Combination antiretroviral therapy (HAART) can result in sustained reduction in human immunodeficiency virus (HIV) growth for three to four years. The immune system does not completely recover even with successful HAART, suggesting that immune system damage may be irreversible if treatment consists of HAART only. Therefore HAART should be coupled with alternative therapeutic approaches that strengthen the anti-HIV immune response to clear the residual virus still present in tissue compartments, such as lymph nodes. In earlier studies, we demonstrated that, ALX40-4C or N-a-acetyl-nona-D-arginine amide, a small-molecule inhibitor directed against the chemokine receptor CXCR4, can inhibit infection by HIV strains, labeled syncytium-inducing (SI), that use this co-receptor (J.Exp.Med. 186:1395, 1997). More recently, we have obtained evidence that programmed cell death or apoptosis of CD8+ T cells isolated from HIV-infected patients is mediated by macrophages (M about), via interaction between the HIV envelope and the chemokine receptor CXCR4 (Nature 395:189, 1998). We also observed, in preliminary experiments, that a small-molecule CXCR4 inhibitor, the bicyclam AMD3100, blocks MO-mediated CD8+ T cell death in vitro. Small-molecule CXCR4 inhibitors, such as ALX40-4C and AMD3100, potentially interfere with both viral replication and immune cell loss, and therefore might improve immune system recovery.
The specific aims are as follows:
Aim 1. To compare the efficiency of small-molecule CXCR4 inhibitors with different chemical structures for the blockade of HIV-induced CD8+ T cell apoptosis, we will test AMD3100, ALX40-4C and an analog of polyphemusin II, T134, for the prevention of CD 8+T cell death.
Aim 2. To characterize the molecular mechanisms underlying the blockade of CD8+ T cell apoptosis by small-molecule CXCR4 inhibitors in HIV infection, we will first determine the role of small-molecule CXCR4 inhibitors in the blockade of CD8+ T cell activation, since apoptosis often results from T cell activation. We will also assess the role of small-molecule CXCR4 inhibitors in the blockade of caspase-mediated CD8+ T cell apoptosis. We will ultimately determine whether small-molecule CXCR4 inhibitors block HIV-induced CD8+ T cell apoptosis by enhancing anti-apoptotic signals mediated via nuclear factor-kappa B activation and/or involvement of members of the Bcl-2 family.
