Hepatitis B Virus DNA in Liver and White Blood Cells of Patients with Hepatoma

Lie‐Injo, Luan Eng; Balasegaram, Manica; Lopez, C G; Herrera, Alejandro R.

doi:10.1089/dna.1983.2.301

Cited by 101 publications

(36 citation statements)

References 25 publications

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“…Replication of the viral genome and production of the 42-nm virion in infected liver tissues are frequently observed. However, the viral DNA and proteins have also been detected in many other tissues, including kidney, spleen, pancreas, bone marrow, and circulating blood cells (16,31,41,45). Furthermore, viral genes, including both the surface and the core genes, can be expressed in cultured systems of heterologous tissue type (18,46,49).…”

Section: Methodsmentioning

confidence: 99%

A liver-specific nuclear factor interacts with the promoter region of the large surface protein gene of human hepatitis B virus.

Chang¹,

Wang²,

Yuh³

et al. 1989

Mol. Cell. Biol.

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The outer envelope of the 42-nm virion of the human hepatitis B virus (HBV) is composed of the large, the middle, and the major surface proteins. Whereas the middle and the major surface proteins are transcribed from the SPIH promoter of the pre-S/S gene, the large surface protein is transcribed from the SPI promoter located upstream of SPIl. We liver-specific genes from human, mouse, and rat, with a consensus sequence (G/A)GTTA(A/C)TNNT(C/T) NNC(A/C). We further identified a nuclear factor present in the nuclear extracts of differentiated human hepatoma cell lines which interacted specifically with this element of the SPI promoter. This nuclear factor was similar to the rat liver-specific factor HNF-1, since an oligonucleotide containing the recognition sequence of HNF-1 could efficiently compete for the human factor in a footprinting assay. The sequence at nt -93 to -68 which was bound by this factor in SPI was termed the EINF-1-binding element. Activation of the SPI promoter by human differentiated hepatocyte nuclear factor 1, described in this report, probably explains, first, the formation of the 42-nm virion specifically in liver but not in several other tissues despite the synthesis of the middle and the major surface proteins in those tissues, and second, why only differentiated hepatoma cell lines are able to produce 42-nm-like virion particles on transfection by HBV DNA.Hepatitis B virus (HBV) causes acute and chronic hepatitis and is closely associated with the development of hepatocellular carcinoma (4, 48). The virion has a diameter of approximately 42 nm with a 27-nm core enclosing a 3.2-kilobase (kb) partially single-stranded DNA genome (5, 49). The outer envelope of the virion is arrayed by three surface (S) proteins. The major S protein, 226 amino acids long, is encoded by the S region of the HBV genome; the middle S protein is encoded by the pre-S2 and S regions, with an additional 55 amino acids at the amino terminus of the major S protein; and the large S protein is encoded by the pre-Sl, pre-S2, and the S regions, with an additional 117 amino acids at the amino terminus of the middle S protein (25,38,47). These three proteins are encoded by the pre-S/S gene, which contains two promoters. The distal TATA-like promoter (SPI) transcribes a 2.4-kb mRNA for the synthesis of the large S protein, whereas the proximal simian virus 40-like promoter (SPII) transcribes a 2.1-kb mRNA for the synthesis of both the middle and the major S proteins (7, 32, 39).The major S protein can be produced from many different tissues in HBV-infected chimpanzees and in transgenic mice carrying HBV DNA (2,7,8,20). However, the large S protein is detected more specifically in liver and, in only a few cases in transgenic mice, in the kidney and heart. Furthermore, the time of appearance of the large S protein is coincident with the appearance of replicative intermediates of the viral genome (2,20). Together, these observations * Corresponding author. strongly indicate that expression of the large S protein gene is hepat...

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Section: Methodsmentioning

confidence: 99%

A liver-specific nuclear factor interacts with the promoter region of the large surface protein gene of human hepatitis B virus.

Chang¹,

Wang²,

Yuh³

et al. 1989

Mol. Cell. Biol.

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“…The virus is responsible for causing acute and chronic hepatitis, and chronic carriers of HBV are at a highly increased risk of developing hepatocellular carcinoma (3). Although there is some evidence for replication of this virus in nonliver tissues (12,22), the principal site of clinical pathology is the liver, and HBV actively replicates in human hepatocytes. Evidence for the hepatocyte restriction of HBV replication comes from clinical data and studies on HBV mRNA transcription.…”

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confidence: 99%

Identification of protein-binding sites in the hepatitis B virus enhancer and core promoter domains.

et al. 1988

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We have investigated the role of liver-specific trans-acting factor(s) in the regulation of hepatitis B virus (HBV) gene expression. A recorder plasmid (pEcoAluCAT; HBV nucleotides 1 through 1878) was constructed containing the HBV enhancer and the promoter region of the pregenomic RNA, which was ligated to the bacterial chloramphenicol acetyltransferase (CAT) gene. Upon transfecting this plasmid into various cell lines, the CAT gene was expressed only in cells of liver origin. Moreover, competition cotransfections with pEcoAluCAT and plasmids containing HBV enhancer sequences in human hepatoblastoma-derived HepG2 cells indicated the presence of titratable trans-acting factor(s) in these cells. Gel mobility shift assays using HBV enhancer and core promoter domains confirmed the existence of sequence-specific DNA-binding proteins in liver cell nuclear extract which bound to these regions. These binding sites encompass 17-and 12-nucleotide palindromes in the HBV enhancer and core promoter domains, respectively, when mapped by the methylation interference assay.The hepatitis B virus (HBV), a small partially doublestranded DNA virus which belongs to the Hepadnaviridae family of animal viruses (38), is a significant worldwide cause of serious illness and mortality (40). The virus is responsible for causing acute and chronic hepatitis, and chronic carriers of HBV are at a highly increased risk of developing hepatocellular carcinoma (3). Although there is some evidence for replication of this virus in nonliver tissues (12,22), the principal site of clinical pathology is the liver, and HBV actively replicates in human hepatocytes. Evidence for the hepatocyte restriction of HBV replication comes from clinical data and studies on HBV mRNA transcription. During productive infection, two major viral RNAs (2.1 and 3.5 kilobases [kb] in length) are transcribed in relatively equal abundance (6, 46). The 3.5-kb RNA, which is greater than the length of the HBV genome, serves as the template for reverse transcription of the HBV genome (31, 39) and thus is integral to viral replication.Recently, many studies on the control of eucaryotic transcription have focused on the regulatory role of trans-acting, sequence-specific, DNA-binding proteins (for reviews, see references 10, 11, and 24). The binding of these regulatory proteins to their respective sites in the DNA has been implicated in mediating the activities of cis-acting viral and cellular DNA elements in various systems (1,5,15,33,37).An enhancer element (ENH), putatively mapped between nucleotides (nt) 1050 and 1250 in the HBV genome (35, 41), has been found to be active selectively in cell lines derived from human hepatocytes (19,42). These reports also suggest that the HBV ENH could be responsible for the hepatocytespecific replication of HBV via hepatocyte-restricted expression of the 3.5-kb RNA replication intermediate.We have investigated the role of sequence-specific DNAbinding proteins on 3.5-kb RNA expression. By using human hepatoblastoma-derived HepG2 cells (21), w...

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“…Not only are there striking similarities in the epidemiology of HBV and AIDS virus infections, but the vast majority of AIDS virus-infected patients show serologic evidence of prior exposure to HBV (6)(7)(8). Furthermore, HBV-related DNA has been detected in lymphoid cells derived from bone marrow (9, 10) and peripheral blood (11)(12)(13)(14) and more recently in T cells from AIDS/ARC patients (15), indicating that HBV is indeed lymphotropic.…”

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confidence: 99%

Extrachromosomal sequences of hepatitis B virus DNA in peripheral blood mononuclear cells of acquired immune deficiency syndrome patients.

Noonan¹,

Yoffe²,

Mansell³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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The primary etiologic agent of the acquired immune deficiency syndrome (AIDS) is a human Tlymphotropic retrovirus (the AIDS virus). However, the pathogenesis of this virus suggests that other cofactors may contribute to the development of clinically overt disease. The hepatitis B virus (HBV) has been implicated as a potential cofactor because HBV and AIDS virus infections frequently coexist, striking similarities exist in their epidemiologic patterns, and recent data indicate that HBV is lymphotropic. To establish the prevalence of HBV infections in lymphoid cells from individuals with AIDS-related disorders, sera and peripheral blood mononuclear cells (PBMC) from 16 males with AIDS virus infections were examined for the presence of HBV DNA by DNADNA blot hybridization. Fifteen (94%) of these individuals had serologic evidence of a recent or prior HBV infection. HBV DNA was detected in the PBMC of all of these patients, regardless of existing HBV serology. Among the 36 control individuals without AIDS-related symptomatology, PBMCassociated HBV DNA was detected in 8 of 14 carriers of hepatitis B surface antigen (HBsAg) and in 3 of 10 individuals immune to HBV, but it was absent from the PBMC of 12 individuals without HBV infection. In all instances, the HBV DNA was extrachromosomal and existed as replicative intermediates or high molecular weight oligomers of the viral genome. Replicative intermediates and serum-associated HBV DNA were detected in all hepatitis B e antigen-positive carriers, regardless of their clinical status. In contrast, the high molecular weight oligomers of HBV DNA were detected in the PBMC of all of the AIDS virus-infected patients examined, but in only 33% of those in the control group who had evidence of HBV infection. This finding suggests that a unique and complex HBV-host-cell interaction exists in patients infected with the AIDS virus.The acquired immune deficiency syndrome (AIDS) is a profound immunoregulatory disorder characterized by severe opportunistic infections, Kaposi sarcoma, and other neoplasias, such as non-Hodgkin lymphoma. Other manifestations of the disease of a milder nature include the AIDSrelated complex (ARC) and the lymphadenopathy syndrome (LAS). A human retrovirus-variously designated HTLV-III, LAV, and ARV-2-has been implicated as the primary etiologic agent of AIDS (1-3). This virus has been isolated from cultured T cells obtained from patients with clinical disease, as well as from asymptomatic individuals who are at risk for the development of AIDS (4, 5). Although the possibility cannot be excluded that all individuals infected with the AIDS virus will eventually develop advanced stages of the disease, the recovery of virus from patients exhibiting a broad spectrum of clinical responses suggests that other potentially important cofactors may be contributing to the development of AIDS. Considerable serologic, epidemiologic, and biologic evidence suggests that one such cofactor may be the hepatitis B virus (HBV). Not only are there striking similarities...

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Hepatitis B Virus DNA in Liver and White Blood Cells of Patients with Hepatoma

Cited by 101 publications

References 25 publications

A liver-specific nuclear factor interacts with the promoter region of the large surface protein gene of human hepatitis B virus.

A liver-specific nuclear factor interacts with the promoter region of the large surface protein gene of human hepatitis B virus.

Identification of protein-binding sites in the hepatitis B virus enhancer and core promoter domains.

Extrachromosomal sequences of hepatitis B virus DNA in peripheral blood mononuclear cells of acquired immune deficiency syndrome patients.

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