Upregulation of Fas Ligand by Simian Immunodeficiency Virus—A nef-arious Mechanism of Immune Evasion?

A IDS is the end result of a prolonged dynamic war of attrition between virus and host, marked by prodigious rates of viral replication opposed by host immune responses and remarkable rates of T cell regeneration (1, 2). Understanding the ultimate failure of the host immune responses to control HIV replication remains one of the central challenges of HIV research. This commentary will focus on efforts to understand why the host cytotoxic T lym-phocyte (CTL) response, normally a potent effector response against viral infections, is unable to contain AIDS virus replication. Most HIV-infected people develop a strong and broadly directed CTL response against HIV (3). This CTL response, which is mediated largely by classical CD8 ϩ , MHC class I–restricted lymphocytes, can often be detected without in vitro stimulation, indicating a high frequency of circulating activated effector cells (4). Direct evidence for a high frequency of HIV-specific CTL (up to 1% of all T cells) has been provided by molecular analysis of the frequency of T cell receptors specific for a single CTL epitope (5) and by flow cytometric analysis of lymphocytes from HIV-infected subjects using fluorescently labeled HLA-A2 molecules complexed with a HIV peptide (6). In addition to their relatively high frequency, HIV-specific CTL typically recognize multiple epitopes in a single subject, generally in conserved regions of the virus (4, 7). Definitive evidence for an in vivo effect of this vigorous in vitro response has been difficult to establish, but the finding that the onset of CTL responses during primary infection with HIV-1 coincides with the control of viral replication, suggests that HIV-specific CTL are likely to suppress viral replication in vivo (8). Yet, viral replication continues to occur in HIV-infected individuals despite CTL responses and replication ultimately increases as individuals progress to AIDS, often in conjunction with a decline in CTL activity (9). A variety of mechanisms have been proposed to account for the failure of CTL responses to effectively control HIV (Table 1) (10, 11), many of which have been previously described for other viral pathogens. Sequence variation has been the leading contender to account for the escape of HIV from CTL control, yet unequivocal evidence to document this hypothesis has proved elusive. HIV replication occurs at a rapid rate in vivo, leading to the production of 10 9 virions per day (1, 2). Coupled with the error-prone nature of reverse transcriptase, this rapid rate of replication …