Viruses, including HIV-1, encode proteins that help them to evade attack by the immune system. For example, HIV Nef promotes immune evasion by reducing the cell-surface expression of MHC class I molecules, so protecting infected cells from cytotoxic T lymphocyte (CTL)-mediated death. Now, Bobbitt and colleagues show for the first time that the activity of Rev, an HIV regulatory protein that is required for the expression of HIV late proteins, can also influence the susceptibility of infected cells to CTLs.

First, the authors tested whether cells infected with different HIV-1 clones differed with respect to their sensitivity to CTL recognition and cytotoxicity. Cells infected with the HIV clone NL-PI were less sensitive to CTL-mediated death than cells infected with another clone (HXB-PI). Further analysis showed that this protection against CTL attack resulted from a single amino-acid change (Leu60Phe) in the coding sequence of Rev in NL-PI.

As Rev is required for the synthesis of late gene products (including Gag, Pol and Env), Bobbitt et al. reasoned that this Rev mutation might reduce CTL-mediated killing by limiting the expression of Gag, so reducing Gag-epitope density on the surface of infected cells (required for Gag-specific CTL-mediated killing). Expression of the Phe60 form of Rev in transfected cell lines and infected primary T cells resulted in a 2–3-fold decrease in Gag protein levels and a small decrease in Env protein levels, but had no effect on the level of Nef in these cells.

So, mutated Rev alleles could protect infected cells from CTL attack in two ways: first, by decreasing the expression of viral proteins, including Gag, which are a source of antigens for recognition by CTLs; and second, by maintaining the expression of Nef, which promotes MHC class I downmodulation.

Finally, primary viral isolates from asymptomatic HIV-infected individuals and from patients with AIDS were screened. Viruses derived from asymptomatic individuals had lower Rev activity, and cells infected with these isolates had reduced levels of Gag proteins and were more resistant to Gag-specific CTL-mediated killing than cells from patients with AIDS. The authors conclude that, in contrast to those individuals with AIDS, immune pressure in asymptomatic individuals might result in the selection of active forms of viral genes, including mutated Rev alleles, that are involved in viral immune evasion.