Faculty Bibliography

Injection drug use has been recognized as a major risk factor for AIDS from the outset of the epidemic. Cocaine, one of the most widely abused drugs in the United States can both impair the functions of macrophages & CD4⁺ lymphocytes and also activate HIV-1 expression in these cells. Cocaine is a multifactorial agent that acts globally to impair the functioning of brain resident cells through multiple pathways. The drug not only promotes virus replication in macrophages, microglia and astrocytes, but can also upregulate CCR5 coreceptor, and reciprocally inhibit its ligands, thereby increasing virus infectivity. Cocaine is known to modulate astroglial function and activation. Cocaine causes a myriad of toxic responses in the neurons: a) it synergizes with viral proteins, Tat and gp120 resulting in exacerbated neuronal apoptosis, b) it causes calcium mobilization and, c) generation of reactive oxygen species. Additionally, cocaine also exerts potent effects on microvascular permeability, thereby impacting the influx of virus-infected inflammatory cells in brain parenchyma. By amplifying the various arms of the toxic responses that characterize HIV-associated dementia (HAD), cocaine skews the balance in favor of the virus leading to accelerated progression and severity of dementia. © 2008 Science Publications.

HIV encephalopathy, one of the major complications of HIV infection, involves productive virus replication in macrophages in the brain in association with heightened expression of several host response factors. One or more of these factors are thought to be the cause of the degenerative changes in neurons in the brain. Macaques infected with SIV and SHIV viruses have provided excellent working models for studying mechanisms of the human disease. Although HIV encephalopathy is primarily associated with CCR5-utilizing viruses, our findings have shown that CXCR4-utilizing SHIVs were also capable of causing the syndrome in rhesus macaques. In SHIV-infected macaques, approximately 30% of the animals developed encephalitis. In order to understand the factors leading to end-stage encephalitis, we performed microarray analyses on brains of encephalitic and non-encephalitic-infected macaques, and found pronounced enhancement of expression of interleukin-4, platelet-derived growth factor-B chain, monocyte chemoattractant protein-1 and CXCL10 in the brains of the encephalitic animals. This review discusses the role of each of these factors in mediating SHIV encephalitis.