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- Title
Comparative transcriptome analysis of endemic and epidemic Kaposi's sarcoma (KS) lesions and the secondary role of HIV-1 in KS pathogenesis.
- Authors
Lidenge, Salum J.; Kossenkov, Andrew V.; Tso, For Yue; Wickramasinghe, Jayamanna; Privatt, Sara R.; Ngalamika, Owen; Ngowi, John R.; Mwaiselage, Julius; Lieberman, Paul M.; West, John T.; Wood, Charles
- 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. Author summary: Despite improved antiretroviral therapy (ART) coverage, Kaposi's sarcoma (KS) remains the most common cancer in people living with HIV/AIDS. KSHV is known to cause KS, but there are no preventive or curative vaccines. Our understanding of the interactions between KSHV, host cell and the microenvironment is lacking. HIV-1 co-infection has been implicated in KS pathogenesis, but its mechanistic role is unclear. We analyzed transcriptomes from lesions and uninvolved control skin from HIV-1-positive and -negative KS patients to determine the direct or indirect role of HIV-1 in KS development. Transcriptomes from the uninvolved control skin from KS subjects were indistinguishable from that of non-KS healthy individuals. This validates the use of uninvolved control skin to control for gene expression pattern in KS lesions. Despite high concordance in gene expression profiles between HIV-1-positive and -negative KS patients, a subset of genes involved in tumorigenesis and inflammation/immune responses showed higher magnitude of dysregulation in EnKS than EpKS patients. The trend toward lower magnitude of gene dysregulation in EpKS coupled with the absence of HIV-1-transcripts in EpKS suggests an indirect or systemic effect of HIV-1 to promote KS tumorigenesis and possibly explain the high KS incidence in regions with endemic KSHV and HIV-1 co-infections.
- Subjects
SUB-Saharan Africa; KAPOSI'S sarcoma; PATHOLOGY; GENE expression profiling; AIDS; GENE expression; HIV infection transmission; IMMUNOSUPPRESSION
- Publication
PLoS Pathogens, 2020, Vol 16, Issue 7, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1008681