The role of interferon-alpha in the pathogenesis of HIV encephalitis

HIV-associated dementia (HAD) is an AIDS-defining illness that affects up to 30% of the HIV-infected population worldwide. The pathogenesis of HAD is incompletely understood. Since antiretroviral therapy is only partially effective in improving the symptoms of HAD, new treatments are needed based on better delineation of HAD pathogenesis. It is hypothesized that HAD occurs because HIV-infected cells produce putative neurotoxins that damage neurons. To study the pathogenesis of HAD, our laboratory developed a HIV-Encephalitis (HIVE) SCID mouse model that recapitulates many of the pathological and behavioral manifestations of HAD.; Interferon-Alpha (IFNalpha) is a pleomorphic cytokine produced by nucleated cells in response to viral infection. Treatment of patients with IFNalpha produces side effects including cognitive impairment resembling subcortical dementia, the hallmark of HAD. IFNalpha is reported to be increased in the cerebrospinal fluid of HAD patients compared to HIV patients without dementia symptoms. I hypothesized that overexpressed IFNalpha in the central nervous system (CNS) is responsible for some of the cognitive dysfunction and pathological abnormalities seen in SCID mice with HIVE.; HIVE mice exhibit cognitive deficits in water radial arm maze (WRAM) testing. A correlation was found between IFNalpha in the CNS and cognitive performance, with higher levels of IFNalpha correlating with increased cognitive deficits during testing. HIVE mice treated with intraperitoneal (i.p) injections of IFNalpha neutralizing antibodies demonstrated significantly improved cognitive function (p<0.05) as determined in the WRAM compared to HIVE mice that received either isotype-matched control antibody or saline injections. Pathological analysis showed presence of IFNalpha neutralizing antibodies in the brain. Anti-IFNalpha antibody treated HIVE mice exhibited decreased microgliosis (p<0.05) compared to HIVE mice with control antibody or saline injections. Anti-IFNalpha antibody treated mice showed improvements in loss of dendritic arborization surrounding HIV-infected cells compared to other HIVE mice. In vitro analysis of the effects of IFNalpha on primary neuron cultures showed IFNalpha has a dose dependent detrimental effect on neuron dendritic arborization. This effect can only be partially blocked by inhibiting glutamate signaling, indicating that IFNalpha uses more than one receptor type in respect to its neurotoxicity. This research shows IFNalpha has a major role in HAD pathogenesis.