P16-25. HIV specific CTL from elite controllers have a unique survival advantage

Background

Understanding how elite controllers (EC), patients controlling virus without antiretroviral therapy (ART), differ from those with chronic disease is an area of intense investigation. HIV Gag specific (sp) cytotoxic T lymphocytes (CTL) play a dominant role in this control. Unfortunately, most HIV sp CTL are primed for apoptosis. We hypothesize that EC up-regulate survival factors allowing them to resist apoptosis.

Methods

We examined pro- and anti-apoptotic factors in HIV Gag specific CTL in EC (viral load (VL) < 50 off ART), successfully treated (ST) (VL < 50 on ART), and untreated viremics (V). Using flow cytometry based assays, we performed cross-sectional and longitudinal analysis of pro-apoptotic (cleaved caspase-3) vs. anti-apoptotic (Bcl-2) markers in HIV specific CD8 T cells examining spontaneous cell death.

Results

VL only partially drives expression of cleaved caspase-3 (CC3). CC3^hi HIV sp CTL in EC were not only lower compared to V (2.3 vs. 13%, respectively) but also lower than ST (5.4%) (p < 0.05). Bcl-2 trended towards higher levels in HIV sp CTL of EC and ST compared to V. Combining these makers we found differences in CC3^hi/Bcl-2^lo HIV sp CTL with the greatest number of HIV sp CTL at risk of apoptosis in viremics (6.5%), followed by ST (2.1%) and EC (0.80%) (p < 0.05). In a longitudinal analysis pre and post ART we found decreases in both CC3^hi HIV sp CTL and CC3^hi/Bcl-2^lo CTL after successful treatment. CC3^hi/Bcl-2^lo populations represent cells at greatest risk of undergoing apoptosis and this phenotype appears to be only partially reversible with ART.

Conclusion

EC have a survival advantage over patients with chronic disease even when treated with ART. Elucidating pro- and anti-apoptotic factors contributing to the survival of CTL in EC including costimulatory signaling necessary to generate these CTL capable of resisting apoptosis is paramount to development of effective HIV-1 vaccines.