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
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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
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Atluri, Venkata Subba Rao; Hidalgo, Melissa; Samikkannu, Thangavel et al. (2015) Synaptic Plasticity and Neurological Disorders in Neurotropic Viral Infections. Neural Plast 2015:138979
Kaushik, Ajeet; Kumar, Rajesh; Arya, Sunil K et al. (2015) Organic-inorganic hybrid nanocomposite-based gas sensors for environmental monitoring. Chem Rev 115:4571-606
Kaushik, Ajeet; Yndart, Adriana; Jayant, Rahul Dev et al. (2015) Electrochemical sensing method for point-of-care cortisol detection in human immunodeficiency virus-infected patients. Int J Nanomedicine 10:677-85
Pilakka-Kanthikeel, Sudheesh; Raymond, Andrea; Atluri, Venkata Subba Rao et al. (2015) Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1)-facilitated HIV restriction in astrocytes is regulated by miRNA-181a. J Neuroinflammation 12:66
Atluri, Venkata Subba Rao; Hidalgo, Melissa; Samikkannu, Thangavel et al. (2015) Effect of human immunodeficiency virus on blood-brain barrier integrity and function: an update. Front Cell Neurosci 9:212

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