P25-19. Increasing differences in CD8 T cell polyfunctionality between HLA-B*57-positive and –negative HIV patients followed from primary infection.

Scharf L [1], Tauriainen J [2], Olsen LR [3], Buggert M [2,4], Lund O [3], Deeks SG [5], Hecht FM [5], Karlsson AC [1]
Affiliates: [1] Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. [2] Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. [3] Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. [4] Department of Microbiology, University of Pennsylvania, Philadelphia, United States of America. [5] Department of Medicine, University of California, San Francisco, United States of America.

Background
During HIV infection, a small proportion of patients shows delayed disease progression in absence of treatment. The host genetic factor with the strongest association to this phenomenon is the MHC class I allele HLA-B*57, linking it to CD8 T cells. CD8 T cells mount an effective response against HIV upon infection and are critical for dampening the acute virus replication and the associated symptoms. However, the effectiveness of this response seizes during the chronic phase of the disease. This exhaustion of CD8 T cells is seen in multiple chronic virus infections, as well as cancer.
As HLA-B*57 is associated with delayed disease progression, we hypothesize, that HLA-B*57-restricted CD8 T cells retain their functions for a longer time, i.e. show delayed T cell exhaustion.

Methods
With the use of multicolor flow-cytometry, we compared the CD8 T cell responses of 6 HLA-B*57-positive and 6 HLA-B*57-negative HIV patients. All subjects remained untreated and were followed longitudinally from primary infection. After stimulation with HIV peptides, we simultaneously stained for 7 functional features of CD8 T cells, as well as the T-box transcription factors T-bet and Eomesodermin. The data were analyzed with FlowJo and SPICE software.

Results
We were able to show significant differences in the functional profile of CD8 T cell responses between HLA-B*57-positive and –negative HIV patients late, but not early during infection.

Conclusions
Differences between HLA-B*57-restricted and non- HLA-B*57-restricted are not apparent early (within the first year) during infection, but arise in the chronic phase of the disease. This is consistent with a role of delayed T cell exhaustion in HLA-B*57-positive HIV patients. This difference could be exploited within the highly discussed “shock and kill” approach, combining immunotherapy (similar to current efforts in cancer therapy) with latency reversing strategies. To move towards this goal, detailed knowledge of exhaustion as it happens during HIV infection is a prerequisite.