HIV-1 transactivator of transcription (TAT) protein causes neurotoxicity via astrocyte activation.
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Date
2015
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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.
Description
Master of Medical Science in Physiology. University of KwaZulu-Natal, Westville 2015.
Keywords
HIV infections--Complications., Neurotoxicology., Central nervous system--Diseases--Complications., AIDS (Disease)--Complications., Theses--Physiology., HIV-1 transactivator of transcription (TAT).