Abstract

In sub-Saharan Africa, endemic Kaposi’s sarcoma (EnKS) is still prevalent despite high incidence of epidemic Kaposi’s sarcoma (EpKS) resulting from the on-going HIV-1 epidemic. While KSHV is clearly the etiologic agent of KS, the mechanisms underlying KS development are not fully understood. For example, HIV-1 co-infection and concomitant immune dysfunction have been associated with EpKS development. However, the direct or indirect role(s) of HIV-1, and therefore of immune suppression, in EpKS remains unclear. How, or whether, EpKS is mechanistically distinct from EnKS is unknown. Thus, the absence of HIV-1 co-infection in EnKS provides a unique control for investigating and deciphering whether HIV-1 plays a direct or indirect role in the EpKS tumor microenvironment. We hypothesized that HIV-1 co-infection would induce transcriptome changes that differentiate EpKS from EnKS, thereby defining the direct intra-tumor role of HIV-1 in KS. Comparison of ART-treated and -naïve patients would further define the impact of ART on the KS transcriptome. We utilized RNA-seq followed by multiparameter bioinformatics analysis to compare transcriptomes from KS lesions to uninvolved control skin. We provide the first transcriptomic comparison of EpKS versus EnKS, ART-treated vs–naïve EpKS and male vs female EpKS to define the roles of HIV-1 co-infection, the impact of ART, and gender on KS gene expression profiles. Our findings suggest that ART-use and gender have minimal impact on transcriptome profiles of KS lesions. Gene expression profiles strongly correlated between EpKS and EnKS patients (Spearman r = 0.83, p<10−10). A subset of genes involved in tumorigenesis and inflammation/immune responses showed higher magnitude, but not unique dysregulation in EnKS compared to EpKS. While gender and ART had no detectable contribution, the trend toward higher magnitude of gene dysregulation in EnKS coupled with the absence of HIV-1 transcripts in EpKS may suggest an indirect or systemic effect of HIV-1 to promote KS tumorigenesis.

Highlights

  • Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gamma-herpesvirus associated with Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [1,2,3,4]

  • Despite improved antiretroviral therapy (ART) coverage, Kaposi’s sarcoma (KS) remains the most common cancer in people living with HIV/AIDS

  • HIV-1 co-infection has been implicated in KS pathogenesis, but its mechanistic role is unclear

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Summary

Introduction

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gamma-herpesvirus associated with Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [1,2,3,4]. In SSA, KSHV seroprevalence is generally high, ranging from 30% to 90% [5,9,10,11]. There are four major forms of KS, classical KS, iatrogenic KS, African-endemic KS (EnKS) and epidemic/HIV-1/AIDS-associated KS (EpKS) [16,17,18,19,20]. EnKS and EpKS are the most common forms in SSA. Before the HIV-1/AIDS epidemic, EnKS caused between 4–10% of sub-Saharan adult cancers [21,22,23]. Concomitant with the HIV-1/AIDS epidemic in SSA, EpKS surpassed EnKS to become one of the most common cancers in both genders, in whom it causes significant morbidity and mortality in the region [24,25,26,27]

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