Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
Michael R. Betts
HIV infection is typically associated with dysfunction of the immune system. Evidence indicates that CD8 T-cells are crucial in the fight against HIV, but with disease progression CD8 T-cells become functionally exhausted rendering them unable to control viral replication and spread. Unlike chronically infected individuals (CP), HIV elite controllers (EC) retain CD8 T-cell polyfunctionality and killing function. These characteristics have been linked to the ability of EC to suppress viral replication to undetectable levels without therapy intervention. It remains unclear whether EC manifest T-cell exhaustion similar to CP, and whether exhaustion level measured in blood is representative of that in lymphatic tissues, a site of persistent viral replication. Current antiretroviral therapies successfully reduce viral replication to undetectable levels in blood, but fail to eliminate the viral reservoir within lymph nodes (LN), highlighting the importance in developing means to reinvigorate immune responses in these tissues.
To date, studies focusing on T-cell exhaustion use a lack of IL-2, IFNγ and TNF together with co-expression of inhibitory receptors to define exhausted populations. However, these studies fail to address conflicting data on the role of these receptors as markers of activation and their involvement in cytolytic activity, a known correlate of protection against HIV in elite controllers. To address this, we assembled a cohort of EC, CP and healthy individuals and simultaneously measured expression PD-1, Lag-3, CD160 and 2B4, cytokines IFNγ and TNF, and cytolytic molecule perforin. We also compared CD8 T-cell exhaustion in blood and LN in a cohort of HIV+ individuals on and off ART.
We report that EC have a high proportion of potentially exhausted (PD1+CD160+2B4+) HIV-specific CD8 T-cells comparable to that in CP, a population also present in HIV+ LN on and off ART. However, EC also harbor a population of HIV-specific CD160+2B4+ CD8 T-cells associated with perforin not commonly present in CP. This indicates that coexpression of CD160 and 2B4 delineates a population of cytolytic CD8 T-cells important for the control of HIV in blood. However this association is not present in LN CD8 T-cells indicating differential regulation of cytolytic factors within these tissues.
Pombo, Carolina, "Expression of Pd-1, Cd160 and 2b4 on Cd8 T Cells During HIV infection: Markers of Exhaustion?" (2015). Publicly Accessible Penn Dissertations. 1951.