SOEDAK2009 --- PREPARE FOR THE LONG RUN

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Titel
Very rapid resonse kinetics to HLA-B57/58 gag-restricted CTL epitopes is asociated with slow diesease progression
Autor
Jan van Lunzen1,2, Julian Schulze zur Wiesch1,2, Philip Hartjen1,2, Ingrid Stahmer1,2
Abstract
Background: Slow progression of HIV-1 infection is associated with B27 and B57/58 -restricted CTL responses against gag epitopes. These responses occur before the integration of proviral DNA and may reduce the seeding of latently infected cell pools in a time sensitive manner. We analysed the response kinetics of these CTL in HIV infected subjects with slow disease progression.
Material and methods: Cyropreserved PBL of 21 HIV-1 infected subjects (median time of infection: 10 yrs, range: 6-22yrs) with different characteristics of disease progression were analysed. Non-progressing patients with good viral control (LTNP, n=11) were compared to a control group with progressive disease who received HAART according to current guidelines. Multiple samples were analysed longitudinally (range 1-6 years) by a specialized IFNg-ELISPOT assay using optimal B clade consensus peptides for HLA-A and B haplotypes derived from gag-/pol/-nef and/or env-regions. The individual CTL response kinetic was assessed by stopping the ELISPOT reaction after various time intervals (range: 30 min. to 24 hours) and were further characterized by tetramer staining.
Results: HLA-B57/58 and B27 haplotypes were evenly distributed in both groups (8/11 vs. 8/10). The B57-and B58-restricted CTL-responses against gag-epitopes were the immunodominant responses and were detected as early as 30min after peptide exposure. This rapid response pattern was conserved in LTNP (2 to 6 yrs of follow up). In contrast most of the HLA-A-restricted responses were only detectable after 24 hrs of in vitro stimulation suggesting a comparatively delayed response kinetic for non-B57/58 restricted epitopes in the control group. Staining with specific B57/B58 tetramers revealed the characteristic phenotype of effector memory CTL.
Conclusion: The dominance of B57/58 haplotypes in slowly progressing HIV-1 infection is not only explained by the breadth and magnitude of CTL-responses but also by preventing establishment of HIV-1 latency via targeting the virus life cycle very early at a pre-integrational level.

Datei SOEDAK_09_OSC2.pdf