Impacts of Avidity and Specificity on the Antiviral Efficiency of HIV-1-Specific CTL

Abstract

Although CD8+ CTLs are presumed to be an important mediator of protective immunity in HIV-1 infection, the factors that determine CTL antiviral efficiency are poorly understood. Two factors that have been proposed to influence CTL antiviral function are antigenic avidity and epitope specificity. In this study we evaluate these by examining the activity of HIV-1-specific CTL against acutely infected cells. The ability of CTL to kill infected cells is variable and depends more on epitope specificity than functional avidity within the range for the tested clones (50% of maximal killing, 50 pg/ml to 100 ng/ml); killing efficiency is similar for different clones recognizing the same epitope, despite their variation in avidity. When CTL clones are tested for their ability to suppress viral replication, similar results are observed. Inhibition is more dependent on epitope specificity than functional avidity among the tested clones (50% of maximal killing, 20 pg/ml to 20 ng/ml). Thus, CTL specificity can be an overriding factor in the ability of CTL to interact with HIV-1-infected cells, indicating that factors determining the process of epitope presentation on infected cells have a key influence on CTL efficiency. These results suggest that CTL specificity may have a pivotal role in the immunopathogenesis of infection, and that simple quantitative measures of CTL may be insufficient indicators of the CTL response to HIV-1.

Reconstitution of anti‐HIV effector functions of primary human CD8 T lymphocytes by transfer of HIV‐specific αβ TCR genes

“…5) despite its modest functional avidity and tetramer binding activity (Table 1). This finding appears to be consistent with the recently reported study demonstrating that epitope specificity of CTL, rather than functional avidity of CTL, is a key factor in the ability of CTL to control HIV replication, and that the process of epitope presentation on HIV-infected cells greatly influences CTL efficiency in vivo [29].…”

Evasion of cytotoxic T lymphocytes is a functional constraint maintaining HIV-1 Nef expression

“…This was not due to loss of viral replication limiting mutation, because the presence of p24 antigen all in the cultures demonstrated ongoing virion production in the presence of CTL, and escape mutation in the targeted non-Nef protein could be observed in some of the mixed CTL cultures (Table 1 and data not shown). Furthermore, this phenomenon was not explained by lesser recognition of infected cells by Nef-specific CTL compared to the Gag-and RT-specific CTL, as indicated by our previous observations that Nefspecific CTL tend to have far greater antiviral activity than Gag-and RT-specific CTL [29,30], and that RTspecific CTL (the IV9-specific CTL clones tested here) often have relatively weak antiviral activities [25,26]. These data, therefore, indicated that the presence of non-Nef-specific CTL add an important functional constraint that limits the ability of HIV-1 to escape from Nef-specific CTL through disruption of Nef.…”

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

“…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). These data suggest a beneficial role of common TRBV usage against conserved epitopes, perhaps as a result of greater functional capacity.…”