Impaired cytotoxic T lymphocyte recognition due to genetic variations in the main immunogenic region of the human immunodeficiency virus 1 NEF protein.

Abstract

SummaryHuman immunodeficiency virus (HIV) induces strong responses from human histocompatibility leukocyte antigen (HLA) class I-restricted cytotoxic T lymphocytes (CTL). In a previous report we identified an immunodominant region (amino acids 73-144) in the NEF protein that was recognized by CD8 + class I-restricted CTL of most asymptomatic individuals. Analysis of the 73-144 region by peptide sensitization experiments using overlapping peptides corresponding to the LAI isolate identified the peptide sequences located between residues 73 and 82 or 84 and 92 and the peptide sequence between residues 134 and 144 as cognate peptides for HLA-A11-and HLA-B18-restricted epitopes, respectively. This report describes the variable demonstrable reactivities of CTL obtained from HLA-A11 or HLA-B18 seropositive, asymptomatic patients who all had a response to the virus NEF protein, but who did not always recognize appropriate cognate peptides. The high mutation rate of HIV probably facilitates the selection of mutants that can avoid the cellular immune response. We therefore analyzed the variability of these epitopes restricted by HLA-A11 and HLA-B18. We sequenced several viral isolates from HLA-All and HLA-B18 donors who recognized certain HLA-peptide complexes and from those who did not. A CTL sensitization assay was used to show that some mutations led to a great reduction in CTL activity in vitro. This might be due to failure of the mutated epitope to bind major histocompatibility complex class I molecule. A simple assay was used to detect peptides that promoted the assembly of class I molecules. Some of these mutations at major anchor positions prevented HLA-A11/peptide binding, and consequently impaired recognition of the HLA-peptide complex by the T cell receptor.

Broadly Increased Sensitivity to Cytotoxic T Lymphocytes Resulting from Nef Epitope Escape Mutations

“…Yet, the nef reading frame is highly maintained in vivo (2,31). Escape from CTL appears to occur predominantly through sequence variation (32), and even in a case where reinfusion of expanded autologous Nef-specific CTL resulted in extreme selective pressure that favored epitope deletion, the reading frame was maintained (33). This suggests that changes in Nef are also highly constrained, and since Nef does not play a direct important structural role for HIV-1, some function(s) of this protein must be important for viral persistence in vivo.…”

Lack of strong immune selection pressure by the immunodominant, HLA-A*0201-restricted cytotoxic T lymphocyte response in chronic human immunodeficiency virus-1 infection.

“…Assessment of class I binding by SL9 variant peptides. Escape from immune recognition has been reported to be due to amino acid sequence variation resulting in decreased class I binding (53)(54)(55) and might be expected to occur in the presence of strong CTL selection pressure. None of the subjects analyzed demonstrated amino acid sequence variation within the dominant anchor residues for HLA-A*0201, namely amino acids L78 and V85.…”

Epitope Escape Mutation and Decay of Human Immunodeficiency Virus Type 1-Specific CTL Responses

“…Clearly, a formidable challenge presented by HIV-1 is its ability to replicate continuously despite strong virus-specific responses. Among the many mechanisms postulated to explain CTL failure are sequence variation within or near their epitopes (7)(8)(9)(10)(11)(12), inefficient maturational state (13), and clonal exhaustion (14). However, comprehensive longitudinal in vivo data to illuminate these important issues in humans are scant (15)(16)(17)(18)(19).…”