[MOAA104] TCR clonotypes responding to an immmunodominant HLA-B*27 restricted epitope are relatively stable over extended periods but their diversity does not correlate with viral escape in HIV-1 infected long term non-progressors (LTNP)

5th International AIDS Society Conference on HIV Pathogenesis and Treatment

Cape Town - July 19 - 22, 2009

TCR CLONOTYPES RESPONDING TO AN IMMMUNODOMINANT HLA-B*27 RESTRICTED EPITOPE ARE RELATIVELY STABLE OVER EXTENDED PERIODS BUT THEIR DIVERSITY DOES NOT CORRELATE WITH VIRAL ESCAPE IN HIV-1 INFECTED LONG TERM NON-PROGRESSORS (LTNP)

IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Abstract No. MOAA104

D. van Bockel ¹, P. Ammaranond², V. Venturi³, M. Davenport⁴, D. Price⁵, D. Douek⁶, J. Zaunders⁷, L. Gelgor¹, J. Kaldor¹, D. Cooper¹, A. Kelleher¹
¹University of New South Wales, NCHECR, Sydney, Australia, ²Chulalongkorn University, Bangkok, Thailand, ³University of New South Wales, Sydney, Australia, ⁴University of New South Wales, Complex Systems in Biology Group, Centre for Vascular Research, Sydney, Australia, ⁵Cardiff University, School of Medicine, Cardiff, United Kingdom, ⁶NIAID/NIH, Human Immunology Section, Vaccine Research Center, Bethesda, United States, ⁷St Vincent‘s Hospital, Centre for Applied Medical Research, Sydney, Australia

BACKGROUND: The determinates of HIV disease progression are poorly understood. Patients with HLA-B*27 are over-represented among LTNP and have focussed, stable CTL responses to the conserved Gag epitope, KK10. Viral escape occurs late, via variant epitopes with reduced affinity for HLA-B*27.

METHODS: The interaction between the generation of viral escape variants within KK10 and disease progression was studied in 20 HLA-B*2705+ve LTNP over more than16yrs post infection. The evolution of CTL and viral escape, and host and viral factors known to impact on disease progression were characterised. In a subset of patients, KK10 tetramer labelled CD8 T cells were FACS isolated, clonotypic TCR b-chain sequences obtained, dominant/ sub-dominant clonotypes determined, and their characteristics summarised using Simpson's diversity and Morista-Horn similarity indices. Responses to the HLAA* 2 restricted immuno-dominant CMV matrix epitope NV9 in the same patients were used as a comparator.

RESULTS: The generation of viral escape mutants at KK10 was the only variable that determined disease progression (P=0.01). Known host and viral factors and the size of KK10 specific response did not impact on generation of KK10 escape mutants. There was no correlation between diversity of the TCR response to KK10 and the generation of escape or disease progression. Surprisingly, the KK10 response was significantly less diverse (P=0.031) and more stable over time than the NV9 response (P=0.004). Despite shifting TCR dominance, functional avidity of both responses was maintained unchanged over extended periods. Dominant clonotypes had higher expression of Bcl2 and CD127, compared to subdominant clones (KK10: P=0.008, NV9: P=0.03), but did not differ in expression of CD45RA/RO, CD27, CD28 or perforin.

CONCLUSIONS: Although escape from CTL responses in HLA-B27 positive patients appears to impact on disease progression, the determinates of escape are not related to known predictors of disease progression or the breadth of the TCR response. Presenting author

2009-07-22
MOAA104
Oral Abstract Session: MOAA1 - Control of HIV by Cellular Immunity

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