Lau et al. took an intriguing new approach to HIV-1 therapy by targeting a host--rather than a viral--protein. Although pharmacological approaches to pathogen treatment that target the molecular differences between host and pathogen often meet with substantial success, the short life cycle and rapid mutation rate of pathogens such as HIV-1 all too often lead to the emergence of drug-resistant strains. Lau et al. showed that mouse embryonic stem cells and human fibroblasts lacking ATM (ataxia telangiectasia mutated), a serine-threonine kinase implicated in the DNA damage response, showed less efficient transduction with HIV-1 integrase-proficient (HIV-1 IN+) viral vectors than did cells expressing ATM. Similarly, human lymphoblasts lacking ATM exhibited lower amounts of viral p24 antigen after exposure to wild-type HIV-1 than did lymphoblasts with ATM. Rather, HIV-1 IN+ transduction of cells lacking ATM was associated with increased cell death. Lymphoblasts infected with HIV-1 IN+ vectors showed activation of the ATM pathway (assessed by immunoblot analysis of various DNA damage-dependent phosphorylation events) compared with lymphoblasts lacking ATM or cells exposed to a mutant (HIV-1 IND64V) in which integrase was inactivated. KU-55933 (2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one, a small-molecule competitive inhibitor of ATM) inhibited HIV-1 IN+ transduction oflymphoblasts and suppressed HIV-1 replication in both a human T cell line and primary blood mononuclear cells. Moreover, KU-55933 was effective against drug-resistant as well as wild-type strains of HIV-1. Thus, small-molecule inhibition of ATM represents a potential approach to HIV-1 therapy that could circumvent the problem of viral resistance to drugs. Daniel and Pomerantz discuss this research in a News and Views article.
A. Lau, K. M. Swinbank, P. S. Ahmed, D. L. Taylor, S. P. Jackson, G. C. M. Smith, M. J. O'Connor, Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase. Nat. Cell Biol. 7, 493-500 (2005). [PubMed]
R. Daniel, R. J. Pomerantz, ATM: HIV-1's Achilles heel? Nat. Cell Biol. 7, 452-453 (2005). [PubMed]