Hepatitis B virus (HBV) infections represent a major worldwide health problem due to the predilection of this virus to cause lifelong chronic infections; 10% of infected adults and 95% of infected newborns become chronic carriers. The chronic infections frequently progress to cirrhosis and liver cancer. Worldwide there are an estimated 350 million chronic carriers of HBV, making HBV infections the fourth leading cause of death due to infectious diseases. Although an efficacious vaccine has been developed, it will be decades before its use will have an impact on the number of people dying from HBV-associated chronic liver disease and liver cancer. Efficacious antiviral are available but unfortunately, these drugs only suppress the virus and do not cure the infections. Eventually, the virus becomes resistant and the antiviral becomes ineffective.

A precise understanding of the replication cycle, as well as, a better understanding of the mechanisms of viral clearance in infected individuals that successfully eliminate the virus, may yield strategies to eliminate the chronic carrier state. HBV replicates via a reverse transcription step similar to the HIV virus that causes AIDS. However, at a molecular level the viruses replicate by very different mechanisms. We have previously focused on several critical events in replication at a molecular level. One of the technologies developed in this program is widely used for the evaluation of antiviral compounds. The technology involved the use of an insect virus to express the HBV reverse transcriptase at very high levels in insect cells. The purified enzyme was active in the early steps of viral replication that include a protein-primed initiation of reverse transcription. We extended this research program to include the initial steps involved in the assembly of a replication competent viral nucleocapsid, including the protein-protein interactions between the reverse transcriptase and the capsid protein. One of our current goals is the identification of the elusive HBV receptor (see WMHBV: Small Primate Model for Hepatitis B Virus). Another current focus is to better understand the mechanism of viral clearance during acute resolving infections using the chimpanzee model of HBV infections. Chimpanzees are the only animals other than man susceptible to HBV infections. Our hope is that a precise understanding of viral clearance will lead to the development of immuno-therapeutics to help eliminate chronic infection.

Selected Publications

Barrera, A., Guerra, B., Lee, H., and Lanford, R.E. Mapping of the Hepatitis B Virus Pre-S1 Domain Involved in Receptor Recognition. J. Virol. 79:9786-9798, 2005.

Barrera A, Guerra B, Lee H, Lanford RE. Analysis of host range phenotypes of primate hepadnaviruses by in vitro infections of hepatitis D virus pseudotypes.J Virol. 78(10):5233-5243, 2004. PMID: 15113905

Lott L, Notvall L, Lanford RE. Expression and purification of functional hepatitis B virus polymerase in the baculovirus insect cell system. Methods Mol Med. 95:271-279, 2004. PMID: 14762310

Barrera A, Lanford RE. Infection of primary chimpanzee hepatocytes with recombinant hepatitis D virus particles: a surrogate model for hepatitis B virus.
Methods Mol Med. 96:131-142, 2004. PMID: 14762265

Lanford RE, Chavez D, Barrera A, Brasky KM. An infectious clone of woolly monkey hepatitis B virus. J Virol. 77(14):7814-7819, 2003.
PMID: 12829821

Lott L, Notvall L, Lanford RE. Transcomplementation of core and polymerase functions of the woolly monkey and human hepatitis B viruses. Virology. 308(2):330-339, 2003. PMID: 12706082

Lott, L., Beames, B., and Lanford, R.E. Interaction between hepatitis B virus core protein and reverse transcriptase. J. Virol. 74:11479-11489, 2000. PubMed ID 11090144

Lanford, R.E., Chavez, D., Rico-Hesse, R. and Mootnick, A. Hepadnavirus infection in captive gibbons. J. Virol. 74: 2955-2959, 2000. PMID: 10684318

zu Putlitz, J., Lanford, R.E., Carlson, R.I., Notvall, L., de la Monte, S.M., and Wands, J.R. Properties of monoclonal antibodies directed against hepatitis B virus polymerase protein. J. Virol. 73:4188-4196, 1999. PubMed ID 10196315

Lanford, R.E., Kim, Y.-H., Lee, H., Notvall, L., and Beames, B. Mapping of the hepatitis B virus reverse transcriptase TP and RT domains by transcomplementation for nucleotide priming and protein-protein interaction. J. Virol. 73:1885-1893, 1999. PubMed ID 9971767

Lanford, R.E., Chavez,D., Brasky, K., Burns, R.B. and R Rico-Hesse, R. Isolation of a new hepadnavirus from the woolly monkey, a New World primate. Proc. Natl. Acad. Sci.USA 95: 5757-5761, 1998. PMID: 9576957

Lanford, R.E., Notvall, L., Lee, H., and Beames, B. Transcomplementation of nucleotide priming and reverse transcription between independently expressed TP and RT domains of the hepatitis B virus reverse transcriptase. J. Virol. 71:2996-3004, 1997. PubMed ID 9060659

Lanford, R.E., Notvall, L., and Beames, B. Nucleotide priming and reverse transcriptase activity of hepatitis B virus polymerase expressed in insect cells. J.Virol. 69:4431-4439, 1995. PubMed ID 7539509

Beames, B. and Lanford, R.E. Insertions within the hepatitis B virus capsid protein influences capsid formation and packaging of the pregenome RNA. J. Virol. 69: 6833-6838, 1995. PMID: 7474096

Lanford, R.E., Michaels, M.G., Chavez, D., Brasky, K., Fung, J. and Starzl, T.E. Persistence of extrahepatic hepatitis B virus DNA in the absence of hepatic replication in patients with baboon liver transplants. J. Med.Virol. 46: 207-212, 1995. PubMed ID: 7561791

Beames B, Lanford RE. Carboxy-terminal truncations of the HBV core protein affect capsid formation and the apparent size of encapsidated HBV RNA. Virology. 194(2):597-607, 1993. PMID: 7684872