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Grant Details

Grant Number: 3R01CA075903-14S1 Interpret this number
Primary Investigator: Wood, Charles
Organization: University Of Nebraska Lincoln
Project Title: Kaposi's Sarcoma and Human Herpesvirus in Africa
Fiscal Year: 2013
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Abstract

DESCRIPTION (provided by applicant): Incidence of Kaposi's sarcoma (KS) - a devastating malignancy closely associated with HIV/AIDS - is still very wide-spread in sub-Saharan African countries such as Zambia, where anti-retroviral therapy (ARV) has only recently become available. Human herpesvirus-8 (HHV-8) or Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent associated with KS. Our laboratory is widely recognized for its study of the transmission of HIV and HHV-8 and the establishment of a large mother-infant cohort in Zambia to study those two viruses. We were the first to establish that HHV-8 can be transmitted perinatally and together with HIV contribute to the increase of Kaposi's sarcoma in children in Africa. More recently, in collaboration with CDC- GAP Zambia, we determined the early childhood infection rate of HHV-8. As such, we are ideally positioned to lead the proposed study, the first of its magnitude in the African setting. We have found perinatal transmission can occur in utero, but most HHV-8 infections occur during early childhood via horizontal transmission, with HHV-8 seroconversion occurring even in instances where the child's mother or entire household is HHV-8 negative. Moreover, HIV-1 is a major risk factor for HHV-8 infection, and we found HIV-1 infected children have a five-fold higher risk for infection by HHV-8 as compared to uninfected children, most likely due to immune suppression as a result of HIV-1 infection. It is possible that restoration of the immune response via ARV will reduce HHV-8 infection of HIV-1 positive children and enhance the immune response against HHV-8 in infected individuals. Unfortunately, the impact of ARV on HHV-8 transmission and on HHV-8 disease pathogenesis is unknown. We hypothesize that the treatment of HIV-1 infected children by ARV will substantially lower their risk of being infected by HHV-8 and reduce the risk of disease progression toward developing KS in infected children by enhancing their anti-HHV-8 immune response and reducing viral reactivation. The overall objective of the proposed study is to make use of our established study infrastructure to determine the impact of ARV treatment on HHV-8 transmission, on anti-HHV-8 immune response, and on viral reactivation. We propose to utilize relevant participants in our existing cohort and to recruit additional subjects for our proposed study, as appropriate. To test the validity of our hypothesis, we are proposing two aims. The first is to determine whether ARV treatment of HIV-1 infected children will reduce their susceptibility to HHV-8 infection. The second is to determine whether ARV treatment of HIV-1 and HHV-8 dually infected children will enhance their immune response against HHV-8 and reduce viral reactivation. We anticipate that the data generated through the proposed effort will be useful in the development of future intervention strategies to prevent HHV-8 transmission.

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Publications

Seroprevalence of human herpesvirus 8 and hepatitis C virus among drug users in Shanghai, China.
Authors: Zhang T, Liu Y, Zhang Y, Wang J, Minhas V, Wood C, He N
Source: Viruses, 2014 Jun 23;6(6), p. 2519-30.
EPub date: 2014 Jun 23.
PMID: 24960274
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Humanized-BLT mouse model of Kaposi's sarcoma-associated herpesvirus infection.
Authors: Wang LX, Kang G, Kumar P, Lu W, Li Y, Zhou Y, Li Q, Wood C
Source: Proc Natl Acad Sci U S A, 2014 Feb 25;111(8), p. 3146-51.
EPub date: 2014 Feb 10.
PMID: 24516154
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Kaposi`s sarcoma associated herpesvirus infection among female sex workers and general population women in Shanghai, China: a cross-sectional study.
Authors: Zhang T, Yang Y, Yu F, Zhao Y, Lin F, Minhas V, Wood C, He N
Source: BMC Infect Dis, 2014 Feb 5;14, p. 58.
EPub date: 2014 Feb 5.
PMID: 24498947
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Risk factors for early childhood infection of human herpesvirus-8 in Zambian children: the role of early childhood feeding practices.
Authors: Crabtree KL, Wojcicki JM, Minhas V, Smith DR, Kankasa C, Mitchell CD, Wood C
Source: Cancer Epidemiol Biomarkers Prev, 2014 Feb;23(2), p. 300-8.
EPub date: 2013 Dec 2.
PMID: 24296855
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Inactivation and viral load quantitation of human immunodeficiency virus in blood collected into Cyto-Chex() BCT blood collection device.
Authors: Kwon E, Minhas V, Phiri T, Wood C, Swindells S, Hunsley BA, Fernando MR
Source: J Virol Methods, 2014 Feb;196, p. 50-5.
EPub date: 2013 Oct 30.
PMID: 24184086
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Kaposi's sarcoma-associated herpesvirus transactivator Rta induces cell cycle arrest in G0/G1 phase by stabilizing and promoting nuclear localization of p27kip.
Authors: Kumar P, Wood C
Source: J Virol, 2013 Dec;87(24), p. 13226-38.
EPub date: 2013 Sep 25.
PMID: 24067984
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Analysis of primary resistance mutations to HIV-1 entry inhibitors in therapy naive subtype C HIV-1 infected mother-infant pairs from Zambia.
Authors: Guo H, Liu C, Liu B, Wood C, Kong X
Source: J Clin Virol, 2013 Sep;58(1), p. 233-9.
EPub date: 2013 Jun 25.
PMID: 23809473
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Low-abundance resistant mutations in HIV-1 subtype C antiretroviral therapy-naive individuals as revealed by pyrosequencing.
Authors: Gonzalez S, Tully DC, Gondwe C, Wood C
Source: Curr HIV Res, 2013 Jan;11(1), p. 43-9.
PMID: 23305169
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Prevalence and correlates of Kaposi's sarcoma-associated herpesvirus infection in a sample of men who have sex with men in Eastern China.
Authors: Zhang T, Lin H, Minhas V, Zhu W, Wood C, He N
Source: Epidemiol Infect, 2013 Sep;141(9), p. 1823-30.
EPub date: 2012 Oct 31.
PMID: 23114099
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Early childhood infection of Kaposi's sarcoma-associated herpesvirus in Zambian households: a molecular analysis.
Authors: Olp LN, Shea DM, White MK, Gondwe C, Kankasa C, Wood C
Source: Int J Cancer, 2013 Mar 1;132(5), p. 1182-90.
EPub date: 2012 Aug 20.
PMID: 22815207
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Dynamics of envelope evolution in clade C SHIV-infected pig-tailed macaques during disease progression analyzed by ultra-deep pyrosequencing.
Authors: Tso FY, Tully DC, Gonzalez S, Quince C, Ho O, Polacino P, Ruprecht RM, Hu SL, Wood C
Source: PLoS One, 2012;7(3), p. e32827.
EPub date: 2012 Mar 12.
PMID: 22427893
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Human herpesvirus 8 seroprevalence, China.
Authors: Zhang T, Shao X, Chen Y, Zhang T, Minhas V, Wood C, He N
Source: Emerg Infect Dis, 2012 Jan;18(1), p. 150-2.
PMID: 22257662
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Human papillomavirus 16 variants from Zambian women with normal pap smears.
Authors: Lei YJ, Makhaola K, Pittayakhajonwut D, Wood C, Angeletti PC
Source: J Med Virol, 2011 Jul;83(7), p. 1230-7.
PMID: 21567426
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The Zambia Children's KS-HHV8 Study: rationale, study design, and study methods.
Authors: Minhas V, Crabtree KL, Chao A, Wojcicki JM, Sifuniso AM, Nkonde C, Kankasa C, Mitchell CD, Wood C
Source: Am J Epidemiol, 2011 May 1;173(9), p. 1085-92.
EPub date: 2011 Mar 28.
PMID: 21447476
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HIV-1 clade B and C isolates exhibit differential replication: relevance to macrophage-mediated neurotoxicity.
Authors: Constantino AA, Huang Y, Zhang H, Wood C, Zheng JC
Source: Neurotox Res, 2011 Oct;20(3), p. 277-88.
EPub date: 2011 Feb 19.
PMID: 21336667
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Subtype-associated differences in HIV-1 reverse transcription affect the viral replication.
Authors: Iordanskiy S, Waltke M, Feng Y, Wood C
Source: Retrovirology, 2010 Oct 12;7, p. 85.
EPub date: 2010 Oct 12.
PMID: 20939905
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Molecular determinants of HIV-1 subtype C coreceptor transition from R5 to R5X4.
Authors: Zhang H, Tully DC, Zhang T, Moriyama H, Thompson J, Wood C
Source: Virology, 2010 Nov 10;407(1), p. 68-79.
EPub date: 2010 Aug 24.
PMID: 20797755
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Short communication: antiretroviral therapy resistance mutations present in the HIV type 1 subtype C pol and env regions from therapy-naive patients in Zambia.
Authors: Gonzalez S, Gondwe C, Tully DC, Minhas V, Shea D, Kankasa C, M'soka T, Wood C
Source: AIDS Res Hum Retroviruses, 2010 Jul;26(7), p. 795-803.
PMID: 20623996
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Prevalence of human herpesvirus 8 and hepatitis C virus in a rural community with a high risk for blood-borne infections in central China.
Authors: Zhang T, He N, Ding Y, Crabtree K, Minhas V, Wood C
Source: Clin Microbiol Infect, 2011 Mar;17(3), p. 395-401.
PMID: 20545961
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Chronology and evolution of the HIV-1 subtype C epidemic in Ethiopia.
Authors: Tully DC, Wood C
Source: AIDS, 2010 Jun 19;24(10), p. 1577-82.
PMID: 20539092
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Enhancement of autophagy during lytic replication by the Kaposi's sarcoma-associated herpesvirus replication and transcription activator.
Authors: Wen HJ, Yang Z, Zhou Y, Wood C
Source: J Virol, 2010 Aug;84(15), p. 7448-58.
EPub date: 2010 May 19.
PMID: 20484505
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Primary gamma-herpesviral infection in Zambian children.
Authors: Minhas V, Brayfield BP, Crabtree KL, Kankasa C, Mitchell CD, Wood C
Source: BMC Infect Dis, 2010 May 12;10, p. 115.
EPub date: 2010 May 12.
PMID: 20462453
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Restricted genetic diversity of HIV-1 subtype C envelope glycoprotein from perinatally infected Zambian infants.
Authors: Zhang H, Tully DC, Hoffmann FG, He J, Kankasa C, Wood C
Source: PLoS One, 2010 Feb 18;5(2), p. e9294.
EPub date: 2010 Feb 18.
PMID: 20174636
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Functional properties of the HIV-1 subtype C envelope glycoprotein associated with mother-to-child transmission.
Authors: Zhang H, Rola M, West JT, Tully DC, Kubis P, He J, Kankasa C, Wood C
Source: Virology, 2010 May 10;400(2), p. 164-74.
EPub date: 2010 Jan 25.
PMID: 20096914
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Human Ubc9 contributes to production of fully infectious human immunodeficiency virus type 1 virions.
Authors: Jaber T, Bohl CR, Lewis GL, Wood C, West JT Jr, Weldon RA Jr
Source: J Virol, 2009 Oct;83(20), p. 10448-59.
EPub date: 2009 Jul 29.
PMID: 19640976
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The human immunodeficiency virus type 1 envelope confers higher rates of replicative fitness to perinatally transmitted viruses than to nontransmitted viruses.
Authors: Kong X, West JT, Zhang H, Shea DM, M'soka TJ, Wood C
Source: J Virol, 2008 Dec;82(23), p. 11609-18.
EPub date: 2008 Sep 10.
PMID: 18786994
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Mortality among HIV-1- and human herpesvirus type 8-affected mother-infant pairs in Zambia.
Authors: Wojcicki J, Mwanahamuntu M, Minhas V, Djokic B, Kankasa C, Klaskala W, Brayfield B, Phiri S, Wood C, Mitchell CD
Source: Cancer Epidemiol Biomarkers Prev, 2008 Sep;17(9), p. 2238-43.
PMID: 18768489
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Early childhood infection by human herpesvirus 8 in Zambia and the role of human immunodeficiency virus type 1 coinfection in a highly endemic area.
Authors: Minhas V, Crabtree KL, Chao A, M'soka TJ, Kankasa C, Bulterys M, Mitchell CD, Wood C
Source: Am J Epidemiol, 2008 Aug 1;168(3), p. 311-20.
EPub date: 2008 May 30.
PMID: 18515794
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Development of an immunofluorescence assay using recombinant proteins expressed in insect cells to screen and confirm presence of human herpesvirus 8-specific antibodies.
Authors: Minhas V, Crosby LN, Crabtree KL, Phiri S, M'soka TJ, Kankasa C, Harrington WJ, Mitchell CD, Wood C
Source: Clin Vaccine Immunol, 2008 Aug;15(8), p. 1259-64.
EPub date: 2008 May 28.
PMID: 18508931
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Genetic variation in mother-child acute seroconverter pairs from Zambia.
Authors: Hoffmann FG, He X, West JT, Lemey P, Kankasa C, Wood C
Source: AIDS, 2008 Apr 23;22(7), p. 817-24.
PMID: 18427199
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Kaposi's sarcoma-associated herpesvirus transactivator RTA promotes degradation of the repressors to regulate viral lytic replication.
Authors: Yang Z, Yan Z, Wood C
Source: J Virol, 2008 Apr;82(7), p. 3590-603.
EPub date: 2008 Jan 23.
PMID: 18216089
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Factors associated with HIV prevalence in a pre-partum cohort of Zambian women.
Authors: St Lawrence JS, Klaskala W, Kankasa C, West JT, Mitchell CD, Wood C
Source: Int J STD AIDS, 2006 Sep;17(9), p. 607-13.
PMID: 16942652
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Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 replication and transcription activator regulates viral and cellular genes via interferon-stimulated response elements.
Authors: Zhang J, Wang J, Wood C, Xu D, Zhang L
Source: J Virol, 2005 May;79(9), p. 5640-52.
PMID: 15827179
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Modulation of human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus replication and transcription activator transactivation by interferon regulatory factor 7.
Authors: Wang J, Zhang J, Zhang L, Harrington W Jr, West JT, Wood C
Source: J Virol, 2005 Feb;79(4), p. 2420-31.
PMID: 15681443
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Infectious molecular clone of a recently transmitted pediatric human immunodeficiency virus clade C isolate from Africa: evidence of intraclade recombination.
Authors: Grisson RD, Chenine AL, Yeh LY, He J, Wood C, Bhat GJ, Xu W, Kankasa C, Ruprecht RM
Source: J Virol, 2004 Dec;78(24), p. 14066-9.
PMID: 15564517
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Epidemiological characteristics of human herpesvirus-8 infection in a large population of antenatal women in Zambia.
Authors: Klaskala W, Brayfield BP, Kankasa C, Bhat G, West JT, Mitchell CD, Wood C
Source: J Med Virol, 2005 Jan;75(1), p. 93-100.
PMID: 15543582
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Distribution of Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 in maternal saliva and breast milk in Zambia: implications for transmission.
Authors: Brayfield BP, Kankasa C, West JT, Muyanga J, Bhat G, Klaskala W, Mitchell CD, Wood C
Source: J Infect Dis, 2004 Jun 15;189(12), p. 2260-70.
EPub date: 2004 May 25.
PMID: 15181574
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The role of Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 regulator of transcription activation (RTA) in control of gene expression.
Authors: West JT, Wood C
Source: Oncogene, 2003 Aug 11;22(33), p. 5150-63.
PMID: 12910252
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