| HIV causes immunodeficiency in part by targeting CD4+ T cells for infection and dysfunction. In infected patients, HIV envelope (Env) present on free virions and infected cells causes dysfunction of uninfected bystander CD4+ T cells via interaction with both CD4 and co-receptors. Env is commonly employed as part of a cocktail of HIV antigens in current vaccine approaches. In DNA and viral vector vaccine approaches, antigen presenting cells (APCs) and non-APCs in the vicinity of the vaccine delivery site and draining lymph node express vaccine derived antigens. Our hypothesis is that similar to virion and infected cell presentation of HIV Env, vaccine delivery of functional HIV Env will inhibit CD4+ T cell activation resulting in deficient vaccine responses. Using in vitro systems that model vaccine delivery of Env to both APCs and non-APCs, we demonstrate that cell surface expression of Env causes an inhibition of antigen induced CD4+ T cell activation. Suppression was characterized by abnormal up-regulation of activation markers and a reduction in proliferation. The signaling pathways used by TCR and IL-2 were not inhibited by Env. Apoptosis and IL-2 dependent anergy, mechanisms described for Env mediated suppression in other studies, were also not observed. Preliminary studies identify suppression by T regulatory (TReg) cells as a possible mechanism, but unlike certain in vivo studies, we do not find that Env expands TReg cells, but instead activates their function likely leading to inhibition of CD4+ T cell activation and expansion. We also identify a functional Env that circumvents suppression due to its inability to bind CD4, suggesting an alternative and potentially superior approach to HIV vaccine design. |
