Dr David Brighty

Our research investigates the molecular biology of human retroviral infections, and explores the fundamental mechanisms of viral gene expression, replication and pathogenesis. We seek to integrate our knowledge of viral replication with the development of a rational approach to anti-viral drug design.

Our present studies focus upon the HIV-1 gene product Rev. Rev enhances viral envelope expression by relieving the nuclear sequestration of env transcripts. The mechanism by which Rev-responsiveness is achieved remains poorly defined. However, we have recently demonstrated that an inhibitory motif within the Rev-responsive element is sufficient to confer selective nuclear retention and Rev-responsiveness to viral transcripts. This inhibitory element is active in a number of different primate and human cell types and, most importantly, is functional in CD4+ T-cells.

Using a variety of experimental systems, we are fine mapping the sequences that confer nuclear retention upon env mRNAs with a view to identifying the inhibitory element at nucleotide resolution. In addition we are using biochemical and genetic methods to investigate, identify, and characterise the cellular co-factors that are involved in all aspects of the Rev-response. By biochemically dissecting the Rev regulatory pathway we will identify new cellular targets for anti-viral drug design and thereby provide new opportunities for inhibition of HIV replication in infected individuals.

In addition to our studies of viral gene expression, we are also investigating the mechanisms by which retroviruses contribute to human cancer. Human T-cell leukaemia virus (HTLV-I) is the aetiologic agent of an aggressive adult T-cell leukaemia-lymphoma (ATLL). Infection of human cells by HTLV-1 is mediated by the viral envelope glycoproteins. The surface glycoprotein binds to an unidentified cell surface receptor, which promotes the envelope-dependent fusion of the viral and cellular membranes. In the absence of membrane fusion viral penetration and entry into the host cell cannot occur. Thus, the envelope glycoproteins are prime targets for the development of small molecule antagonists of viral entry. We are now examining the molecular basis for receptor recognition by envelope and characterising novel inhibitors of HTLV-1 infection.

• Lamb D, Mirsaliotis A, Kelly SM, Brighty DW. 2009. Basic residues are critical to the activity of peptide inhibitors of human T cell leukemia virus type 1 entry. J Biol Chem. 284:6575-84.

• Romer D, Brighty DW, Robson CL, Sattentau QJ. 2009. Candidate polyanionic microbicides inhibit human T-cell lymphotropic virus type 1 receptor interactions, cell-free infection, and cell-cell spread. Antimicrob Agents Chemother. 53:678-87.

• Lamb D, Schüttelkopf AW, van Aalten DM, Brighty DW. 2008. Highly specific inhibition of leukaemia virus membrane fusion by interaction of peptide antagonists with a conserved region of the coiled coil of envelope. Retrovirology. 5:70.

• Mirsaliotis A, Lamb D, Brighty DW. 2008. Nonhelical leash and alpha-helical structures determine the potency of a peptide antagonist of human T-cell leukemia virus entry. J Virol. 82:4965-73.

• Mirsaliotis A, Nurkiyanova K, Lamb D, Kuo CW, Brighty DW. 2007. Resistance to neutralization by antibodies targeting the coiled coil of fusion-active envelope is a common feature of retroviruses. J Biol Chem. 282:36724-35.

• Mirsaliotis A, Nurkiyanova K, Lamb D, Woof JM, Brighty DW. 2007. Conformation-specific antibodies targeting the trimer-of-hairpins motif of the human T-cell leukemia virus type 1 transmembrane glycoprotein recognize the viral envelope but fail to neutralize viral entry. J Virol. 81:6019-31.

• Mirsaliotis A, Nurkiyanova K, Lamb D, Kuo CW, Brighty DW. 2007. An antibody that blocks human T-cell leukemia virus type 1 six-helix-bundle formation in vitro identified by a novel assay for inhibitors of envelope function. J Gen Virol. 88:660-9.

• Phenotypic analysis of human immunodeficiency virus type 1 Rev trimerization-interface mutants in human cells. Trikha R, Brighty DW. J Gen Virol. 2005 May;86(Pt 5):1509-13.

• Piñon JD, Klasse PJ, Jassal SR, Welson S, Weber J, Brighty DW, Sattentau QJ. 2003 Human T-cell leukemia virus type 1 envelope glycoprotein gp46 interacts with cell surface heparan sulfate proteoglycans. J Virol. 2003 Sep;77(18):9922-30.

• Piñón JD, Kelly SM, Price NC, Flanagan JU, Brighty DW. An antiviral peptide targets a coiled-coil domain of the human T-cell leukemia virus envelope glycoprotein. J Virol. 2003 Mar;77(5):3281-90.

• Brighty DW, Jassal SR. 2001. The synthetic peptide P-197 inhibits human T-cell leukemia virus type 1 envelope-mediated syncytium formation by a mechanism that is independent of Hsc70. J Virol. 75:10472-8.

• Jassal SR, Lairmore MD, Leigh-Brown AJ, Brighty DW. 2001 Soluble recombinant HTLV-1 surface glycoprotein competitively inhibits syncytia formation and viral infection of cells. Virus Res. 78:17-34.

• Human T-cell leukemia virus type 1 receptor expression among syncytium-resistant cell lines revealed by a novel surface glycoprotein-immunoadhesin. Jassal SR, Pöhler RG, Brighty DW. J Virol. 2001 Sep;75(17):8317-28.

• A leptomycin B-sensitive homologue of human CRM1 promotes nuclear export of nuclear export sequence-containing proteins in Drosophila cells. Fasken MB, Saunders R, Rosenberg M, Brighty DW. J Biol Chem. 2000 Jan 21;275(3):1878-86.

• A cis-acting repressive sequence that overlaps the Rev-responsive element of human immunodeficiency virus type 1 regulates nuclear retention of env mRNAs independently of known splice signals. Brighty DW, Rosenberg M. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8314-8.

• Envelope proteins from clinical isolates of human immunodeficiency virus type 1 that are refractory to neutralization by soluble CD4 possess high affinity for the CD4 receptor. Brighty DW, Rosenberg M, Chen IS, Ivey-Hoyle M. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7802-5.