Recent progress in antiretroviral therapy makes the immunosuppression of human immunodeficiency virus, type 1 (HIV) disease partially reversible, however the degree of immune recovery is more complete in some individuals than in others. Despite effective suppression of HIV replication with highly active antiretroviral therapy (HAART), CD4+ T cells do not increase in some HAART-treated individuals. Even in the setting of quantitative CD4+ T cell recovery, HAART recipients retain qualitative abnormalities in immune function that include impairments in peripheral T cell proliferation and maturation, and marked deficits in HIV-specific immunity. The long-term goal of this research is to explore and develop immune-based strategies that will enhance T cell production and function in immunodeficient individuals. Growth hormone (GH) and its proximal mediator, insulin-like growth factor (IGF-1), are important regulators of T cell development and function in mammals. GH and IGF-1 reverse age-related declines in thymopoiesis in older rodents and accelerate immune reconstitution in immunodeficient animals. Recently these findings were extended to human studies, which demonstrated that GH treatment of HIV-infected adults was associated with a dramatic increase in thymic mass and an increase in circulating naive CD4+ T cells. Accumulating evidence from in vitro and in vivo studies suggest that GH and IGF-1 may also regulate and potentiate peripheral immune function. The central hypothesis of this proposal is that growth hormone will enhance antigen-specific T cell responses in HIV infected adults. Augmentation of peripheral immune responses may be mediated by GH induction of de novo T cell production by the thymus, or by its effects on targets within the peripheral immune system.
The specific aims of our research are to: 1. Investigate the effects of GH and IGF-1 on human T cell function in vitro. We will conduct analyses to examine how GH and IGF-1 modulate the survival, proliferation, activation, cytokine production and cytotoxicity of peripheral T cells, including specific analysis of na'ive and memory/effector subsets. 2. Determine whether growth hormone treatment enhances antigen-specific immune responses in HIV-infected adults. We will perform longitudinal analysis of HIV and CMV-specific immune responses in the context of a randomized prospective clinical study examining the effects of GH on the immune system of HIV-infected adults.
| Napolitano, Laura A; Schmidt, Diane; Gotway, Michael B et al. (2008) Growth hormone enhances thymic function in HIV-1-infected adults. J Clin Invest 118:1085-98 |
