Shilpa Buch, Ph.D.

University, Baroda, India, 1982

4017 Wahl Hall West
3901 Rainbow Boulevard Kansas City, KS 66160
Phone: 913- 588-7389
Fax: 913-588-7430
sbuch@kumc.edu

RESEARCH

Our research examines the pathogenesis of CNS diseases, focusing on NeuroAIDS and PneumoAIDS resulting from HIV infection. We study its effects in the brain and lungs, and the interactions that lead to disruption of normal function. Viral and host factors and their interplay in exacerbating the disease are both under investigation, thereby enabling development of therapeutic interventions to prevent and treat neuroAIDS.

HIV-encephalitis (HIV-E), one of the major complications of HIV infection, results from a cascade of viral-host interactions that lead to cytokine and chemokine imbalance, monocytic infiltration, formation of microglial nodules, highly productive infection in the brain macrophage/microglia and neuronal dysfunction and death. The pathogenesis of HIV encephalopathy revolves around two processes characterized first, by productive replication of the virus in macrophages in the brain, a process that leads to encephalitis, and second, neuronal degeneration that results from byproducts of the infected macrophages, leading to dementia.

Our recent research interest has focused on understanding mechanisms of development of HIV-associated dementia (HAD). Using macaques infected with Simian Human Immunodeficiency Viruses (SHIVs), as a model system we have explored questions about mechanisms of pathogenesis of the syndrome in these animals. The main target cell of the virus in the brain is the macrophage. Our early studies have shown that the virus invades the brain during the systemic phase of hate infection when the virus is replicating highly productively in lymphoid tissues. However, minimal replication occurs in the brain at this time. Late in the disease process, encephalitis develops and this is accompanied by massive infusion of monocytes from the blood into the brain. These cells rapidly differentiate into macrophages, and virus now begins to replicate productively with the result of encephalitis and death of neurons. We are using cultures of monocyte-derived macrophages (MDMs), viruses of known biological properties, and host factors (cytokines and chemokines) to explore mechanisms that initially inhibit virus replication in these cells and later enhance the virus replication process.

Our current interest focuses on identifying host factors that are critical for lentiviral neuropathogenesis. Using commercial and custom microarrays, we have identified several of these factors that are up-regulated during SHIV-encephalitis. Our recent studies are aimed at exploring in depth the role of two such host factors, CXCL10 (a chemokine) and PDGF-B chain (a growth factor) in HAD. We have exploited the in vitro cell culture system to tease out the mechanisms at the cellular level and these findings are then validated in the animal model system.

While HIV infection is the leading cause of death among Americans 25-44 years old, injection drug use now accounts for about one-third of all new US AIDS cases reported each year. Cocaine, often abused by HIV-infected patients, has been suggested to worsen the HIV-associated dementia (HAD) via unknown mechanisms. The brain is a target organ for both, cocaine and HIV-1.

The goal of my current research is to explore the effect of cocaine on HIV-1 replication in monocyte-derived macrophages (MDM) and in the chronically infected promonocytic cell line (U1). We have observed cocaine enhanced virus production in both U1 cells and in HIV-1-infected MDMs and this effect was at the level of transcriptional activation of HIV-1. Our recent findings have shown that cocaine can modulate the expression of IL-10, a cytokine that has been shown to promote HIV-1 replication. Additionally, cocaine caused enhancement of both, IL-10 and virus replication in macrophages infected with SHIV89.6P. We have also shown that virus replication and exogenous cocaine can up-regulate production of the chemokine, CXCL10, in SHIV/HIV-1-infected macaque/human MDMs. Cocaine can thus act at multiple steps in the accelerating the progression of HIV-dementia.

MOST RECENT PUBLICATIONS:

M.Zhang, S.Buch, M. Norberg and W.Truog (2005) Responses of pulmonary platelet-derived growth factor peptides and receptors to hyperoxia and nitric oxide. Pediatric Research, Vol. 57.

Y Sui, S Li, D Pinson, I Adany, Z Li, F Villinger, O Narayan, and S Buch (2005). Simian Human Immunodeficiency Virus associated pneumonia correlates with increased expression of MCP-1, CXCL10 and viral RNA in the lungs of rhesus macaques Amer. J Pathol. 166; 355-365

N Dhillon, Y Sui, R Potula, S Dhillon, I Adany, Z Li, F Villinger, D Pinson, O Narayan, and S Buch (2005) Inhibition of Pathogenic SHIV Replication in Macaques Treated With Antisense DNA of Interleukin-4 Blood. 105(8):3094-3099.

Smith, M.S., Y. Niu, S. Buch, Z. Li, I. Adany, D.M. Pinson, R. Potula, F. J. Novembre, and O. Narayan. (2005) Active Simian Immunodeficiency Virus (strain smmPGm) Infection in Macaque CNS Correlates with Neurologic Disease. J. AIDS, 38(5):518-30.

Y Sui, L Stehno-Bittel, S Li, R Loganathan, D Pinson, A Nath, D Kolson, O Narayan, S Buch. (2006) CXCL10-induced Cell Death in Neurons: Role of Calcium Dysregulation. Eur.J Neurosci., 23(4):957-64.

N Dhillon, S Dhillon, Y Chebloune, D Pinson, F Villinger, A Kumar, O Narayan and S Buch. (2006) Therapy of SHIV Infected Macaques with Liposomes Delivering Antisense IL-4 DNA. AIDS, 20(8):1125-30

Z Liu, D Singh, D Sheffer, Y Chebloune, R Hegde, M Smith, S Buch and O Narayan (2006) Immunoprophylaxis against AIDS in macaques with a lentiviral DNA vaccine (Virology – In Press)

A Datta, U Sinha-Datta, N Dhillon, S Buch and C Nicot. (2006) HTLV-I and innate immunity: Interference with TLR4 signaling by p30 modulates the release of pro-and anti-inflammatory cytokines from Human macrophages. (JBC - In press).

R Kumar, S Orsoni, L Norman, G Tirado, A Verma, S Staprans, G Miller, S Buch and A Kumar (2006) Morphine addiction causes pronounced virus replication in cerebral compartment and accelerated onset of AIDS in SIV/SHIV-infected Indian rhesus macaques (Virology – In Press).

V Rivera-Amill, R Noel, S Orsini, G Tirado, J García, S Buch and A Kumar (2006) Variable Region 4 of SIV Envelope Correlates with Rapid Disease Progression in Morphine-exposed Macaques Infected with SIV/SHIV Virology (In Press)

LAB PERSONNEL:

Sirosh Bokhari: Senior Research Associate

Shannon Callen: Research Assistant

Navneet Dhillon, Ph.D.: Senior Research Associate

Ramakrishna Hegde, Ph.D.: Senior Scientist

Zhuang Li: Senior Research Associate

Fuwang Peng, Ph.D.: Research Associate

Rachel Williams: Graduate Student

Honghong Yao: Research Assistant

Xuhui Zhu: Research Assistant

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