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
Atluri, Venkata Subba Rao; Pilakka-Kanthikeel, Sudheesh; Samikkannu, Thangavel et al. (2014) Vorinostat positively regulates synaptic plasticity genes expression and spine density in HIV infected neurons: role of nicotine in progression of HIV-associated neurocognitive disorder. Mol Brain 7:37
Kaushik, Ajeet; Jayant, Rahul Dev; Sagar, Vidya et al. (2014) The potential of magneto-electric nanocarriers for drug delivery. Expert Opin Drug Deliv 11:1635-46
Agudelo, Marisela; Khatavkar, Pradnya; Yndart, Adriana et al. (2014) Alcohol abuse and HIV infection: role of DRD2. Curr HIV Res 12:234-42
Saxena, Shailendra K; Tiwari, Sneham; Swamy, M L Arvinda (2014) An insight into flaviviral budding: a need to know more. Future Microbiol 9:125-8
Samikkannu, Thangavel; Rao, Kurapati V K; Kanthikeel, Sudhessh Pilakka et al. (2014) Immunoneuropathogenesis of HIV-1 clades B and C: role of redox expression and thiol modification. Free Radic Biol Med 69:136-44
Atluri, Venkata Subba Rao; Kanthikeel, Sudheesh P; Reddy, Pichili V B et al. (2013) Human synaptic plasticity gene expression profile and dendritic spine density changes in HIV-infected human CNS cells: role in HIV-associated neurocognitive disorders (HAND). PLoS One 8:e61399
Saiyed, Zainulabedin M; Gandhi, Nimisha; Agudelo, Marisela et al. (2011) HIV-1 Tat upregulates expression of histone deacetylase-2 (HDAC2) in human neurons: implication for HIV-associated neurocognitive disorder (HAND). Neurochem Int 58:656-64
Pilakka-Kanthikeel, Sudheesh; Saiyed, Zainulabedin M; Napuri, Jessica et al. (2011) MicroRNA: implications in HIV, a brief overview. J Neurovirol 17:416-23
Agudelo, Marisela; Gandhi, Nimisha; Saiyed, Zainulabedin et al. (2011) Effects of alcohol on histone deacetylase 2 (HDAC2) and the neuroprotective role of trichostatin A (TSA). Alcohol Clin Exp Res 35:1550-6
Boukli, Nawal M; Saiyed, Zainulabedin M; Ricaurte, Martha et al. (2010) Implications of ER stress, the unfolded protein response, and pro- and anti-apoptotic protein fingerprints in human monocyte-derived dendritic cells treated with alcohol. Alcohol Clin Exp Res 34:2081-8