C lass I MHC-restricted cytotoxic T lymphocytes (CTL) have been demonstrated to have potent antiviral activity both in vitro and in vivo (1-3). It is therefore not surprising that viruses have evolved sophisticated mechanisms to escape the effects of CTL. Almost by definition, a persistent virus is one that has evolved some mechanism for avoiding the CTL response of the host. In most persistent virus infections, escape from CTL results in life-long infection of the host with some small fraction of the population suffering pathologic consequences from the virus infection (4). In HIV infection, however, both viral persistence and the devastating consequences of that infection are the rule, rather than the exception. Assuming that escape from CTL plays a role in the ability of HIV to maintain persistent infection, it becomes imperative to better understand this phenomenon and the mechanisms specifically employed by this virus. In this issue of the Journal, Couillin et al.(5) provide insight into how HIV may escape CTL recognition through genetic variation. Several lines of evidence suggest that CTL are an important component of the protective immune response to HIV infection. HIV-specific CTL precursors are present at high frequency very early during infection, often being detectable before seroconversion (6). During the subsequent prolonged asymptomatic phase of infection, HIV-specific CD8+ MHC class I-restricted CTL activity can routinely be detected directly from the peripheral blood in the absence of in vitro stimulation (7, 8). Limiting dilution analysis has confirmed that a high frequency of activated and memory HIV-specific CTL are present in the peripheral blood of these patients (9-11). However, despite this vigorous CTL response, the virus continues to replicate (12, 13). Progression to AIDS is marked by an increase in virus replication accompanied by a loss of the CD8+ HIV-specific CTL response (11, 14). The association of the CTL response with the initial, acute decrease in viremia and the subsequent loss of that control with progression to AIDS strongly implicates the CTL response in control of HIV replication during the asymptomatic phase of infection.

How then might HIV, or any other persistent virus, evade the CTL response of the host? On first inspection one might assume that a virus would simply escape a CTL response by altering the amino acid sequence within the epitope (s) recognized by that response. While this may be the most intensively studied, it is by no means the only, or the most frequently used, viral escape mechanism. Table 1 provides a listing of defined and proposed mechanisms utilized by viruses to avoid the CTL response of the host. This commentary will