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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.

Cerebral white matter changes including tissue water diffusion abnormalities detected with diffusion tensor magnetic resonance imaging (DTI) are commonly found in humans with Human Immunodeficiency Virus (HIV) infection, as well as in animal models of the disorder. The severities of some of these abnormalities have been reported to correlate with measures of disease progression or severity, or with the degree of cognitive dysfunction. Accordingly, DTI may be a useful translational biomarker. HIV-Tat protein appears to be an important factor in the viral pathogenesis of HIV-associated neurotoxicity. We previously reported cerebral gray matter density reductions in the GT-tg bigenic mouse treated with doxycycline (Dox) to conditionally induce Tat protein expression. Presently, we administered intraperitoneal (i.p.) Dox (100 mg/kg/day) for 7 days to GT-tg mice to determine whether induction of conditional Tat expression led to the development of cerebral DTI abnormalities. Perfused and fixed brains from eight GT-tg mice administered Dox and eight control mice administered saline i.p. were extracted and underwent DTI scans on a 9.4 Tesla scanner. A whole brain analysis detected fractional anisotropy (FA) reductions in several areas including insular and endopiriform regions, as well as within the dorsal striatum. These findings suggest that exposure to Tat protein is sufficient to induce FA abnormalities, and further support the use of the GT-tg mouse to model some effects of HIV.

The HIV-1 trans-activator of transcription (Tat) protein, interacts with psychostimulants to potentiate cocaine-reward in rodents. Sex steroids may protect against Tat-induced deficits. Female GT-tg transgenic mice conditionally-expressed Tat protein targeted to brain via a doxycycline-dependent, GFAP-linked promoter. Mice were tested for cocaine-conditioned place preference (CPP) and cocaine-induced locomotion when in the proestrous (high-hormone) or diestrous (low-hormone) phases of their estrous cycle. Cocaine-CPP was potentiated by Tat induction via 50, 100, or 125 (but not 25) mg/kg doxycycline daily treatment for 7 days. Diestrous mice exposed to Tat protein demonstrated significantly greater cocaine-CPP than did proestrous mice. Tat induction interacted with estrous cycle to decrease acute cocaine-induced locomotion among Tat-induced diestrous mice, but not their uninduced or proestrous counterparts, and attenuated cocaine-sensitization. In a cocaine-challenge, previously cocaine-sensitized mice demonstrated greater cocaine-locomotion over cocaine-naive counterparts and Tat-induction attenuated locomotion. Altogether, data demonstrate Tat and circulating sex steroid influences over cocaine-reward and psychostimulation.

Exposure to HIV-1 trans-activator of transcription (Tat) protein potentiates the psychostimulant effects of cocaine, but the functional consequences of the interaction between HIV-1 Tat and other abused drugs is poorly understood. We hypothesized that exposure to HIV-1 Tat would potentiate the rewarding effects of ethanol. GT-tg transgenic mice, where Tat protein is conditionally expressed in brain by a doxycycline-dependent GFAP-linked promoter, were used to test the effects of Tat on ethanol-conditioned place preference (CPP). Compared to uninduced littermates or doxycycline-treated C57BL/6J mice, Tat-induced GT-tg mice demonstrated a 3-fold increase in ethanol-CPP. The potentiation of ethanol-CPP was dependent on the dose and duration of doxycycline treatment used to express Tat protein. Moreover, induction of Tat protein after the extinction of CPP produced reinstatement without additional exposure to ethanol. Together, these data suggest that CNS exposure to HIV-1 Tat protein potentiates the rewarding effects of ethanol in mice.