A significant number of patients (>20%, more males than females) with acquired immunodeficiency syndrome (AIDS) develops cerebral atrophy and associated neuropsychiatric problems and dementia complex. After entering the brain via activated macrophages or microglias, the human immunodeficiency type one virus (HIV-1) may produce and release cytotoxic factors in the brain. Earlier studies indicate that HIV-1 envelope protein (gp-120) may be one of the neurotoxic factors produced by the virus. Based on the protein crystallographic structure we propose that HIV-1-derived protease could induce oxidative stress and cytotoxicity, contributing to brain atrophy. The present results revealed that HIV-1-derived protease is as toxic as gp-120 at nanomolar concentrations in human neuroblastoma cells. HIV-1 protease-induced cytotoxicity was blocked by a selective aspartate protease inhibitor Kynostatin (KNI-272) and also by antioxidants such as 17-beta-estradiol and melatonin. Moreover, mutation of cysteine 67 and 95 moieties of the HIV-1 protease significantly reduced protease-elicited apoptotic cell death. Furthermore, protease-induced oxidative damages were prevented by iron chelators such as deferoxamine and S-nitrosothiol. The present results indicate that free radicals generated by cysteinyl iron-sulfur redox sites may mediate HIV-1 protease induced neurotoxicity. In addition to gp-120, HIV-1-derived protease may play a role in cerebral atrophy and thus AIDS dementia complex. After replicating this finding in vivo, centrally active protease inhibitors and antioxidants can then be developed and used for slowing protease-induced cerebral atrophy and associated neuropsychiatric syndrome and dementia complex. - AIDS, HIV- 1 protease, free radical, cerebral atrophy, neuroprotection, KNI-272, 17-beta-estradiol, gp-120, melatonin
| Hawkins, V; Shen, Q; Chiueh, C C (1999) Kynostatin and 17beta-estradiol prevent the apoptotic death of human neuroblastoma cells exposed to HIV-1 protease. J Biomed Sci 6:433-8 |
