Viral Profiling Identifies Multiple Subtypes of Kaposi’s Sarcoma

Abstract

Kaposi’s sarcoma (KS), caused by KS-associated herpesvirus (KSHV), is the most common cancer among HIV-infected patients in Malawi and in the United States today. In Malawi, KSHV is endemic. We conducted a cross-sectional study of patients with HIV infection and KS with no history of chemo- or antiretroviral therapy (ART). Seventy patients were enrolled. Eighty-one percent had T1 (advanced) KS. Median CD4 and HIV RNA levels were 181 cells/mm3 and 138,641 copies/ml, respectively. We had complete information and suitable plasma and biopsy samples for 66 patients. For 59/66 (89%) patients, a detectable KSHV load was found in plasma (median, 2,291 copies/ml; interquartile range [IQR], 741 to 5,623). We utilized a novel KSHV real-time quantitative PCR (qPCR) array with multiple primers per open reading frame to examine KSHV transcription. Seventeen samples exhibited only minimal levels of KSHV mRNAs, presumably due to the limited number of infected cells. For all other biopsy samples, the viral latency locus (LANA, vCyc, vFLIP, kaposin, and microRNAs [miRNAs]) was transcribed abundantly, as was K15 mRNA. We could identify two subtypes of treatment-naive KS: lesions that transcribed viral RNAs across the length of the viral genome and lesions that displayed only limited transcription restricted to the latency locus. This finding demonstrates for the first time the existence of multiple subtypes of KS lesions in HIV- and KS-treatment naive patients.

Diagnosis and Treatment of Kaposi Sarcoma

“…At any given time only a low percentage of KS tumor cells replicate the virus, while the majority of cells only express the viral latent genes and viral latent miRNAs [19–21]. This gene expression pattern suffices to maintain KS lesions.…”

“…KSHV is necessary for KS development [26, 64]. All KSHV-infected cells transcribe so-called latent messenger RNAs and a minimal set of viral proteins [19, 21, 65]. The KSHV latency-associated nuclear antigen (LANA) has become the deciding diagnostic marker for KS.…”

HIV-associated malignancies in sub-Saharan Africa

“…Overall, heterogeneity among HIV-associated KS patients in SSA, including development of IRIS, remains poorly understood, and numerous groups are working to define KS subtypes and clinical implications more clearly. In Malawi, our group demonstrated the possible existence of KS subtypes defined by KSHV transcription either limited to latency loci or extending across the viral genome [31]. Other groups have provided novel descriptions of pediatric KS [32**–34], a distinct form of KS frequently characterized by lymphadenopathy and peripheral blood cytopenias, which is highly geographically restricted to SSA where HIV and KSHV are prevalent and both often acquired during childhood [35**].…”

Kaposi sarcoma, oral malformations, mitral dysplasia, and scoliosis associated with 7q34‐q36.3 heterozygous terminal deletion

“…Prior to emigrating to France, our patient resided for 12 years in Haiti and Guadalupe, both HHV-8 endemic regions, and infected with a Sub-Saharan African HHV-8 strain found in Sub-Saharan Africans or persons of such origin living outside of Africa. There exists some major HHV-8 genotypes, many of which are geographically restricted, with little evidence to support whether any genotype is more virulent or more associated with KS [Dittmer and Damania 2013; Hosseinipour et al, 2014; Meng et al, 1999; Tornesello et al, 2010; Zhang et al, 2001]. Hence, why this patient developed KS but not others with terminal 7q deletions may be secondary to 1) the region deleted, 2) previously reported patients with terminal 7q deletion were not infected by HHV-8, or 3) incomplete penetrance of KS at the age of their last follow-up.…”