Heterogeneity and Breadth of Host Antibody Response to KSHV Infection Demonstrated by Systematic Analysis of the KSHV Proteome

Nazzarena Labo,Denise Whitby,Mark N Polizzotto,Wendell Miley,Robert Yarchoan,Alexandra Turano,Thomas Uldrick,Dominic Esposito,Vickie Marshall,Kathleen M Wyvill,Rachel Bagni,William Gillette,Matthew Bess,Dirk P Dittmer

doi:10.1371/journal.ppat.1004046

Abstract

The Kaposi sarcoma associated herpesvirus (KSHV) genome encodes more than 85 open reading frames (ORFs). Serological evaluation of KSHV infection now generally relies on reactivity to just one latent and/or one lytic protein (commonly ORF73 and K8.1). Most of the other polypeptides encoded by the virus have unknown antigenic profiles. We have systematically expressed and purified products from 72 KSHV ORFs in recombinant systems and analyzed seroreactivity in US patients with KSHV-associated malignancies, and US blood donors (low KSHV seroprevalence population). We identified several KSHV proteins (ORF38, ORF61, ORF59 and K5) that elicited significant responses in individuals with KSHV-associated diseases. In these patients, patterns of reactivity were heterogeneous; however, HIV infection appeared to be associated with breadth and intensity of serological responses. Improved antigenic characterization of additional ORFs may increase the sensitivity of serologic assays, lead to more rapid progresses in understanding immune responses to KSHV, and allow for better comprehension of the natural history of KSHV infection. To this end, we have developed a bead-based multiplex assay detecting antibodies to six KSHV antigens.

Highlights

Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), primary effusion lymphoma (PEL) and a type of multicentric Castleman’s disease (MCD) [1,2,3]
We systematically expressed and purified 73 of the 85 proteins encoded by KSHV and analysed serologic responses in patients with KSHV-associated malignancies compared to healthy subjects
We identified significant reactivity to ORF38, ORF61, ORF59 and K5, in addition to the known K8.1, ORF73 and ORF65

Summary

Introduction

Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), primary effusion lymphoma (PEL) and a type of multicentric Castleman’s disease (MCD) [1,2,3]. KSHV is not ubiquitous in human populations. The prevalence of KSHV infection generally parallels the incidence of KS, and varies strikingly according to geography, ethnicity, and certain behavioral risk factors [4]. In South America, prevalence is high in Amerindians but not in nonAmerindians living in adjoining areas in comparable conditions [10,11]. In the US and Western Europe, prevalence is generally low but is elevated in men who have sex with men (MSM) [12,13] and in those born in certain areas of elevated KSHV prevalence [14]

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Conclusion