HIV-1 Tat protein has been shown to have a crucial role in HIV-1-associated
neurocognitive disorders (HAND), which includes a group of syndromes ranging from
undetectable neurocognitive impairment to dementia. The abuse of psychostimulants, such as
cocaine, by HIV infected individuals, may accelerate and intensify neurological damage. On the
other hand, exposure to Tat potentiates cocaine-mediated reward mechanisms, which further
promotes HAND. Here, we show that didehydro-Cortistatin A (dCA), an analog of a natural
steroidal alkaloid, crosses the blood-brain barrier, cross-neutralizes Tat activity from several
HIV-1 clades and decreases Tat uptake by glial cell lines. In addition, dCA potently inhibits Tat
mediated dysregulation of IL-1β, TNF-α and MCP-1, key neuroinflammatory signaling proteins.
Importantly, using a mouse model where doxycycline induces Tat expression, we demonstrate
that dCA reverses the potentiation of cocaine-mediated reward. Our results suggest that adding a Tat inhibitor, such as
dCA, to current antiretroviral therapy may reduce HIV-1-related neuropathogenesis.