P14. HIV-1 Elite Controllers maintain low frequency of CD4+ T cells expressing inhibitory markers associated with T cell exhaustion

Kajsa Noyan1, Mike R Betts2, Jan Vesterbacka3, Marcus Buggert2,4, Anders Sönnerborg1,3
Affiliates: 1Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden, 2Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA, 3Division of Infectious Diseases, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, 4Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

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Background
HIV-1 Elite Controllers (ECs) are a unique group of infected patients who contain viral replication for many years without antiretroviral therapy (ART). Less is known about the T cell dysfunction and exhaustion commonly associated with HIV-1 infection and disease progression, in the EC with natural viral control. Here, we investigate the expression of inhibitory markers (associated with T cell exhaustion) on different CD4+ T cell memory populations in ECs, and HIV-1 patients with or without ART.

Methods
19 ECs were recruited from clinics around Sweden as well as 19 ART-treated patients with viral suppression (<20 copies/ml), 8 untreated viremic patients with immunodeficiency and 17 healthy non-infected individuals (Table 1). CD4+ T cell exhaustion was determined by expression of PD-1, CTLA-4 and TIGIT on peripheral blood mononuclear cells by multiparametric flow cytometry (Figure 1a). T cell activation and other markers of T cell memory population and dysfunction were analyzed. Results were related to clinical parameters (e.g. CD4 T cell count, viral load).

Results
The inhibitory receptor expression pattern (defined by PD-1, CTLA-4 and TIGIT) in ECs was significantly different in ART-treated subjects compared to untreated viremic patients (Figure 1b and 1c). The pattern was found to vary across distinct memory CD4+ T cell subsets with central-, transitional- and effector memory T cells displaying the highest levels of all three makers. The expression pattern in ECs was not different to non-infected individuals. CD4+ T cells co-expressing all inhibitory markers were strongly correlated to T cell activation (CD38+HLA-DR+, r=0.81, p<0.0001) and clinical parameters (CD4 count (r=-0.48, p=0.0007), CD4/CD8 ratio (r=-0.37, p=0.011) and viral load (r=0.37, p=0.01)).

Conclusion
ECs are able to maintain lower expression levels than untreated and long-term treated patients and do not differ from healthy controls. Markers associated with T cell exhaustion varied among different CD4+ T cell subsets and highest levels were found in transitional memory T cells, which is one of the principal reservoirs for latent infection. Successful ART did not normalize levels of T cell exhaustion markers. Our finding confirms that ECs harbor a “healthy state” of CD4+ T cell subsets that might play part in maintenance of their control status.

P14-kajsa_noyan