The predominant HIV-1 subtype found in US and Western World is clade B, which differs significantly from clade C that exists in sub-Saharan Africa and Asia. Estimates suggest that out of about 33.2 million people infected with HIV-1, about 60% of the infection is with clade C alone and HIV-1C infection is rapidly spreading to other parts of the world. AIDS is often accompanied by neuropathological abnormalities. Current understandings of HIV-1 neuropathogenesis emanate from B clade from U.S and Western countries and very little information is available on neuropathogenesis of C clade. We hypothesize that clade B and C exert differential effects on CNS cells leading to differential neuropathogenesis and the mechanisms may be mediated by dysregulation of mitogen activated protein (MAP) kinases signal transduction pathways. Accordingly we will study for the first time :
(Aim #1 a) the effects of in vitro infection with clade B and C virus on production and gene expression of pro-inflammatory cytokines (TNF1 &IL-6), chemokines (MCP-1 &RANTES), and neurotoxin (IDO) by primary monocytes and CNS cells (astrocytes, microglial cells) and examine (Aim #1b), whether the mechanism of differential dysregulation induced by clade specific virus infection is mediated by modulation of mitogen activated protein (MAP) kinases signal transduction pathways. Further these in vitro infection studies will be compared, correlated and complemented with ex vivo studies (Aim #2) using monocytes from HIV-1B infected subjects being studied in Miami and HIV-1C infected subjects being studied at the collaborating institute in India. The results emanating from these studies may a) unravel the differential effect of clade specific infection on neuropathogenesis, b) help to develop therapeutically useful agents which could attenuate or prevent the neuropathogenesis associated with clade specific HIV-1 infection and c) design novel strategies to develop preventive and therapeutic global vaccines that can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States where non B subtypes have been recently reported in migrant populations and among our military personals.

Public Health Relevance

This application has significant relevance to the purpose of the PA-07-089. Using both in vitro infection and ex vivo models, this project will study for the first time the production and gene expression of neuropathogenic molecules associated with HIV-1B and HIV-C infection. Identification of the mechanisms of clade specific neuropathogenesis will help to design novel strategies to prevent neuropathogenesis in HIV infected subjects and can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085259-05
Application #
8625335
Study Section
Special Emphasis Panel (ZRG1-AARR-F (02))
Program Officer
Joseph, Jeymohan
Project Start
2010-07-05
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$331,860
Indirect Cost
$94,773
Name
Florida International University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
071298814
City
Miami
State
FL
Country
United States
Zip Code
33199
Shyam, Hari; Singh, Satyendra K; Kant, Ravi et al. (2017) Mesenchymal stem cells in regenerative medicine: a new paradigm for degenerative bone diseases. Regen Med 12:111-114
Huang, Zaohua; Nair, Madahavan (2017) A CRISPR/Cas9 guidance RNA screen platform for HIV provirus disruption and HIV/AIDS gene therapy in astrocytes. Sci Rep 7:5955
Atluri, Venkata Subba Rao; Jayant, Rahul Dev; Pilakka-Kanthikeel, Sudheesh et al. (2016) Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection. Int J Nanomedicine 11:4287-98
Samikkannu, Thangavel; Atluri, Venkata S R; Nair, Madhavan P N (2016) HIV and Cocaine Impact Glial Metabolism: Energy Sensor AMP-activated protein kinase Role in Mitochondrial Biogenesis and Epigenetic Remodeling. Sci Rep 6:31784
Atluri, Venkata Subba Rao; Pilakka-Kanthikeel, Sudheesh; Garcia, Gabriella et al. (2016) Effect of Cocaine on HIV Infection and Inflammasome Gene Expression Profile in HIV Infected Macrophages. Sci Rep 6:27864
Chitti, Sai V; Prasad, Anil K; Saxena, Shailendra K (2016) Emerging Zika virus disease: a public health emergency of global concern. Virusdisease 27:211-214
Saxena, Shailendra K; Elahi, Asif; Gadugu, Srinivasulu et al. (2016) Zika virus outbreak: an overview of the experimental therapeutics and treatment. Virusdisease 27:111-5
Kaushik, Ajeet; Tiwari, Sneham; Dev Jayant, Rahul et al. (2016) Towards detection and diagnosis of Ebola virus disease at point-of-care. Biosens Bioelectron 75:254-72
Kurapati, Kesava Rao V; Samikkannu, Thangavel; Atluri, Venkata Subba Rao et al. (2015) Cell cycle checkpoints and pathogenesis of HIV-1 infection: a brief overview. J Basic Clin Physiol Pharmacol 26:1-11
Yndart, Adriana; Kaushik, Ajeet; Agudelo, Marisela et al. (2015) Investigation of Neuropathogenesis in HIV-1 Clade B and C Infection Associated with IL-33 and ST2 Regulation. ACS Chem Neurosci 6:1600-12

Showing the most recent 10 out of 43 publications