Laboratory of Howard Fox, M.D., Ph.D.
Durham Research Center
58800 Nebraska Medical Center
Omaha, NE 68198-5800
Keywords: HIV infection of the CNS, substance abuse, neuro-inflammation, oxidative stress, miRNAs, co-morbidities and viral reservoirs.
My research interests include elucidating role of miRNAs in genomic adaptation of HIV CNS disease in opiate-abusers and related co-infections.
Opiate-abusers are at a high-risk for Human Immunodeficiency Virus (HIV) infection. In USA 30% of HIV-infected individuals are opiate-abusers and new HIV infections continue to increase. These individuals experience severe psychological stress, neurological-dysfunction, depression & hepatitis-C virus infection. More importantly, the resultant high-risk sexual behavior, poor adherence to antiretroviral regimens and onset of co-morbid conditions such as hepatitis-C virus infection collectively accelerate disease progression. As HIV replication in the central nervous system (CNS) cannot be inhibited efficiently despite advances in antiretroviral therapy efficacy, latent viral reservoir is established in the CNS. Since the antiretrovirals poorly access the CNS, reactivation of the latent virus manifests in a broad range of HIV-associated neurocognitive disorders that could include HIV-associated dementia (HAD), HIV encephalitis (HIVE), or mild cognitive motor dysfunction (MCMD). Viral proteins and pro-inflammatory cytokines and chemokines secreted by HIV-infected microglia and perivascular macrophages induce inflammation and oxidative damage. As a result, HIV-infected opiate-abusers are susceptible to accelerated disease progression and neurological dysfunction.
My current research interest is focused on investigating the role of microRNAs (miRNAs) and inflammation, in HIV neuropathogenesis in opiate-abusers. As evidenced from our studies in h-mdms and fetal cells derived from the CNS, there is a strong basis for implicating miRNAs and inflammation in the neuroAIDS paradigm. These studies indicate that pathologic (HIV) and biochemical (opiates) insults to the CNS induce inflammation and alter miRNA expression. In this paradigm we observed differential expression of 26 miRNAs (p<0.01) from h-mdms exposed to morphine. Importantly, miRNAs (15b/21) that could intersect neurogenesis and cell cycle regulation were identified to be responsive to morphine. Interestingly, expression of this miRNA pair (15b/21) was inversely correlated in morphine-exposed h-mdms, with miR15b exhibiting the strongest expression. Of note, a direct correlation was observed between miR15b (strongest induction) and suppression of its target gene expression fibroblast growth factor-2 (FGF-2). In parallel we have observed an induction of potent inflammatory response from morphine-exposed h-mdms resulting in secretion of interleukin-6 (IL-6), monocyte chemoattractant protein 2 (MCP-2) and tumor necrosis factor α (TNF-α). These results provide insights into how macrophage/microglia may affect disease progression in HIV-infected opiate-abusers. However, the role of miRNAs and inflammation in these disease processes is not clearly understood and has to be further elucidated.
Jaffe, R.J., Dave R.S., Byrareddy, S.N. Meningeal lymphatics in aging and Alzheimer’s disease. Ann Transl Med 2019;7(Suppl 1):S2. doi: 10.21037/atm.2019.01.06. PubMed: PMID: 31032283; PMCID: PMC6462592.
Woollard, S.M., Olwenyi, O.A., Dutta, D., Dave, R.S., Mathews, S., Gorantla, S., Johnson, Giavedoni, L., Norgren, R.B., Byrareddy, S.N. Immune Response and Viral Pathogenesis of Zika virus in Rhesus Macaque models. Pathogens 2018 7(3) DOI: 10.3390/pathogens7030070 PMID: 30127237.
Dave, R.S., Jain P. & Byrareddy S.N. Follicular Dendritic Cells of Lymph Nodes as Human Immunodeficiency Virus/Simian Immunodeficiency Virus Reservoirs and Insights on Cervical Lymph Node. Frontiers in Immunology 2018 9: 805. https://doi: 10.3389/fimmu.2018.00805. PMID: 29725333.
Dave, R.S., Jain P. & Byrareddy S.N. Functional Meningeal Lymphatics and Cerebrospinal Fluid Outflow”. Journal of Neuroimmune Pharmacology 2018, https://doi: 10.1007/s11481-018-9778-5. PMID: 29464588.
Dave, R.S., Sharma, R.K., Muir, R.R., Haddad, E., Gumber, S., Villinger, F., Nehra, A., Khan, Z., Wigdahl, B., Ansari, A., Byrareddy, S.N. and Jain, P. FDC:TFH Interactions within Cervical Lymph Nodes of SIV-Infected Rhesus Macaques. Journal of Neuroimmune Pharmacology 2017, https://doi.org/10.1007/s11481-017-9775-0. PMID: 29288344.
Pustylnikov S, Dave RS, Khan ZK, Porkolab V, Rashad AA, Hutchinson M, Fieschi F, Chaiken I, Jain P. Short Communication: Inhibition of DC-SIGN-Mediated HIV-1 Infection by Complementary Actions of Dendritic Cell Receptor Antagonists and Env-Targeting Virus Inactivators. AIDS research and human retroviruses. 2016;32(1):93-100. Epub 2015/09/19. doi: 10.1089/aid.2015.0184. PubMed PMID: 26383762; PMCID: PMC4692117.
Dave, RS* and Langord D. Is Achieving Undetectable Viral Load in the CNS Reservoir an Important Benchmark for Curing HIV Infection? Epidemiol 4: e114. 2014.doi:10.4172/2161-1165.1000e114
Ozdemir AY, Rom I, Kovalevich J, Yen W, Adiga R, Dave RS, Langford D. PINCH in the cellular stress response to tau-hyperphosphorylation. PLoS One. 2013;8(3):e58232. Epub 2013/04/05. doi: 10.1371/journal.pone.0058232. PubMed PMID: 23554879; PMCID: PMC3595241.
Dave RS*. Morphine affects HIV-induced inflammatory response without influencing viral replication in human monocyte-derived macrophages. FEMS immunology and medical microbiology. 2012;64(2):228-36. Epub 2011/11/10. doi: 10.1111/j.1574-695X.2011.00894.x. PubMed PMID: 22066570; PMCID: PMC3336009.
Regan PM, Dave RS, Datta PK, Khalili K. Epigenetics of micro-opioid receptors: intersection with HIV-1 infection of the central nervous system. Journal of cellular physiology. 2012;227(7):2832-41. Epub 2011/10/29. doi: 10.1002/jcp.24004. PubMed PMID: 22034138; PMCID: PMC3971722.
Dave RS*, Khalili K. Morphine treatment of human monocyte-derived macrophages induces differential miRNA and protein expression: impact on inflammation and oxidative stress in the central nervous system. Journal of cellular biochemistry. 2010;110(4):834-45. Epub 2010/06/22. doi: 10.1002/jcb.22592. PubMed PMID: 20564181; PMCID: PMC2923828.
Dave RS*. RNAi and tumor angiogenesis: bridging the gap towards anti-cancer therapy? Leukemia research. 2007;31(4):421-2. Epub 2006/12/13. doi: 10.1016/j.leukres.2006.10.024. PubMed PMID: 17157908.
Dave RS*, McGettigan JP, Qureshi T, Schnell MJ, Nunnari G, Pomerantz RJ. siRNA targeting vaccinia virus double-stranded RNA binding protein [E3L] exerts potent antiviral effects. Virology. 2006;348(2):489-97. Epub 2006/02/17. doi: 10.1016/j.virol.2006.01.013. PubMed PMID: 16480752.
Fang J, Acheampong E, Dave R, Wang F, Mukhtar M, Pomerantz RJ. The RNA helicase DDX1 is involved in restricted HIV-1 Rev function in human astrocytes. Virology. 2005;336(2):299-307. Epub 2005/05/17. doi: 10.1016/j.virol.2005.03.017. PubMed PMID: 15892970.
Dave, R.S.*, and Pomerantz, R.J., “HIV-1 Neuropathogenesis: Persistent Infection, Persistent Questions,” Science and Medicine, 10 (2), 112-123, 2005.
Dave RS, Pomerantz RJ. Antiviral effects of human immunodeficiency virus type 1-specific small interfering RNAs against targets conserved in select neurotropic viral strains. J Virol. 2004;78(24):13687-96. Epub 2004/11/27. doi: 10.1128/jvi.78.24.13687-13696.2004. PubMed PMID: 15564478; PMCID: PMC533941.
Dave RS, Pomerantz RJ. RNA interference: on the road to an alternate therapeutic strategy! Reviews in medical virology. 2003;13(6):373-85. Epub 2003/11/20. doi: 10.1002/rmv.407. PubMed PMID: 14625885.
Saha, K., Zhang, J., Gupta, A., Dave, R.S., Yimen, M., and Zerhouni, B., “Isolation of Primary HIV-1 that Target CD8+ T Lymphocytes using CD8 as a Receptor,” Nature Medicine, 7, 65-72, 2001. PMID: 11135618
Dave, R.S. & Mitra, R.K., “Partial Characterization of the cDNA Clone of a Low Temperature Induced Gene from Groundnut,” International Arachis Newsletter, 20, 36-37, 2000.
Dave, R.S. & Mitra, R.K., “A Low Temperature Induced Apoplastic Protein from Arachis hypogaea,” Phytochemistry, 49, 2207-2213, 1998. PMID: 988752
Dr. Dave's biographical information