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Charles Wood, PhD
HIV and Kaposi’s Sarcoma Associated Herpesvirus
Pathogenesis
Acquired
immune deficiency syndrome (AIDS) is a devastating disease that
is caused by a retrovirus known as the human immunodeficiency
virus (HIV). Infected individuals are not only immunosuppressed
but also frequently develop malignancies, such as lymphomas and
Kaposi’s sarcoma. The Wood laboratory has been involved in
the molecular biology of HIV and a recently identified human herpesvirus
associated with Kaposi’s sarcoma (KS) named KSHV.
KSHV has
been linked to HIV and Kaposi’s sarcoma but its
route of transmission and whether infection by this virus can directly
cause KS are not known. Dr. Wood’s laboratory has found that
the infection rate is extremely high in Zambia, a central African
nation that lies in the heart of the AIDS epidemic. Dr. Wood’s
study involves the recruitment of mother/infant pairs at birth
to determine (1) the seroprevalence for HIV and KSHV, (2) whether
KSHV DNA can be found in infants’ blood, and (3) to determine
the source of vertical and/or horizontal transmission.
One of the
laboratory’s findings is that HIV infects 30%
of Zambia’s normal female population and 40% are infected
by KSHV. Therefore, the implications for disease development and
transmission of both HIV and KSHV to babies are enormous. Given
this high incidence of infection, the Wood lab has been studying
whether KSHV can be transmitted from mothers to their newborns,
whether infected children will develop KS, and whether HIV is a
co-factor for transmission.
The laboratory has also found that almost
all Zambian HIV are of subgroup C and are rapidly spreading in
Zambia. Unfortunately,
very little is known about subgroup C’s viral biological
properties, pathogenesis, and genetic evolution in infected individuals.
Dr. Wood has been characterizing a panel of subtype C HIV isolated
from infected infants at various time points after birth to understand
the natural evolution of these viruses and to correlate them to
disease progression. The goal of these studies is to better understand
the biology of this virus and its transmission so that strategies
can be developed to block its transmission. Studies are now underway
to generate a chimeric virus between the subtype C HIV-1 and a
simian immunodeficiency virus so that an animal model can be generated
to test various strategies to block vertical HIV transmission.
Another
focus of the Wood laboratory is the control of KSHV replication
at the molecular level. KSHV characteristically establishes latent
infections in target cells where viral gene expression is highly
limited and tightly controlled. The virus can then periodically
reactivate to go through lytic replication. Although latent infection
may play a role in sustained viral infection and tumorigeneisis,
lytic reactivation has been implicated to be important for KS development.
Therefore, the understanding of how the virus maintains latency
and of the viral genes involved is of significance. The laboratory
has been studying a viral gene called “Regulator of Transcription
Activation” (RTA), which is the central gene involved in
the switch from latent to lytic replication. The laboratory has
identified a cellular factor that interacts with RTA and enhances
its transactivation function, and is actively deciphering the molecular
mechanism involved in their interaction and transactivation of
viral gene transcription. This study will lead to the development
of strategies in preventing the virus from going through lytic
replication and KS development.
Selected Refereed Published Journal Articles since 2000:
West J and Wood C. 2003. The Role of Kaposi's Sarcoma-Associated
Herpesviruses/Human Herpesvirus-8 Regulator of Transcription Activation
(RTA) in Control of Gene Expression. Oncogene, 22:5150-5163
Ghosh SK, Wood C, Boise LH, Mian AM, Deyev VV, Feuer G, Toomey
NL, Shank NC, Cabral L, Barber GN and WJ Harrington Jr. 2003. Potentiation
of TRAIL-induced apoptosis in primary effusion lymphoma through
azidothymidine-mediated inhibition of NF-kappa B. Blood, 101:2321-2327.
Brayfield, B., S. Phiri, C. Kankasa, J. Muyanga, H. Mantina, G.
Kwenda, J. West, G. Bhat, D. Marx, W. Klaskala, C. Mitchell, and
C. Wood. 2003. Postnatal human herpesvirus-8 and human immunodeficiency
virus-1 infection in mothers and infants from Zambia. J. Inf. Dis.
187:559-68.
Zhang. H., G. Orti, Q. Du, J. He, C. Kankasa, G. Bhat, and C.
Wood. Phylogenetic and phenotypic analysis of HIV-1 env gp120 in
cases of subtype C mother to child transmission. 2002. AIDS Res. & Human
Retroviruses 18:1415-1423..
Lu, M., L. Zheng, K. Mitchell, S. Kapil, C. Wood, and H. Minocha.
2002. A unique epitope of bovine immunodeficiency virs gag protein,
which spans the cleavage site between p16MA and p2L. Clin. Diag.
Lab. Immunol 9:1277-1281.
Pahan K, Jana M, Liu X, Taylor BS, Wood C, Fischer SM. 2002. Gemfibrozil,
a lipid-lowering drug, inhibits the induction of nitric-oxide synthase
in human astrocytes. J Biol Chem. 277:45984-91.
Liu, X., M. Jana, S. Dasgupta, S. Koka, J. He, C. Wood, and K.
Pahan. 2002. Human immunodeficiency virus type-1 (HIV-1) tat
gene induces nitric oxide synthase in human astroglia. J. Biol
Chem 277:39312-9.
McCarthy, M., J. He, D. Auger, R. Geffin, C. Woodson, C. Hutto,
C. Wood, and G. Scott. 2002. Cellular Tropisms and Co-receptor
Usage of HIV-1 Isolates from Vertically Infected Children With
Neurological Abnormalities and Rapid Disease Progression. J Med
Virol. 67:1-8.
Chen, G., S. Wang, K. Xiong, J. Wang, T. Ye, W. Dong, Q. Wang,
Q. Chen, Y. Geng, C. Wood, and Y. Zeng. 2002. Construction and
characterization of a chimeric virus (BIV/HIV-1) carrying the bovine
immunodeficiency virus gag-pol gene. AIDS 16:123-5.
Duan, W., S. Wang, S. Liu, and C. Wood. 2001. Characterization
of Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8
ORF57 promoter. Arch Virol 146:403-13.
Mantina, H., C. Kankasa, W. Klaskala, B. Brayfield, J. Campbell,
Q. Du, G. Bhat, F. Kasolo, C. Mitchell, and C. Wood. 2001. Vertical
transmission of Kaposi's sarcoma-associated herpesvirus. Int J
Cancer 94:749-52.
Sosa, C., J. Benetucci, C. Hanna, L. Sieczkowski, G. Deluchi,
A. M. Canizal, H. Mantina, W. Klaskala, M. Baum, and C. Wood. 2001.
Human herpesvirus 8 can be transmitted through blood in drug addicts.
Medicina (B Aires) 61:291-4.
Toomey, N. L., V. V. Deyev, C. Wood, L. H. Boise, D. Scott, L.
H. Liu, L. Cabral, E. R. Podack, G. N. Barber, and W. J. Harrington,
Jr. 2001. Induction of a TRAIL-mediated suicide program by interferon
alpha in primary effusion lymphoma. Oncogene 20:7029-40.
Wang, S., S. Liu, M. H. Wu, Y. Geng, and C. Wood. 2001. Identification
of a cellular protein that interacts and synergizes with the RTA
(ORF50) protein of Kaposi's sarcoma-associated herpesvirus in transcriptional
activation. J Virol 75:11961-73.
Wang, S., S. Liu, M. Wu, Y. Geng, and C. Wood. 2001. Kaposi's
sarcoma-associated herpesvirus/human herpesvirus-8 ORF50 gene product
contains a potent C-terminal activation domain which activates
gene expression via a specific target sequence. Arch Virol 146:1415-26.
Xu, W., B. A. Smith-Franklin, P. L. Li, C. Wood, J. He, Q. Du,
G. J. Bhat, C. Kankasa, H. Katinger, L. A. Cavacini, M. R. Posner,
D. R. Burton, T. C. Chou, and R. M. Ruprecht. 2001. Potent neutralization
of primary human immunodeficiency virus clade C isolates with a
synergistic combination of human monoclonal antibodies raised against
clade B. J Hum Virol 4:55-61.
Zheng, L., S. Zhang, C. Wood, S. Kapil, G. E. Wilcox, T. A. Loughin,
and H. C. Minocha. 2001. Differentiation of two bovine lentiviruses
by a monoclonal antibody on the basis of epitope specificity. Clin
Diagn Lab Immunol 8:283-7.
Flebbe-Rehwaldt, L., Wood, C., and Chandran, B. 2001 Characterization
of transcripts expressed from human herpesvirus 6A strain GS immediate-early
region B U16-U17 open reading frames. J. Virology, 74: 11040-11054,
2000.
Chen H, Wood C, and Petito C. Comparisons of HIV-1 Viral Sequences
in Brain, Choroid Plexus, and Spleen: Potential Role of Choroid
Plexus in the Pathogenesis of HIV Encephalitis. J. NeuroVirology,
6:498-507, 2000.
Zheng L, Swanson M, Liao J, Wood C, Kapil S, Snider R, Loughin
TA, and Minocha H. Cloning of the Bovine Immunodeficiency Virus
gag Gene and Development of a Recombinant-Protein-Based Enzyme-Linked
Immunosorbent Assay. Clin and Diag Laboratory Immunology 7:557-562,
2000.
Pahan K, Liu X, McKinney M, Wood C, Sheikh F, and Raymond J.
Expression of a dominant-negative mutant of p21ras inhibits induction
of nitric oxide sythase an activation of NF-kB in primary astrocytes.
J. Neurochem, 74:2288-2295, 2000.
Chen H, He J, Fong S, Wilcox G, and Wood C. Jembrana Disease Virus
Tat Can Regulate Human Immunodeficiency Virus (HIV) Long Terminal
Repeat-Directed Gene Expression and Can Substitute for HIV Tat
in Viral Replication. J. Virology, 74:2703-2713, 2000.
Pahan K, Liu X, Wood C and Raymond J. Expression of a costitutively
formof phosphatidylinositol 2-kinase inhibits the induction of
nitric oxide synthase in human astrocytes. FEBS Letters 472:302-207,
2000.
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