Background:  Slow progression of HIV-1 infection is associated with B27- and B57-restricted cytotoxic T lymphocyte (CTL) responses directed against gag-derived epitopes. These responses against p24-epitopes are generated before the integration of proviral DNA occurs and might thus reduce the seeding of latently infected cell pools in a time sensitive manner. Thus we analysed the response kinetics of these CTL in HIV infected subjects with slow disease progression.

Methods:  Cyropreserved peripheral blood lymphocytes (PBL) of 12 HIV-1-infected subjects (median time of infection: 10 years, range 6 to 22 years) with different characteristics of disease progression were analysed. Patients with non-progressive disease and good viral control (LTNP, n = 8) in the absence of HAART were compared to a control group of patients who received HAART according to current treatment guidelines. Multiple samples were analysed longitudinally (range 1 to 6 years) by a specialized interferon-g (IFN-g) ELISpot assay using optimal B clade consensus peptides for HLA-A and B haplotypes derived from gag-, pol-, nef-, or env-regions. The individual CTL response kinetic was assessed by stopping the ELISpot reaction after various time intervals (range 30 minutes to 24 hours) and were further characterized by tetramer staining.

Results:  HLA-B57/58 and B44/B57 haplotypes were detected in 6 of 9 LTNP but in none of the controls. The B57- and B58-restricted CTL-responses against gag epitopes were the immunodominant responses in these patients. Less frequently B44-gag, B44-env, and B27-gag-restricted responses were detected in descending order. Only 1 patient showed an A02-restricted -env dominance. The B57- and B58-restricted gag-responses were detected as early as 30 minutes after peptide exposure in vitro and gradually increased thereafter. This rapid response pattern was conserved in 5 of 7 LTNP for more than 2 years and lasted as long as 6 years of follow-up. In contrast most of the HLA-A-restricted responses were only detectable after 24 hours 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.

Conclusions:  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.