(P1) Features of early HIV-specific CD8 T cell responses in association with protective HLA-alleles

Författare/Medförfattare

Annika C Karlsson 1, Lydia Scharf 1, Johanna Tauriainen 1, Marcus Buggert 2,3, David J Nolan 4,5, Steven G Deeks 6, Marco Salemi 4, Frederick M Hecht 7

Affiliates

1 Department of Laboratory Medicine, Karolinska Institutet, 14186 Stockholm, Sweden; 2 Department of Medicine, Karolinska Institutet, 14186 Stockholm, Sweden 3 Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104-6076, USA 4 Department of Pathology, Immunology and Laboratory Medicine, University of Florida, FL 32610, USA 5 Bioinfoexperts LLC, Alachua, FL 32615, USA 6 Department of Medicine, University of California, San Francisco, San Francisco, CA 94110; 7Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA

Abstract

Background
While the relationship of protective HLA class I alleles (e.g. HLA-B*57:01) and HIV progression is well defined, the interaction of HLA-mediated protection and CD8 T-cell exhaustion is less well defined. To gain insight in the influence of HLA-B*57:01 on the deterioration of CD8 T-cell responses during HIV infection in the absence of antiretroviral treatment, we compared HLA-B*57:01-restricted HIV-specific CD8 T-cell responses to responses restricted by other HLA class I alleles longitudinally from early HIV infection.

Methods
Detailed characterization of polyfunctionality, differentiation phenotypes, transcription factor and inhibitory receptor expression on HIV-specific T cells were evaluated over the course of the infection in HLA-B*57:01-positive and –negative patient groups. All subjects were followed retrospectively from early chronic infection up to seven years while remaining off treatment (OPTIONS cohort).

Results
We find that HLA-B*57:01-restricted HIV-Gag-specific CD8 T-cell responses express lower frequencies of the inhibitory receptors PD1 and TIGIT than non-B*57:01-specific T-cells in early HIV-infection. No differences in the expression of the inhibitory receptors 2B4, CD160 and KLRG1 were detected. Albeit the function profiles, defined by the expression of CD107, GrzA, GrzB, IFNg, IL2, perforin, and TNF, are similar between the groups, the HLA-B*57:01-restricted CD8 T-cells are more prone to produce multi-functional combinations in early infection. Over time, the differential expression of the inhibitory receptors PD1 and TIGIT and functional combinations vanish in association with declining CD4 T-cell count.

Conclusions
While numerous mechanisms for delayed disease progression in HLA-B*5701-positive HIV-infected patients have been suggested, our findings suggest a detrimental influence of early TIGIT/PD-1 co-expression on HIV-specific CD8 T-cells. Studies of the immuno-pathological events that occur during HIV infection remain important to increase the quality of life of HIV-infected individuals. As T-cell exhaustion strikes the entirety of a patient´s T-cell population and the inhibitory networks include all hematopoietic cell types, targeted interference with these networks could improve not only the direct HIV burden, but also non-AIDS complications. Given the synergistic nature of TIGIT and PD-1, the co-expression of those inhibitory receptors should be considered when developing immunomodulatory therapies or vaccines for HIV.