Neurotrophic Factor Regulation of Human Immunodeficiency Virus Type 1 Replication in Human Blood-derived Macrophages Through Modulation of Coreceptor Expression

Abstract

Macrophages are a major target for human immunodeficiency virus type-1 (HIV-1) infection in vivo and represent a reservoir of chronically infected cells in patients receiving highly active retroviral therapy 1,2. The entry of virus into cells is mediated by binding of the viral glycoprotein gp120 with CD4 and chemokine receptors. The T-cell-tropic strains of HIV-1 utilize the CXC chemokine receptor 4 (CXCR4), while the CC chemokine receptor 5 (CCR5) predominantly binds macrophage-tropic (M-tropic) HIV-1 strains (reviewed in Rucker 3). Increased cell surface expression of CCR5 during monocyte maturation to macrophages correlates with susceptibility to HIV-1 infection 4. However, efficient usage of CCR5 and CXCR4 as CD4-independent HIV-1 receptors was recently shown 5,6. Interestingly, primary isolates and dual-tropic stains of HIV-1 can utilize a plethora of additional G protein coupled coreceptors including CXCR4, CCR5, and the receptors, CCR3 or CCR2b, among others, to gain access into primary T lymphocytes and monocytic lineage cells 3. Nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are members of the neurotrophic factor (NTF) family that are known to influence neuronal growth, differentiation and survival. NGF modulates the expression of enzymes that remove free radicals, while BDNF regulates calcium concentration via CREB 7. Expression of neurotrophic factors and their receptors have been observed in in vitro