HIV-1 transactivator of transcription (TAT) protein causes neurotoxicity via astrocyte activation.

Abstract

HIV is most well-known for its negative effects on the immune system and the resulting development of AIDS, however it also has severe damaging effects on the central nervous system. Many infected individuals exhibit neuropsychological and behavioral dysfunctions which are collectively referred to as HIV-associated dementia (HAD). One of the worrying aspects of HAD is the fact that current anti-retroviral therapy, while being effective in managing the onslaughts of HIV on the immune system, is less efficient in addressing the impact of HIV on the CNS. The HIV-1 regulatory protein, transactivator of transcription (Tat), is responsible for the transactivation of viral transcription, and has been identified as a possible etiological factor of HAD. Neurotoxicity caused by HIV-1 is an indirect effect since the virus is unable to infect neurons directly. We subsequently hypothesized that HIV-1 infects non-neuronal cells in the CNS which leads to their activation, resulting in the release of cytokines that are detrimental to neurons. The aims of this study was therefore to (i) determine whether Tat activates astrocytes, (ii) establish whether astrocytes exposed to Tat result in the release of IL-6 and TNF-α, and to (iii) assess whether these cytokines can induce apoptosis of neuronal cells. Our study has shown that Tat does activate astrocytes and that activated astrocytes do indeed release cytokines IL-6 and TNF-α into their growth medium. Tat treated cells release more than double the amount of IL-6 than the control group of untreated astrocytes. We also observed that exogenous administration of these cytokines (individually or collectively) to neurons has the ability to cause neuronal apoptosis. Interestingly in combination, these cytokines show no cooperative effect. Our data also showed that neurons, when exposed to the culture medium of astrocytes that were subjected to Tat, exhibit hallmarks of apoptosis similar to that induced by IL-6 and TNF-α. Our findings led us to conclude that in individuals with HIV-infection, the virus activates astrocytes possibly via the production and release of Tat. This causes the astrocytes to secrete pro-inflammatory cytokines (e.g. TNF- α and IL-6) that may induce apoptotic cell death of neurons. This mechanism may explain the development of HAD.