Characterizing and Enhancing T-cell Effector Mechanisms

Canonically, HIV-specific CD8+ T-cells are thought to achieve partial suppression of viremia by directly recognizing and killing infected cells; with recognition occurring via TCR engagement of peptide-MHC-I and killing driven by the release of the cytotoxic molecules perforin and granzyme or by the engagement of ‘death receptors’ such as Fas. However, this is not the full story. Human and animal studies support the existence of populations of CD8+ T-cells that recognize infected cells independently of MHC-I, using innate immune receptors. Furthermore, many studies over the years have pointed to the existence of CD8-mediated mechanisms of HIV suppression that are independent of cytolysis (killing).

Ongoing work in our lab aims to both test methods of enhancing the potency of canonical infected-cell killing, as well as to delineate the mechanisms of non-canonical CD8+ T-cell activity described above. These aims are generally pursued separately, but each leverage a similar set of unique assets and resources of our lab, including clinical samples and our PDX mouse models for assessing in vivo antiviral activity of CD8+ T-cells.

Regarding canonical CD8+ T-cell killing, a key goal is determining whether this can be sufficiently enhanced to enable consistent elimination of HIV reservoir-harboring cells from ex vivo CD4+ T-cells of individuals on long-term ARV therapy in HIVE assays (1,2)– which may also require methods to suppress mechanisms of resistance to killing in target cells.

One highlight of current efforts on the innate/non-cytolytic front is assessing whether our clinical trial of IL-15 will show expansion/enhancement of these populations, and whether this will have an impact on viral rebound.

1 .         Ren, Y. et al. BCL-2 antagonism sensitizes cytotoxic T cell-resistant HIV reservoirs to elimination ex vivo. J Clin Invest 130, 2542-2559, doi:10.1172/JCI132374 (2020).

2.          Huang, S. H. et al. Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells. J Clin Invest 128, 876-889, doi:10.1172/JCI97555 (2018).