The Differential Ability of HLA B*5701+ Long-Term Nonprogressors and Progressors To Restrict Human Immunodeficiency Virus Replication Is Not Caused by Loss of Recognition of Autologous Viral gag Sequences

Direct evidence from the rhesus macaque model of simian immunodeficiency virus (SIV) infection and correlative data from human studies have convincingly shown that CD8+ T cells play a major role in restricting lentivirus replication and determining the rate of disease progression (28, 30, 33, 36, 49). However, the reasons why cellular immune responses ultimately fail to contain virus replication in the majority of human immunodeficiency virus (HIV)-infected patients remain unclear. The accumulation of sequence mutations within or near epitopes targeted by HIV- or SIV-specific CD8+ T cells during the acute (1, 7, 29, 47) and chronic phases of infection (4, 10, 15, 25, 29, 45) has been demonstrated and is consistent with selection pressure exerted by dominant HLA-restricted immune responses. When associated with loss of recognition by cytotoxic T lymphocytes (CTLs), as measured in standard in vitro assays, stable sequence variations are thought to represent a major mechanism of virus escape from immune control (4, 7, 8, 10, 15, 23, 25, 29, 45, 47). To better understand the components of an effective HIV-specific immune response, we have focused our investigation on a unique group of HIV-infected long-term nonprogressors (LTNPs), who maintain normal CD4+ T-cell counts and <50 copies of HIV RNA/ml of plasma despite almost 20 years of infection. The HLA B*5701 class I allele has been found to be dramatically overrepresented in this cohort (15 of 17 thus far identified). However, the B*5701 allele is also present in 11% of patients with progressive disease, similar to the frequency in the Caucasian U.S. population (41). The virus-specific CD8+ T-cell response of LTNPs is typically highly focused on four conserved B*5701-restricted epitopes within the product of the HIV gag gene, suggesting that these epitopes and the B5701 molecule are critically involved in the restriction of viral replication in these patients. In contrast, the response in progressors is broader and includes responses restricted by other class I alleles carried by an individual patient. These observations have suggested that the difference between the HIV-specific CD8+ T-cell responses in B*5701+ LTNPs and progressors is either qualitative or due to partial or complete virus escape from immune recognition at these epitopes (20). In this study, we investigated the prevalence and recognition of autologous viral sequence variants in patients with highly divergent abilities to restrict virus replication but with a common HLA B*5701 allele. To determine their role in escape from immune system-mediated control over virus replication, sequence changes in immunodominant HLA B57-restricted gag epitopes and the responses to these variations in 10 B*57+ LTNPs and 17 B*57+ progressors were examined. In addition, we estimated the total frequency of CD8+ T cells that respond to autologous virus by using primary CD4+ T-cell targets expressing high levels of autologous viral gene products. These results confirm that high frequencies of HIV-specific CD8+ T cells persist in most patients. They also suggest that mutations within highly immunodominant B5701-restricted gag epitopes do not result in a loss of recognition by CD8+ T cells and do not account for the vast differences in the ability to restrict virus replication between LTNPs and patients with progressive infection.