Valganciclovir as Add-On Therapy Modifies the Frequency of NK and NKT Cell Subpopulations in Disseminated Kaposi Sarcoma Patients.

Abstract

Simple SummaryKaposi sarcoma is one disease that develops in people living with HIV with severe immunosuppression and impacts morbidity and associated mortality. This disease is currently treated with antiretroviral therapy and chemotherapy agents that can further contribute to immunosuppression in patients. Thus, searching for new therapies to induce a robust immune system activation in these patients is necessary. Herein, the frequency and phenotype of natural killer subpopulation cells in people living with HIV with Kaposi sarcoma were evaluated. After KS diagnosis, patients started antiretroviral therapy or valganciclovir plus antiretroviral therapy. Results showed that in patients treated with valganciclovir plus antiretroviral therapy, the expression of CD57 and CD27 proteins on natural killer cells was regulated, enhancing the immune response of the study cohort. This finding contributes to understanding more about the immune response of people living with HIV with Kaposi sarcoma.Human herpesvirus-8 infection (HHV-8) is the causative agent of Kaposi sarcoma (KS) and is highly prevalent among people living with HIV (KS/HIV). It has been reported that valganciclovir (VGC) reduces HHV-8 replication in KS/HIV patients. However, currently it is unclear if VGC modifies the frequency and induces changes in markers of immune regulation of immune cells necessary to eliminate HHV8-infected cells, such as Natural Killer (NK) and NK T cells (NKT). This study evaluated the effect of VGC used as antiviral HHV8 therapy in KS patients on the frequency of NK and NKT subpopulations based on the CD27 and CD57 expression, and the immunosenescence markers, PD-1 and KLRG1. Twenty KS/HIV patients were followed-up at baseline (W0), 4 (W4), and 12 weeks (W12) of the study protocol. Among them, 10 patients received a conventional treatment scheme (CT), solely antiretroviral therapy (ART), and 10 patients received a modified treatment regime (MT), including VGC plus ART. In both groups, bleomycin/vincristine was administrated according to the treating physician’s decision. The soluble levels of IL-15, PD-L1, PD-L2, and E-cadherin were quantified across the follow-up. Our results showed that the higher IL-15 levels and lower NK frequencies cells in KS/HIV patients reach almost normal values with both treatments regimes at W12. CD27+ NK and NKT cell frequencies increased since W4 on KS/HIV patients with MT. Furthermore, PD-1 expression decreased while KLRG1 increased on NK and NKT subpopulations at W12, and it is accompanied by increased PD-L1 plasma level since W4. Our study highlights the disruption of NK and NKT subpopulations in patients with KS/HIV and explores VGC treatment’s contribution to immune reconstitution during the first weeks of treatment.