Sequencing of Kaposi’s Sarcoma Herpesvirus (Kshv) Genomes From Persons of Diverse Ethnicities and Provenances With Kshv-Associated Diseases Demonstrate Multiple Infections, Novel Polymorphisms, and Low Intra-host Variance

Authors

Vickie A Marshall
Elena M Cornejo Castro
Charles A Goodman
Nazzarena Labo
Isabella Liu
Nicholas C Fisher
Kyle N Moore
Ananthakrishnan Nair
Taina Immonen
Brandon F Keele
Mark N Polizzotto
Thomas S Uldrick
Yunxiang Mu
Tanuja Saswat
Laurie T Krug
Kevin M McBride
Kathryn Lurain
Ramya Ramaswami
Robert Yarchoan
Denise Whitby

Publication Date

7-1-2024

Journal

PLoS Patogens

Abstract

Recently published near full-length KSHV genomes from a Cameroon Kaposi sarcoma case-control study showed strong evidence of viral recombination and mixed infections, but no sequence variations associated with disease. Using the same methodology, an additional 102 KSHV genomes from 76 individuals with KSHV-associated diseases have been sequenced. Diagnoses comprise all KSHV-associated diseases (KAD): Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated large cell lymphoma (KSHV-LCL), a type of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). Participants originated from 22 different countries, providing the opportunity to obtain new near full-length sequences of a wide diversity of KSHV genomes. These include near full-length sequence of genomes with KSHV K1 subtypes A, B, C, and F as well as subtype E, for which no full sequence was previously available. High levels of recombination were observed. Fourteen individuals (18%) showed evidence of infection with multiple KSHV variants (from two to four unique genomes). Twenty-six comparisons of sequences, obtained from various sampling sites including PBMC, tissue biopsies, oral fluids, and effusions in the same participants, identified near complete genome conservation between different biological compartments. Polymorphisms were identified in coding and non-coding regions, including indels in the K3 and K15 genes and sequence inversions here reported for the first time. One such polymorphism in KSHV ORF46, specific to the KSHV K1 subtype E2, encoded a mutation in the leucine loop extension of the uracil DNA glycosylase that results in alteration of biochemical functions of this protein. This confirms that KSHV sequence variations can have functional consequences warranting further investigation. This study represents the largest and most diverse analysis of KSHV genome sequences to date among individuals with KAD and provides important new information on global KSHV genomics.

Keywords

Adult, Aged, Female, Humans, Male, Middle Aged, Castleman Disease, Ethnicity, Genome, Viral, Herpesviridae Infections, Herpesvirus 8, Human, Phylogeny, Polymorphism, Genetic, Sarcoma, Kaposi

DOI

10.1371/journal.ppat.1012338

PMID

39008527

PMCID

PMC11271956

PubMedCentral® Posted Date

7-15-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes