Chapter 5.3 - HIV-1-Associated Dementia

Abstract

This chapter discusses the role of chemokine receptors and their ligands in the disease mechanisms. HIV-1-associated dementia (HAD) results from complex interactions between viral and host factors. Four chemokine receptors and their ligands (CXCR4/SDF-1, CCR5/MIP-1α and β, RANTES, CCR2/MCP-1, and CX3CR1/fractalkine) are of particular importance in HAD. HIV-1 infection of macrophages and microglia in the CNS is primarily mediated by CCR5. A subset of strains can infect macrophages and microglia via CXCR4. Increased monocyte trafficking into the CNS of patients with HAD is likely to result from increased expression of MCP-1, in addition to CCR5 chemokines. Neurodegenerative mechanisms in HAD may involve interactions between the HIV-1 envelope glycoproteins (Env) and CXCR4, or possibly other chemokine receptors on neurons, and possibly other CNS cell types. CCR5 and CXCR4 are promising targets for the prevention and treatment of HAD. Several compounds that selectively block virus entry without affecting physiological functions of these receptors are being developed, and some are in early clinical trials. Understanding the role of CCR5, CXCR4 and other chemokine receptors and their ligands in HIV-1 neuropathogenesis will be important for advancing the development of new therapeutic strategies for the prevention and treatment of HAD and other neurological complications of HIV-1 infection.