Lentiviral vectors expressing effective HIV-specific TCR clonotypes can transform naïve CD8+ T cells into potent HIV-specific CTLs, a possible gene therapy approach to increase HIV-specific immunity. To optimize this approach, it is crucial to identify TCR clonotypes which confer the most potent anti-HIV activity. CTLs with superior antiviral efficacy, termed effective CTLs, are well-represented in HIV-1 controllers but are rare or absent in HIV-1 progessors. However, the contributory role of the HIV-specific CTL TCR clonotype on the potency of its antiviral activity is unclear; this compromises our ability to identify which HIV-1 specific TCR α and β chain genes most effectively convert primary CD8+ T cells into potent HIV-specific CTLs.
To directly evaluate the contribution of the TCR clonotype on the differences observed in effective or ineffective CTL clones, we cloned into TCR-expressing lentivectors the TCR α and β chain genes from one effective and two ineffective CTL clones specific for the same viral peptide, KK10, but with different TCR clonotypes, isolated from an HLA*B2705 elite controller (Chen et al., Nature Immunology 2012;13:691). We used these lentivectors to transduce Jurkat/MA cells, a T cell line engineered to measure TCR signaling using a luciferase reporter, and primary CD8+ T cells to delineate the contribution of the TCR on the functional activity of HIV-specific CTLs.
Jurkat/MA cells transduced with lentiviral vectors encoding TCRs cloned from the effective or the two ineffective CTL clones expressed equivalent levels of KK10-specific TCR clonotypes and displayed comparable TCR activation by their cognate peptide, KK10. Primary CD8+ T cells transduced with lentivirus expressing the TCR from the effective CTL clone or the two ineffective CTL clones displayed equivalent levels of the KK10-specific TCR clonotypes and exhibited equivalent potent inhibition (>80%) of in vitro HIV-1 infection.
Taken together, these data indicated that TCR clonotypes from ineffective CTLs have the intrinsic capacity to direct primary CD8+ T cells to effectively kill HIV infected cells and support the proposition that other TCR-independent factors such as epigenetic modifications may also contribute to the effective vs. ineffective functions of some CTL clones. The effective control of HIV-1 infection in elite controllers may be due to their capacity to generate and expand these effective clonal CTL populations.