University of Nebraska Medical Center

Laboratory of Shilpa Buch, PhD

The long term goal of our group is to identify novel therapeutic strategies that may enhance neuronal function and survival in NeuroAIDS, with possible implications in other neurodegenerative diseases.

Infection with HIV-1 is frequently complicated in its late stages by a neurological syndrome, HIV-associated dementia (HAD), clinically characterized by abnormalities in cognition, motor performance, and behavior. While the exact mechanism(s) by which HIV-1 causes CNS pathology are not completely understood, increasing evidence suggests that a state of immune activation associated with increased levels of pro-inflammatory cytokines is an important factor contributing to neuronal damage.

These pro-inflammatory cytokines can, in turn, synergize with the viral proteins released from HIV-infected cells to generate neurotoxins resulting in progressive neuronal damage associated with HAD. Interestingly, it is becoming increasingly clear that although the initial trigger of HAD is the virus, the severity of the disease correlates more closely with the presence of activated cells than with the presence and amount of HIV-infected cells in the brain.

Despite the preponderance of HIV for macrophages and CD4+T cells, virtually all the resident cells of the CNS are players contributing to the disease process.

To date, several aspects of HAD pathogenesis remain to be dissected. Using a multipronged approach comprising of in vitro cell systems, complemented with rodent models and the higher more relevant macaque model of SIV pathogenesis, and archival human tissue, our research aims to dissect the mechanism(s) of CNS pathology triggered by the host-virus interplay. Specifically, we are interested in the role of each CNS cell type as it contributes cumulatively to the disease process.

Research Interests

The Chemokine Connection

CXCL10 or interferon γ-inducible peptide has been detected in the CSF 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, we have identified the role of this chemokine as a potent neurotoxin that is linked to virus-associated encephalitis. Specifically, we have demonstrated the signaling pathways by which viral proteins cause regulated induction of this chemokine, thereby resulting in apoptotic cell death. Additionally, papers from our 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.

Endogenous Neuroprotective Pathways

CNS homeostasis is a fine balance of neuroprotective and neurotoxic pathways. However, this can be a double-edged sword, as a well-intentioned protective response, if extended for a long time, can go awry. We have been interested in exploring endogenous cellular pathways that can augment neuronal survival. In our recent findings we report unconventional role for the HAD-associated chemokine, MCP-1 - that of neuroprotection against virus toxicity. Similarly, we 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. Our 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.

Drugs of Abuse and HIV Co-operativity

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 CNS. We are actively pursuing how cocaine synergizes with HIV/HIV proteins to exacerbate disease pathogenesis. Our findings imply that 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 our lab is aimed at examining the effect of morphine on progression of HIVE in SIV-infected macaques, which are an excellent analog of HIV encephalopathy.

HIV, aging and NeuroAIDS

The now chronic nature of HIV has led to a major advancement in AIDS care. While HIV infected individuals are living longer, damaging effects of HIV persist in the brain and may interact with other neurodegenerative disorders. Dr. Buch, along with dR. Howard Fox, leads the Chronic HIV infection and Aging in NeuroAIDS Center (CHAIN). The Center is supported by NIH, NIMH P30 MH062261. The goal of the CHAIN Center is to provide the necessary leadership and backbone of support to continue the outstanding research on HIV/AIDS, aging and the central nervous system ongoing at the University of Nebraska Medical Center and throughout the nation. Experts in a number of fields direct the Cell-Tissue-Animal, Imaging, Omics, and Therapeutics cores, along with the Administrative and Developmental cores. Visit the CHAIN Center web site for more information.


  • Confocal Microscopy
  • Chromatin Immunoprecipitation (ChiP) Assays
  • Transmigration Assays
  • In situ hybridization


Emeritus Professor, University of Kansas

Professor, Department of Neurological Sciences
Senior Associate Dean of Research and Development, College of Medicine
Director, Center for Integrative and Translational Neuroscience

Howard Fox

Margaret R. Larson Professor of Internal Medicine and Infectious Diseases
Chair, Department of Pharmacology and Experimental Neuroscience


Laboratory of Howard E. Gendelman, MD

Howard E. Gendelman, MD


PDGF-CC Mediated Reversal of Synaptodendritic Injury in HAND

PI: S. Buch

Source: NIH/NIMH 5R01MH106425

The overarching goal of this application is to explore the role of platelet-derived growth factor (PDGF)-CC in reversing synaptodendritic injury & the associated cognitive decline, both of which comprise the hallmark features of HIV-associated neurocognitive disorders (HAND). Combinatorial in vitro, in vivo and ex vivo approaches are proposed to test the efficacy of PDGF-CC as a therapeutic agent.

Uncovering HIV/opioid effects in the brain at the single cell level: transcription, chromatin accessibility, and reservoir analysis in the SIV/cART/morphine/rhesus monkey model

MPI: H. Fox and S. Buch

Source: NIH/NIDA/5U01DA053624

In this proposal, we will study the interplay of HIV pathogenesis and opioid abuse in the gold-standard SIV/nonhuman primate system, using single-cell RNA sequencing (scRNA-seq) to assess individual cellular transcriptomes.

Pharmacokinetic, pharmacodynamic, and toxicological interactions among Opioids and Cabotegravir

MPI: N. El-Hage, S. Buch, and CV. Fletcher

Source: NIH/NIDA/R01DA057145

The purpose of this grant application is to evaluate the drug-drug interactions among opioid abuse (morphine), medications to treat opioid use disorders (naltrexone), and medications for HIV prevention (Cabotegravir). Pharmacokinetic, pharmacodynamic, and toxicological interactions among the three classes of pharmaceuticals will be studied using mouse models and non-human primate systems.

Single cell determinants of brain in the context of viral persistence in SIV/cART/cocaine non-human primates

MPI: T. Rana and S. Buch

Source: NIH/NIDA/1U01DA058402

In this proposal, we will establish a well characterized non-human primate model to investigate effects of SIV, cocaine, and cART on brain, and will determine the gene expression and epigenetic programs involved in SIV, cART, and cocaine-mediated neuropathogenesis.
Chronic HIV Infection and Aging in NeuroAIDS (CHAIN) Center

MPI: S. Buch and H. Fox

Source: NIH/NIMH 3P01MH062261

This is a Center grant to provide Administrative and Core Support for scientists investigating NeuroAIDS.

The combinatorial effects of Opiates and the emerging promoter-variant strains of HIV-1 subtype C on HIV neuropathogensis and latency

PI: S. Buch

Source: NIH 1 R01 DA041751-01

In this proposal we plan investigate the involvement of the combinatorial effects of Opiates and the emerging promoter-variant strains of HIV-1 subtype C on HIV neuropathogensis and latency and testing this hypothesis in a primate model.

HIV Tat & cocaine-mediated alterations in microglial migration & activation involve epigenetic regulation or miRNAs

PI: S. Buch

Source: NIH 1 R01 DA043138-01

The goal of this proposal is to explore how cocaine and HIV Tat modulate increased microglial activation and migration respectively, via DNA methylation of microRNA 124 promoter, leading in turn, to increased TLR4 signaling and also via up regulation of miR-9 leading to enhanced microglial migration

HIV Tat and Morphine Induce Microglial Migration and Activation via Release of miR-9 and 138

PI: S. Buch

Source: 5 R01 DA040397-05

This grant aims to explore how viral protein such as Tat induces miRNA-9 in exosomes from the astrocytes leading to increased migration of microglia. We also propose to understand how morphine exposure of astrocytes can upregulate miRNA-138 in exosomes, which leads to increased microglial activation. Together HIV proteins and opiates co-operate to inflict increased glial migration and activation, thereby contributing to disease severity.

The brain as a SIV reservoir under suppressive cART potentiation by drugs of abuse

MPI: H. Fox/S. Buch

Source: NIH 1 R01DA043164

Using the SIV/macaque system, we will determine whether the brain is a viral reservoir in the setting of effective treatment, and will measure the effect of two commonly used drugs of abuse, morphine and methamphetamine, on the brain reservoir. Mechanisms by which drug abuse affect the viral reservoir will be examined, thus leading to strategies to target this reservoir to effect a cure in those with and without substance abuse.

HIV-1 mediated synaptodendritic injury and microglial activation: Role of extracellular vesicle miRNAs

PI: G. Hu; Co-I: S. Buch

Source: NIH R01MH112848

The goal of this project is to assess the molecular pathways by which PDGF-CC reverses the synaptodendritic injury induced by HIV Tat.

Combinatorial effects of HIV, cART, & morphine on neuroinflammation: implications for HAND

PI: M. Guo; Co-I: S. Buch

Source: NIH 5 R01 DA044586-03

In this grant, we will test the hypothesis via two specific aims - SA1: Investigate the molecular mechanism(s) underlying TAT, morphine & ARVs (3 drug regimen) mediated activation of microglia in vitro; and SA2: To determine the mechanisms underlying Tat, morphine and cART-mediated neuroinflammation in vivo in a rodent model of HAND.

Mechanisms underlying dysregulated neuroimmune signaling and neuronal dysfunction in HIV (+) individuals with cART and cocaine

PI: M. Guo; Co-I: S. Buch

Source: NIH 1 R01 DA047156-01

This grant is to explore the critical roles of NLRP3 inflammasome on microglial activation and the involvement of non-long coding RNA malat1 in neuronal injuries in the context of cocaine, cART, and HIV-TAT.

Molecular mechanisms underlying HIV & cocaine-mediated microglial activation: targeting NLRP3 inflammasome

MPI: S. Buch and M. Guo

Source: NIH 1 R01 DA050545

In this proposal, we will assess the molecular signaling pathways by which the comorbidity of HIV and cocaine abuse exerts combinatorial activation of microglia in the brain with a focus on the multiprotein complex – the NLRP3 inflammasome. We will also test the efficacy of the NLRP3 inflammasome inhibitor in abrogating HIV and cocaine-mediated microglial activation in rodent models of HIV & cocaine administration. Understanding the mechanisms responsible for microglial activation induced by HIV & cocaine will set the stage for future development of novel therapeutics aimed at dampening the neuro-inflammatory responses.

Exosome-mediated anti-microRNA delivery in the CNS: A Novel Therapeutic for HAND in opiate users

MPI: G. Hu and S. Buch

Source: NIH R21 DA042704

MicroRNAs play important roles in regulation of disease pathogenesis including HIV associated cognitive impairment. Our goal in this grant is to develop therapeutic interventions using extracellular vesicle (EV)-based RNA drug delivery in vivo for the treatment of cognitive impairment in HIV-infected opiate abusers.

Rural Drug Addiction Research Center

PI: S. Buch

Source: University of Nebraska - Lincoln

Ocular Biological senescence evaluation & science study (OBSESSS)

PI: S. Buch

CRDF Global