Identification of cell surface targets for HIV-1 therapeutics using genetic screens

Stephen J. Dunn, Imran Khan, Ursula A. Chan, Robin L. Scearce, Claudia L. Melara, Amber M. Paul, Vikram Sharma, Fong Yih Bih, Tanya A. Holzmayer, Paul A Luciw, Arie Abo

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Human immunodeficiency virus (HIV) drugs designed to interfere with obligatory utilization of certain host cell factors by virus are less likely to encounter development of resistant strains than drugs directed against viral components. Several cellular genes required for productive infection by HIV were identified by the use of genetic suppressor element (GSE) technology as potential targets for anti-HIV drug development. Fragmented cDNA libraries from various pools of human peripheral blood mononuclear cells (PBMC) were expressed in vitro in human immunodeficiency virus type 1 (HIV-1)-susceptible cell lines and subjected to genetic screens to identify GSEs that interfered with viral replication. After three rounds of selection, more than 15000 GSEs were sequenced, and the cognate genes were identified. The GSEs that inhibited the virus were derived from a diverse set of genes including cell surface receptors, cytokines, signaling proteins, transcription factors, as well as genes with unknown function. Approximately 2.5% of the identified genes were previously shown to play a role in the HIV-1 life cycle; this finding supports the biological relevance of the assay. GSEs were derived from the following 12 cell surface proteins: CXCR4, CCR4, CCR7, CD11C, CD44, CD47, CD68, CD69, CD74, CSF3R, GABBR1, and TNFR2. Requirement of some of these genes for viral infection was also investigated by using RNA interference (RNAi) technology; accordingly, 10 genes were implicated in early events of the viral life cycle, before viral DNA synthesis. Thus, these cell surface proteins represent novel targets for the development of therapeutics against HIV-1 infection and AIDS.

Original languageEnglish (US)
Pages (from-to)260-273
Number of pages14
JournalVirology
Volume321
Issue number2
DOIs
StatePublished - Apr 10 2004

Keywords

  • Cell surface targets
  • Genetic suppressor element
  • HIV

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

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    Dunn, S. J., Khan, I., Chan, U. A., Scearce, R. L., Melara, C. L., Paul, A. M., Sharma, V., Bih, F. Y., Holzmayer, T. A., Luciw, P. A., & Abo, A. (2004). Identification of cell surface targets for HIV-1 therapeutics using genetic screens. Virology, 321(2), 260-273. https://doi.org/10.1016/j.virol.2004.01.010