Selective Depletion of High-Avidity Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8 ⁺ T Cells after Early HIV-1 Infection

Abstract

Human immunodeficiency virus type 1 (HIV-1)-specific CD8؉ T cells in early infection are associated with the dramatic decline of peak viremia, whereas their antiviral activity in chronic infection is less apparent. The functional properties accounting for the antiviral activity of HIV-1-specific CD8 ؉ T cells during early infection are unclear. Using cytokine secretion and tetramer decay assays, we demonstrated in intraindividual comparisons that the functional avidity of HIV-1-specific CD8 ؉ T cells was consistently higher in early infection than in chronic infection in the presence of high-level viral replication. This change of HIV-1-specific CD8 ؉ T-cell avidity between early and chronic infections was linked to a substantial switch in the clonotypic composition of epitope-specific CD8 ؉ T cells, resulting from the preferential loss of high-avidity CD8 ؉ T-cell clones. In contrast, the maintenance of the initially recruited clonotypic pattern of HIV-1-specific CD8 ؉ T cells was associated with low-level set point HIV-1 viremia. These data suggest that high-avidity HIV-1-specific CD8 ؉ T-cell clones are recruited during early infection but are subsequently lost in the presence of persistent high-level viral replication.

Despite Biased TRBV Gene Usage against a Dominant HLA B57-Restricted Epitope, TCR Diversity Can Provide Recognition of Circulating Epitope Variants

“…Our finding that TRBV7 clonotype avidity tended to be lower than that of the other KF11 specific clonotypes is consistent with the early deletion of high avidity T cell clonotypes after acute infection (37). Dominant TRBV7 usage may therefore represent convergent evolution toward populations of epitope-specific T cells with sufficient avidity to mediate control of viremia during chronic infection.…”

“…Yet, because the HIV specific TCR repertoire shapes and directs the HIV-specific CTL immune response, we extended our analysis to the structural and functional aspects of the KF11-specific TCR repertoire at the clonotype level. TRBV7 structural avidity was assessed by a tetramer off-rate assay similar to recently published methods (37). Recent findings have indicated high structural avidity as a beneficial characteristic of HIV specific CTL (5,(37)(38)(39)(40), as well as convergent evolution of epitope-specific responses in murine models and human influenza studies (41)(42)(43).…”

“…HIV-1 infection has been associated with immune exhaustion, as measured by the expression of surface markers such as CD57 and PD-1 (45)(46)(47). When Ag is persistently present, it is possible that high structural avidity is disadvantageous, leading to constant activation and eventual exhaustion of the high avidity clonotypes (37).…”

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…Moreover, several studies in active chronic infections established links between the magnitude of T-cell stimulation (or TCR avidity) and T-cell fate. Accordingly, lower avidity or weaker stimulated T-cells are more prone to retain a normal phenotype while higher avidity T-cells acquire a chronic infection phenotype or become deleted 62,63 . This is somewhat reminiscent of the fact that T-cells retain a rather normal effector phenotype in latent infections in which T-cells most likely receive lower TCR stimulation due to a lower level of antigen-exposure.…”

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

“…Many studies have analyzed the TCR repertoire in T cell lines and/or clones obtained in vitro from a limited number of subjects (21,22) and/or have been based on the use of an incomplete panel of anti-Vb mAbs (14,15,(21)(22)(23), raising the question of to what extent these data were representative of the in vivo situation. With regard to the direct sequencing of the TCR b-chain by anchored PCR in ex vivo Ag-specific sorted cells (19,20,24), it is possible that the TCR repertoire diversity might be underestimated, as the degree of diversity measured will be dependent upon the extent of sequencing with the potential for preferential detection of dominant CD8 T cell clonotypes.…”