Altered immune states: Exploring predictors of differential immune efficacy and outcomes during aging and advanced HIV disease

Increased immunosuppression is seen during the natural process of aging as well as during HIV disease progression. Clinically, these states are characterized by an increased rate of de novo infection, reactivation of latent infection, and decreased vaccine efficacy. Pan-immunologic alterations are observed during both age related and HIV induced senescence, nonetheless, significant inter-individual variability in immune efficacy has been shown. This dissertation explores the variability associated with immune efficacy in two distinct contexts; during the aging process and during advanced HIV disease. In the first paper, using a longitudinal cohort we demonstrate substantial loss of the most naive CD4+ T-cells (CD31+CD45RA+) during aging concomitant with an age related proliferation of the CD31-CD45RA+ naive subset with unknown immunologic potential. We also show that the CD31+CD45RA+ subset is not spared from on-going proliferation, albeit to a lesser extent, as evidenced by an age related loss of TREC and shortening of telomeres observed in this subset. The second study explores the associations between NK cell markers and survival duration in a cohort of patients with advanced HIV disease (<50 CD4/mul). We find that longer survival duration is associated with a larger percentage of NK cells, higher target cell killing on a per cell basis, and increased expression of KIR2DL1 and/or KIR2DS1 on NK cells. The finding of an association between KIR and survival motivated a larger genetic study of KIR/HLA interactions and survival with advanced HIV disease. We show that individuals carrying an allele bearing the HLA Bw4-80Ile motif have a significantly reduced mortality hazard (HR = 0.44 95% CI 0.23--0.84). While KIR3DS1 alone is not associated with a significant increase in hazard, those carrying both KIR3DS1 and Bw4-80Ile (a receptor/ligand pair), however, demonstrate a significantly increased mortality hazard (HR = 3.27 95% CI 1.36--7.38). The direction of this synergy is opposite of that reported in other reports for individuals earlier in infection, where KIR3DS1/Bw4-80Ile has been shown to delay progression to AIDS. Elucidating predictors of more favorable immunologic states and, in turn, clinical outcomes, will lead to more targeted interventions during states of immunosuppression.