C Virus (HCV) is a major cause of chronic active hepatitis, hepatocellular
carcinoma and liver cirrhosis. There is no vaccine available against
this virus and the current standard therapy for HCV entails a concoction
of pegylated interferon alfa (PEG-IFN a)
and ribavirin (RBV), both of which are non-specific antiviral drugs.
Although this therapy has shown some promising results, it is fraught
with limited efficacy, resistance problems, poor tolerability and
high cost of manufacture, underscoring the need for new and more
effective therapy. The present focus of research is to inhibit the
viral replication using siRNA. This is highly versatile, simple,
straightforward and cost effective approach, which is able to significantly
down regulate, the target genes in a sequence specific manner. This
is a promising approach, which can overcome the limitations associated
with the existing therapy. The main strategy in this study will
be to deliver multiple short hairpin RNAs (shRNA) targeted against
both the host cell factors and the conserved domains of viral 5'
and 3' untranslated regions (UTR) and nonstructural genes through
self inactivating (SIN) lentiviral vectors. The SIN lentiviral vectors
unlike other vectors (adeno and retro virals) can effectively integrate
even in non-dividing host cells and manifest lasting RNAi effect.
Among the HIV infected people mitochondrial dysfunction in hepatocytes
and other HIV infected cells is a leading cause of cellular death.
Several viral proteins such as HIV-1 Vpr and Gag interact with and
alter the organization of the mitochondrial membrane. This may impair
oxidative phosphorylation and electron transport mechanisms resulting
in depletion of cellular ATP pool and accumulation of reactive oxygen
species (ROS). Interestingly, presence of a high copy number of
HIV-1 RNA has been reported in the mitochondrial compartment. The
rationale for this accumulation is not well understood. Another
pertinent question is the origin of HIV-1 RNA with in the mitochondria.
These questions need to be addressed meticulously and carefully
so that drugs directed to the mitochondria can be designed in order
to contain the viral propagation in the mitochondria as well as
sustain the mitochondrial integrity. This may significantly influence
the ongoing treatment decisions of AIDS patients and aid in better
drug designing and consequently improved management and control
of AIDS patients.
1. Binay Chaubey,
Snehlata Tripathi, and Virendra N. Pandey (2007) Single Acute-dose
and Repeat-doses Toxicity of anti HIV-1 PNATARPenetratin Conjugate
after Intraperitoneal Administration to Mice. (Accepted in Oligonucleotide).
2. Binay Chaubey,
Snehlata Tripathi, Jérome Désiré, Isabelle Baussanne, Dylan Harris,
Jean-Luc Décout and Virendra N. Pandey (2007) Mechanism of RNA Cleavage
Catalyzed by Sequence Specific Polyamide Nucleic Acid -Neamine Conjugate.
Oligonucleotide 17(3): 302-13.
Tripathi, Binay Chaubey, Beverly E. Barton, and Virendra N. Pandey
(2007) Anti HIV-1 virucidal activity of polyamide nucleic acid-membrane
transducing peptide conjugates targeted to primer binding site of
HIV-1 genome. Virology 363: 91-103.
D. Zhang, Z. Chaubey, B. Pandey, V. N. (2006) Identification of
cellular factors associated with the 3' nontranslated region of
the hepatitis C virus genome. Mol Cell Proteomics. 5 (6): 1006-1018.
Tripathi, Binay Chaubey, Sabyasachi Ganguly, Dylan Harris, Ralph
A Casale and Virendra N. Pandey (2005) Anti-HIV-1 Activity of Anti-TAR
Polyamide Nucleic Acid Conjugated with Various Membrane Transducing
Peptides. Nucleic Acids Research 33 (13): 4345-4356.
6. Binay Chaubey,
Snehlata Tripathi, Sabyasachi Ganguly, Dylan Harris,Ralph A. Casale,
Virendra N. Pandey (2005) PNA-transportan conjugate targeted to
the TAR region of the HIV-1genome exhibits both antiviral and virucidal
properties. Virology 331, 418-428.
Riguet, Snehlata Tripathi, Binay Chaubey, Je´roˆme De´sire´, Virendra
N. Pandey and Jean-Luc De´cout (2004) A Peptide Nucleic Acid-Neamine
Conjugate That Targets and Cleaves HIV-1 TAR RNA Inhibits Viral
Replication. J. Med. Chem. 47, 4806-4809.
8. Sarin BC,
Chaubey B, Kallan BM and Sehajpal PK (2000) PCR: A tool in detection
of M. tuberculosis. In Environmental Protection. Eds IS Grover,
AK Thukral and GS Virk. Scientific Publishers, Jodhpur, India.
A, Chaubey B, Sarin BC, Mittar D and Sehajpal PK (2000) A new rapid
method for the isolation of mycobacterial DNA. Ind J Vet Pathol
dysfunction in response to HIV infection and antiretroviral drug
treatment. Funded by Department of Biotechnology (DBT), Govt of
India, New Delhi.
ups and Collaborations
Dr. V. N. Pandey,
Associate Professor, Department of Biochemistry and Molecular Biology,
University of Medicine and Dentistry (UMDNJ), Newark, NJ, USA.
Shukla, Associate Director, Marshfield Research Foundation, Marshfield,