Current therapies for HIV are capable of controlling the virus, but do not represent a definitive cure. HIV invades the CNS relatively early during infection and sets the stage for long term inflammatory events. Relatively poor penetration of the CNS by highly active anti-retroviral therarpy (HAART) makes it a haven for the virus and permits ongoing inflammation that leads to moderate to potentially severe HIV-associated dementia. This spectrum of viral neurologic disease is collectively referred to as HIV-Associated Neurocognitive Disorders (HAND). Drug abusers are one of the fastest growing populations of HIV infected individuals and make up approximately one third of the HIV positive population in the USA. There is considerable evidence in the literature that HIV positive drug abusers are at greater risk for HAND and generally have a heightened pathology compared to non-drug abusers. There is evidence that drugs of abuse drive changes in chromatin structure and therefor may alter gene expression. My hypothesis is that changes in chromatin modification driven by drugs of abuse have a role to play in the long term detrimental effects seen in drug abusers and are a confounding factor in latency reversal. The premise of this proposal is that the effect of morphine and benzodiazepines on HIV-1 can serve as a model for the broader effects of these drugs in both the CNS and periphery. The rationale for this work is based on preliminary data from our lab and the literature. Drug abusers make up a large sub-population of HIV-1 positive individuals and are the most rapidly growing HIV-1 positive group. There is significant evidence that drug abusing patients have worse clinical outcomes than non-drug abusers. As such, there is a need to study the mechanisms by which drugs of abuse exacerbate HIV-1 pathogenesis. Chromatin modifications play an important role in HIV-1 transcription. Indeed, efforts to extinguish the latent reservoir that is the current barrier to a cure center on using agents that alter the chromatin state of the integrated promoter. Preliminary data from our lab indicates that morphine exacerbates the neuropathogenesis of HIV-1 and broadly alters the chromatin state in cells of the central nervous system (CNS). We have other findings that show benzodiazepines can alter the chromatin of the HIV-1 LTR in T-cells and reverse viral latency. To better examine epigenetic changes in cells we have developed a new microscopic technique for observing alterations in a single nucleus. Understanding the interaction between drugs of abuse and latency reversing agents will be key to treating the large population of HIV positive drug abusers. Understanding the alterations of the epigenetic landscape driven by drugs of abuse is critical in understanding the exacerbation of HAND and how these changes might affect efforts to clear the latent pool. My lab proposes to address these issues using a combination of traditional molecular biology, computational modeling and novel high resolution imaging techniques.
Drug abusers are one of the fastest growing populations of HIV-1 infected individuals and there is evidence that drug abusers are at greater risk for neuropathogenic effects of HIV-1 infection. Understanding the pathways by which drugs of abuse exacerbate neuropathogenesis is crucial to our ability to treat this population and will help elucidate the underlying mechanisms that drive HIV-associated neurocognitive disorders. 1
| Sardo, Luca; Lin, Angel; Khakhina, Svetlana et al. (2017) Real-time visualization of chromatin modification in isolated nuclei. J Cell Sci 130:2926-2940 |
