Current drugs against HIV type-1 (HIV-1) target a variety of viral proteins. Unfortunately, the genes encoding these proteins mutate rapidly, leading to drug-resistant viral variants arising during therapy and limiting the usefulness of a particular drug. An alternative approach is to inhibit non-essential host-cell proteins that are required for viral replication. In the May issue of Nature Cell Biology, Mark O'Connor and colleagues have identified a host protein, the ataxia-telangiectasia-mutated (ATM) kinase, as a new target for the development of antiretroviral therapies to treat HIV-1. This new research could allow the development of a new therapy that is effective against all HIV strains, substantially reducing the likelihood of drug resistance.

Mammalian cells respond to DNA damage by activating a number of response pathways to maintain genomic integrity. Integration into the host DNA is an essential step in the retroviral life cycle. A viral integrase is necessary for integration of viral product into the host genome, which cleaves the host DNA and then utilizes the host repair response in order to complete the integration process. Retroviral infections, such as those caused by HIV-1, activate a poorly understood repair pathway.

Evidence exists that the Ku-dependent non-homologous end-joining (NHEJ) pathway is required to support efficient retroviral infection. There is also some evidence of involvement of ATM kinase and a related protein, ataxia Rad-related (ATR), in this pathway. Both ATM and ATR are phosphatidyl-3-OH-kinase-like serine/threonine kinases that regulate cellular responses to DNA damage by controlling cell-cycle arrest and DNA-repair pathways. ATM is mutated in a rare genetic disease, A-T, that can lead to cancer, particularly leukaemia and lymphoma, and premature ageing.

The authors used genetic and pharmacological approaches to show that ATM has an important role in retroviral replication. They showed that the activity of HIV-1 integrase stimulates an ATM-dependent DNA-damage response and that a deficiency of ATM sensitizes cells to retrovirus-induced cell death. ATM helps to repair DNA damage caused by viral integration in the host-cell genome and is therefore essential to the survival of infected cells. Furthermore, treating HIV-1-infected cells with an ATM-specific small-molecule inhibitor, KU-55933 (not effective in targeting ATR), led to increased cell death and suppression of both wild-type and drug-resistant HIV-1 replication.

If effective in animal and clinical studies, ATM inhibitors could provide a new class of anti-HIV inhibitors. However, an important and outstanding question is whether or not inhibition of ATM will be associated with the same safety issues as the genetic disease. The effect of ATM kinase inhibition is likely to be less dramatic than the complete absence of ATM protein.