Virus escape from CTL recognition

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 not discuss all available mechanisms, but will concentrate upon the role of sequence variation in CTL escape. Sequence variation is thought to affect CTL recognition in any one of three ways: blocking correct transport and processing of the antigen, blocking peptide binding to the MHC molecule, or blocking optimal recognition of the peptide/MHC complex by the TCR. In the last mechanism, either the peptide/MHC complex will fail to engage the TCR (15), or the TCR may be suboptimaUy engaged by the altered peptide/MHC complex, resulting in a decreased ability of that CTL to respond upon encountering a cell that presents the peptide/MHC complex to which the CTL was originally generated (a phenomenon referred to as "antagonism") (16-19). The exact mechanism involved in antagonism, however, is still unclear. These escape mechanisms are diagramatically shown in Fig. 1. It should be noted that this figure does not depict the recently described pathway utilized in the processing of some HIV envelope epitopes which is independent of the Tapl/Tap2 transporter complex (20). There is evidence, in viral infections other than HIV, for all three mechanisms of sequence variation leading to CTL escape. Variation in regions surrounding an epitope has been shown to lead to nonrecognition by influenza virus-specific CTL, though it remains uncertain ffproteolytic cleavage, transport, or another step in processing is affected by the sequence changes (21). In addition, lymphocytic choriomeningitis virus has been shown to alter sequences within defined epitopes as a mechanism of escape both in vitro and in vivo (22, 23). It has also recently been shown that EBV sequences recovered from a population with a high prevalence of HLA-A11-expressing individuals have an alteration in a key amino acid residue critical for binding of the peptide epitope to the HLAAll molecule (24). In addition to changes affecting peptide binding to MHC, there is also evidence that variation which allows altered peptide ligands to bind MHC may affect TCR recognition either directly or by the mechanism of antagonism (16-19). Several investigators had previously attempted to determine whether changes in amino acid sequences within defined CTL epitopes are responsible for the ability of HIV to escape the CTL response in vivo (25-29). By looking at sequences within defined epitopes, it has been shown that CTL clones or shortterm lines from HIV-infected individuals will fail to recognize some, but not all, strains of HIV (23, 25-28). Some studies compared virus sequences within the patients from whom the CTL lines were derived (25, 29), while in other studies virus sequences from a national database were used