Interferon (IFN)a is an antiviral cytokine that has adverse effects on neuronal function. When IFNa is used as a treatment for diseases such as viral hepatitis and cancer, it can cause cognitive dysfunction if it is given in sufficient quantities and for prolonged periods. IFNa is elevated in the central nervous system (CNS) of a number of diseases associated with cognitive dysfunction, most prominently in HIV associated neurocognitive disorders (HAND). There is abundant data both in animal studies and in vitro demonstrating that IFNa is associated with neuronal dysfunction. IFNa is elevated in SCID mice with HIV encephalitis (HIVE) and is correlated with the degree of behavioral dysfunction exhibited during water radial arm maze (WRAM) testing. When HIVE mice are treated with neutralizing antibodies (NAb) to IFNa, behavioral abnormalities on WRAM testing and some aspects of HIVE histopathology are prevented or substantially reduced. To begin to understand the effects of IFNa on MAP2 expression and dendritic formation in neurons, an in vitro system using fetal rat neurons was used. These neuronal cultures reveal a dose dependent decrease in dendritic length and branching when exposed to IFNa. This effect is blocked by NAb to IFNa and partially ameliorated by NMDA antagonists. In this competitive renewal it is proposed that in vivo studies initiated during the previous grant (see above) will be extended by treating HIVE mice with a novel IFNa blocker, B18R (NormferonTM-alpha). This agent is more practical than NAb to IFNa for moving into human trials, primarily because it is less immunogenic, among other potential advantages. It appears likely that B18R crosses the blood brain barrier and inhibits CNS IFNa during encephalitis. Studies initiated in the previous granting period included the determination of effectiveness using a current combined antiretroviral therapy (cART) regimen in treating HIVE mice. These studies will also be extended by combining B18R with this cART regimen to determine if the combination is more efficacious than either alone. Importantly, these studies using both the B18R plus the cART regimen should more closely simulate human conditions, where cART reduces viral load but does not prevent HAND; therefore it is hypothesized that the two together will reduce viral load and ameliorate behavioral abnormalities in mice.. Moreover, proposed in vitro studies will extend previous in vitro results by examining the effects of IFNa on neurons to further elucidate the mechanisms of IFNa neurotoxicity. It is assumed that neurotoxicity stems from IFNa receptor (IFNaR) engagement, although previous studies mentioned above indicate that NMDA receptors also play a role. Therefore in vitro studies will determine whether IFNaR engagement correlates with downstream IFNa signaling and dendritic abnormalities. In addition, pathways involved in dendritic formation will be investigated through gene array analysis in neurons after IFNa exposure. Identification of pathways involved in the disruption of dendritic formation will contribute to understanding the basic mechanisms of memory formation and could lead to better treatments of cognitive dysfunction.
This research seeks to determine the reason why a substance that is normally produced by the body to fight infections (i.e., interferon-alpha or IFNa) can cause nerve cells in the brain to become sick. We will use nerve cells in a dish to determine why IFNa makes them sick. In addition, we want to further investigate the effects of IFNa in relation to HIV infection of the brain. We have already shown that IFNa is produced during HIV brain infection in mice. If we block IFNa in these HIV-infected mice with antibodies we can effectively treat their memory problems. We are now trying to develop a compound that would be safer than antibodies. The first step is to determine if this compound is safe in HIV-infected mice and helps their memory. If we show that the compound is safe and effective in mice, we will try to treat people with HIV brain disease.
|Kessing, Cari F; Tyor, William R (2015) Interferon-? induces neurotoxicity through activation of the type I receptor and the GluN2A subunit of the NMDA receptor. J Interferon Cytokine Res 35:317-24|
|Koneru, Rajeth; Olive, M Foster; Tyor, William R (2014) Combined antiretroviral therapy reduces brain viral load and pathological features of HIV encephalitis in a mouse model. J Neurovirol 20:9-17|
|Fritz-French, Cari; Shawahna, Ramzi; Ward, Jennifer E et al. (2014) The recombinant vaccinia virus gene product, B18R, neutralizes interferon alpha and alleviates histopathological complications in an HIV encephalitis mouse model. J Interferon Cytokine Res 34:510-7|
|Fritz-French, Cari; Tyor, William (2012) Interferon-? (IFN?) neurotoxicity. Cytokine Growth Factor Rev 23:7-14|