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Kaposi sarcoma in ART-treated PLWH and HIV-uninfected people: differences in viral and immune characteristics

Title
Kaposi sarcoma in ART-treated PLWH and HIV-uninfected people: differences in viral and immune characteristics
Presenter
Léna Royston
Authors
L. Royston * (1,2,3), S. Isnard (4,1), A. Jary (5), C. Berini (1,6), J. Lin (2), J. Girouard (1,2), V. Leducq (5), V. Calvez (5), A.-G. Marcelin (5), J.-P. Routy (1,2,7)
Institutions
(1) Chronic Viral Illness Service, McGill University Health Centre, Montreal, Canada, (2) Research Institute of the McGill University Health Centre, Montreal, Canada, (3) Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland, (4) McGill University Health Centre, Montreal, Canada, (5) Sorbonne Université, INSERM, Institut Pierre Louis d''Epidémiologie et de Santé Publique, Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Pitié-Salpêtrière, Paris, France, (6) CONICET - Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Buenos Aires, Argentina, (7) Division of Hematology, McGill University Health Centre, Montreal, Canada

BACKGROUND: The incidence of HHV-8-induced Kaposi sarcoma (KS) in people living with HIV (PLWH) has dramatically decreased with antiretroviral therapy (ART). However, emergence of KS in ART-treated PLWH with restored CD4 and sustained HIV control is reported, raising concerns on HHV-8 pathogenesis and optimal management.
METHODS: We compared ART-treated PLWH with KS (KS ART+) and HIV-uninfected patients with classic KS (KS HIV-). We assessed CD4 and CD8 counts, anti-HHV-8 IgGs, gut permeability (LPS/I-FABP/Reg3) and senescence plasmatic markers (GDF15/suPAR). In PBMCs and skin biopsies, HHV-8 viral loads were quantified by digital-droplet PCR and positive samples are currently sequenced by next-generation sequencing. In skin biopsies, cells were isolated and analyzed by flow cytometry.
RESULTS: 11 KS ART+ and 11 KS HIV- have been recruited. KS ART+ were younger than KS HIV- (53 vs 77 years, p<0.001). Despite similar CD4 counts, KS ART+ had higher CD8 counts (p=0.007) and lower CD4/CD8 ratios (p=0.03). Gut permeability markers were similar while GDF15 and suPAR plasmatic levels were higher in KS HIV- (p=0.01). In PBMCs, HHV-8 DNA was detected in 6/11 KS ART+ while only in 3/11 KS HIV-. Anti-HHV-8 IgG titers tended to be higher in KS ART+ than KS HIV- (p=0.07). In skin biopsies, HHV-8 DNA was detected in all participant and isolated CD4 and CD8 T-cells highly expressed PD1 (>50%) in both groups. Among KS ART+, 3 HHV-8 strains were classified as subtype C and one as subtype A. In KS HIV-, 2 HHV-8 strains were classified as subtype A, 2 as subtype C and one strain, found in an Inuit patient from Northern Canada, constitutes a newly identified variant.
CONCLUSIONS: ART-treated PLWH with KS exhibited younger age and higher CD8 counts compared to HIV-uninfected KS patients. HHV-8 control seems altered in KS ART+, with HHV-8 DNA more frequently detected in PBMCs despite higher anti-HHV-8 IgG titers. Although still ongoing, HHV-8 sequencing revealed a new HHV-8 variant in an Inuit participant. Finally, PD1 expression on lymphocytes suggests T-cell dysfunction in skin lesions, constituting a potential therapeutical target. Such insights will help reducing KS-induced stigma and developing therapeutical strategies.

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