492 Immunological and Virological Failure following Antiretroviral Therapy is Associated with Enhanced Thymic and Peripheral T-cell Pathogenicity A Solomon1, P Cameron1, M Bailey2, A Dunne3, S Crowe3, J Hoy4, S Lewin*1 1Univ of Melbourne, Australia; 2Monash Univ, Melbourne, Australia; 3The Burnet Inst, Melbourne, Australia; and 4The Alfred Hosp, Melbourne, Australia
Background: Following antiretroviral therapy (ART) some individuals achieve increases in CD4 T-cells despite persistent viremia. The pathogenesis of this "discordant CD4 T-cell response" has been explained by reduced thymic pathogenicity of HIV-containing mutations in the protease (PR) gene. If mutations in PR impair CD4 T-cell pathogenicity, either in the thymus or periphery, it remains unclear why viremic individuals ultimately fail therapy immunologically.
Methods: HIV-infected individuals (n = 75) on ART, who were viremic and had increasing (immunological responders, DIR; n = 20) or decreasing CD4 T-cell counts (non-responders, NR; n = 11) were compared with aviremic individuals with increasing CD4 T-cell counts (complete responders, CR; n = 44). Thymic function was assessed by quantification of T-cell receptor excision circles (TREC) in CD45RA+ T-cells. Intracellular staining for Ki67 and TUNEL and surface staining for CD38 assessed T-cell proliferation, apoptosis, and activation, respectively. HIV-1genotype was determined by RT-PCR and sequencing.
Results: A multivariate analysis for CD4 slope following ART demonstrated a positive correlation with CD4+ T-cell count on therapy and a negative correlation with age and %CD38+CD8+ T-cells (R2 = 0.57, 0.48, 0.13 and p < 0.001, 0.001, and < 0.001, respectively). NR had higher levels of activated T-cells (both CD4 and CD8), T-cell proliferation and apoptosis when compared with CR and DIR (p < 0.05). Individuals with a DIR had intermediate levels of HIV viral load (VL), immune activation, proliferation, and apoptosis between that of CR and NR. When adjusted for VL, differences in activation and apoptosis were no longer significant across the 3 groups, except CD4 T-cell proliferation remained significantly higher in NR than in DIR and CR (p = 0.04 and 0.02, respectively). There was a significantly lower level of CD4+ and CD4- CD45RA+TREC in NR, when compared with DIR and CR (p < 0.005), not accounted for by the absolute level of VL or T-cell proliferation, suggesting a reduction in production or shortening of the life span of thymic emigrants. Mutations in PR and reverse transcriptase (RT) were frequent in DIR and NR; however, the RT mutation, Y181C, was strongly associated with NR (p = 0.006).
Conclusions: Immunological and virological failure following antiretroviral therapy is associated with enhanced peripheral and thymic pathogenicity. The role of RT mutation Y181C in immunological failure requires further exploration.
