THE ROLE OF HIV ENVELOPE GLYCOPROTEIN GP120 AND PROINFLAMMATORY CYTOKINES IN ALTERING NEURONAL FERRITIN HEAVY CHAIN EXPRESSION
L Festa1, O Meucci1,2
Departments of Pharmacology & Physiology1 & Microbiology & Immunology2, Drexel University College of Medicine
HIV infection of the CNS and its clinical manifestations continue to be an unmet medical need, with the underlying mechanisms of neuronal injury poorly understood. Ferritin is a ubiquitous protein involved in iron sequestration and storage, composed of two different subunits, heavy chain (FHC) and light chain (FLC). Recent evidence has identified a novel role for FHC as a negative regulator of the CXCL12/CXCR4 chemokine signaling pair. Our previous studies have shown that this chemokine/receptor axis increases dendritic spine density, suggesting an important role in synaptic transmission. In line with this, opiates, including morphine, inhibit CXCR4 neuroprotective signaling via FHC. Further, in vivo data show greater expression of FHC and inhibition of CXCR4 activation in brain tissue of HIV+/drug abusers compared to controls. Thus, we hypothesized that components of HIV infection regulate neuronal FHC. Our results suggest that the inflammatory cytokines, TNF-α and IL-1β, as well as the HIV envelope protein gp120 upregulate neuronal FHC expression. While both cytokines induced increases in FHC in the presence and absence of glia, gp120 only caused significant FHC changes in neuronal/glial co-cultures, suggesting glia are necessary for the action of gp120 on FHC. IL-1β is responsible for this observed effect as the presence of a neutralizing antibody or receptor antagonist abrogated gp120-induced changes in FHC. In two in vivo models of HIV neuropathology (HIV-Tg and gp120-ICV injected rats), we discovered a significant reduction in cortical neuronal dendritic spine density compared to control animals. Overall, these findings suggest that the effect of HIV gp120, proinflammatory cytokines, and opiates may converge, through FHC, on dendritic spines and enhance synaptic injury in HIV/drug abuse patients.