Selection, Transmission, and Reversion of an Antigen-Processing Cytotoxic T-Lymphocyte Escape Mutation in Human Immunodeficiency Virus Type 1 Infection

Abstract

Numerous studies now support that human immunodeficiency virus type 1 (HIV-1) evolution is influenced by immune selection pressure, with population studies showing an association between specific HLA alleles and mutations within defined cytotoxic T-lymphocyte epitopes. Here we combine sequence data and functional studies of CD8 T-cell responses to demonstrate that allele-specific immune pressures also select for mutations flanking CD8 epitopes that impair antigen processing. In persons expressing HLA-A3, we demonstrate consistent selection for a mutation in a C-terminal flanking residue of the normally immunodominant Gag KK9 epitope that prevents its processing and presentation, resulting in a rapid decline in the CD8 T-cell response. This single amino acid substitution also lies within a second HLA-A3-restricted epitope, with the mutation directly impairing recognition by CD8 T cells. Transmission of the mutation to subjects expressing HLA-A3 was shown to prevent the induction of normally immunodominant acute-phase responses to both epitopes. However, subsequent in vivo reversion of the mutation was coincident with delayed induction of new CD8 T-cell responses to both epitopes. These data demonstrate that mutations within the flanking region of an HIV-1 epitope can impair recognition by an established CD8 T-cell response and that transmission of these mutations alters the acute-phase CD8 ؉ T-cell response. Moreover, reversion of these mutations in the absence of the original immune pressure reveals the potential plasticity of immunologically selected evolutionary changes.

HIV-1 Epitope-Specific CD8+ T Cell Responses Strongly Associated with Delayed Disease Progression Cross-Recognize Epitope Variants Efficiently

“…Viral sequence variation may lead to escape from T cell responses by impairing epitope processing (9 -11), impairing epitope binding to the restricting HLA class I molecule (7,9) and/or directly impairing recognition of the HLA:peptide complex by Ag-specific T cells (12). Where the favored mechanism of escape is via direct effects on TCR recognition, escape may be limited in the presence of a functionally cross-reactive response.…”

“…Escape occurs commonly in HIV-1 infection (4, 5) (sometimes coinciding with the onset of disease progression; Refs. 6 -8) and may be mediated by amino acid sequence variation in CD8 ϩ T cell epitopes (or epitope-flanking regions) leading to impaired peptide processing (9 -11), impaired peptide binding to the HLA class I molecule (7,9) or alterations to the TCR contact surface of the epitope (12), all of which can result in reduced TCR recognition of the HLA:peptide complex.…”

HIV-Specific Cytotoxic Cell Frequencies Measured Directly Ex Vivo by the Lysispot Assay Can Be Higher or Lower Than the Frequencies of IFN-γ-Secreting Cells: Anti-HIV Cytotoxicity Is Not Generally Impaired Relative to Other Chronic Virus Responses

“…Depletion of CD8 ϩ cells from macaques results in a dramatic increase of SIV viral load, either during acute (1) or chronic (2) (3) infection. In humans, CD8 epitope escape mutants emerge during the course of HIV infection within one individual, and the original epitopes can re-emerge on transfer of the infection to a new individual (4). These data suggest that effective CD8 immune responses exert selective pressure on the virus (5,6).…”

Estimate of Within Population Incremental Selection Through Branch Imbalance in Lineage Trees

“…It is also often addressed at the micro-evolution level, as happens for example in viral escape mutations to avoid immune mediated destruction (4)(5)(6), the dynamics of specific clones in the B cell response against pathogens (7,8) or maternal inheritance within a population (9,10). These cases are examples of processes involving rapid asexual reproduction, where constant diversification and possibly adaptation occur with a high mutation rate.…”