Shilpa J Buch

Dr. Buch’s research activities include the examination of drugs abuse and HIV/SIV cooperativity, the assessment of chemokine connection and the study of endogenous neuroprotective pathways.

The long-term goal of Dr. Buch and her research team is to identify novel therapeutic strategies that may enhance neuronal function and survival in NeuroAIDS in conjunction with substance abuse, with possible implications in other neurodegenerative diseases. Injection drug abuse is a major cause of the spread of HIV/AIDS. Heroin, morphine and other opioids not only promote HIV infection and the progression of AIDS, but also appear to intrinsically exacerbate the frequency and severity of HIV encephalitis (HIVE) in the central nervous system (CNS). Dr. Buch and her team are actively pursuing an understanding of how cocaine synergizes with HIV and HIV proteins to exacerbate disease pathogenesis. Their findings imply that cocaine can act at multiple steps within the CNS to promote neuronal toxicity, specifically impacting the blood-brain barrier breach and enhancing virus replication in macrophages. Another highly relevant area of research in their lab is aimed at examining the effect of morphine on progression of HIVE in SIV-infected macaques, which are an excellent analogue of HIV encephalopathy. Dr. Buch’s research team is also pursuing mechanisms by which cocaine enhances HIV toxicity in the CNS with regards to the enodthelial cells, astrocytes, microglia and neurons. Animal models are also used to validate cell culture findings in vivo. Another important research project examines the role of chemokine connections. CXCL10 or interferon γ-inducible peptide has been detected in the cerebrospinal fluid of individuals with HIV-1 infection, and is closely associated with the progression of HIV-1-related CNS infection and neuropsychiatric impairment. Using the macaque model of HIV neuropathogenesis, Dr. Buch and her team have identified the role of this chemokine as a potent neurotoxin that is linked to virus-associated encephalitis. Specifically, they have demonstrated the signaling pathways by which viral proteins cause regulated induction of this chemokine, thereby resulting in apoptotic cell death. Additionally, papers from their laboratory suggest that in astrocytes, the interplay of viral proteins with the inflammatory mediators (IFN-γ/TNF-α) can lead to synergistic induction of this neurotoxin via the oxidative stress pathway. Dr. Buch’s third research field is the study of endogenous neuroprotective pathways. CNS homeostasis is a fine balance of neuroprotective and neurotoxic pathways. Dr. Buch and her team have been interested in exploring endogenous cellular pathways that can augment neuronal survival. In their recent findings, they report an unconventional role for the HAD-associated chemokine, MCP-1: that of neuroprotection against virus toxicity. Similarly, they have also reported the paradoxical role of platelet-derived growth factor as a neuroprotective factor against HIV toxicity. These are very intriguing findings as they lend credence to the existence of selective “anatomical niches” in the CNS. Dr. Buch’s ultimate goal is to examine the roles of these host mediators as therapeutic agents that can mitigate CNS inflammation and impaired synaptic transmission in vivo.

University of Nebraska, Omaha, United States