellular targets (51). These data suggest that γδ T cells lose the ability to respond to the HIV/SIV or invading opportunistic pathogens potentially impacting the disease outcome in infected humans/monkeys. In contrast to pathogenic HIV/SIV infections, natural host primate species in Africa, such as sooty mangabeys (Cercocebus atys), can be infected with SIV but generally remain free of clinical disease (17, 21, 23, 44, 47). The absence of clinical disease signs in SIV+ sooty mangabeys does not appear to be due to any differences inherent in virus replication, as mangabey viral loads are comparable to those of HIV-infected patients (105 to 107 copies per milliliter of plasma) and passage of virus to rhesus macaques results in simian AIDS (46). The presence of high levels of SIV replication in mangabeys suggests that protection from AIDS is not due to species-specific innate antiviral mechanisms or a more robust adaptive immune response (14, 37). To date, studies indicate that the ability of mangabeys to resist progression to AIDS may be due in part to reduced levels of immune activation and bystander apoptosis, as well as a preservation in the levels of peripheral CD4+ T cells (7, 37, 47). While investigating the nonpathogenic mechanisms associated with SIV+ mangabeys, we observed that some mangabeys undergo an extreme, persistent, and generalized depletion of CD4+ T cells to levels associated with disease during HIV infection yet do not exhibit clinical AIDS signs (37, 48). These findings suggested that low CD4+ T-cell levels are not sufficient to induce disease in these natural hosts of SIV. Furthermore, we observed that γδ T cells from both SIV+ CD4-healthy (>200 CD4+ T cells/μl blood) and CD4-low (<200 CD4 cells/μl blood) mangabeys maintained their ability to proliferate in response to the bacterial antigens isopentenyl pyrophosphate (IPP) and lipopolysaccharide (LPS) (37). Studies presented here expand upon the previous analyses through a comparative assessment of the levels and functions of γδ T cells during pathogenic HIV infection of humans and nonpathogenic SIV infection of mangabeys. Our findings indicate that γδ T cells from SIV+ mangabeys maintain their ability to express Th1 cytokines in response to both γδ T-cell-specific and nonspecific stimulation. These data provide a rationale for investigating the use of therapies aimed at increasing γδ T-cell functionality in HIV+ humans.