Glycoprotein K8.1 shapes KSHV liver and bone marrow tropism in the marmoset infection model

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus. Common marmosets, a potential non-human primate model for vaccine development and infection studies, have previously been shown to support KSHV infection. We established infection of marmosets with BAC-derived, recombinant KSHV to analyze the role of individual glycoproteins (GPs) in tissue tropism. Three groups of four animals were infected intravenously with BAC-derived KSHV wild type (wt), EphA2-receptor-binding-deficient KSHV gHASAELAAN, or KSHV{triangleup}K8.1, lacking glycoprotein K8.1. Viral DNA was detected in multiple tissues of all animals, with the highest loads in spleen, liver, heart, and bone marrow. In most tissues, viral DNA loads did not significantly differ between groups. However, KSHV{triangleup}K8.1-infected animals exhibited significantly lower KSHV DNA levels in liver and bone marrow. KSHV wt infection induced activation of CD4+ and CD8+ T-cells. In animals infected with KSHV wt, KSHV gHASAELAAN or KSHV{triangleup}K8.1, different B cell subpopulations expanded after infection, which suggests that the glycoproteins themselves or the cell tropism imparted by their presence or absence might shape the host response to KSHV. In summary, our findings demonstrate that neither the Eph receptor interaction nor GP K8.1 is essential for intravenous infection, but K8.1 critically contributes to KSHV tissue tropism in vivo.