Nebraska Center for Virology and the School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
Wistar Institute, Philadelphia, Pennsylvania, United States of America.
PLoS Pathog. 2018 Jan 19;14(1):e1006844. doi: 10.1371/journal.ppat.1006844. eCollection 2018 Jan.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS). It is endemic in a number of sub-Saharan African countries with infection rate of >50%. The high prevalence of HIV-1 coupled with late presentation of advanced cancer staging make KS the leading cancer in the region with poor prognosis and high mortality. Disease markers and cellular functions associated with KS tumorigenesis remain ill-defined. Several studies have attempted to investigate changes of the gene profile with in vitro infection of monoculture models, which are not likely to reflect the cellular complexity of the in vivo lesion environment. Our approach is to characterize and compare the gene expression profile in KS lesions versus non-cancer tissues from the same individual. Such comparisons could identify pathways critical for KS formation and maintenance. This is the first study that utilized high throughput RNA-seq to characterize the viral and cellular transcriptome in tumor and non-cancer biopsies of African epidemic KS patients. These patients were treated anti-retroviral therapy with undetectable HIV-1 plasma viral load. We found remarkable variability in the viral transcriptome among these patients, with viral latency and immune modulation genes most abundantly expressed. The presence of KSHV also significantly affected the cellular transcriptome profile. Specifically, genes involved in lipid and glucose metabolism disorder pathways were substantially affected. Moreover, infiltration of immune cells into the tumor did not prevent KS formation, suggesting some functional deficits of these cells. Lastly, we found only minimal overlaps between our in vivo cellular transcriptome dataset with those from in vitro studies, reflecting the limitation of in vitro models in representing tumor lesions. These findings could lead to the identification of diagnostic and therapeutic markers for KS, and will provide bases for further mechanistic studies on the functions of both viral and cellular genes that are involved.
卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）的病原体。它在撒哈拉以南的一些非洲国家流行，感染率>50%。HIV-1 的高流行率加上晚期出现晚期癌症分期，使 KS 成为该地区主要的癌症，预后不良，死亡率高。与 KS 肿瘤发生相关的疾病标志物和细胞功能仍未得到明确界定。几项研究试图通过体外感染单培养模型来研究基因谱的变化，但这可能无法反映体内病变环境的细胞复杂性。我们的方法是对 KS 病变与同一个体的非癌组织中的基因表达谱进行特征描述和比较。这种比较可以确定对 KS 形成和维持至关重要的途径。这是第一项利用高通量 RNA-seq 对非洲流行 KS 患者的肿瘤和非癌活检组织中的病毒和细胞转录组进行特征描述的研究。这些患者接受了抗逆转录病毒治疗，HIV-1 血浆病毒载量无法检测到。我们发现这些患者的病毒转录组存在显著的变异性，其中潜伏和免疫调节基因表达最为丰富。KSHV 的存在也显著影响了细胞转录组谱。具体而言，涉及脂质和葡萄糖代谢紊乱途径的基因受到了很大影响。此外，免疫细胞浸润到肿瘤中并没有阻止 KS 的形成，这表明这些细胞存在一些功能缺陷。最后，我们发现我们的体内细胞转录组数据集与体外研究的数据集之间只有最小的重叠，这反映了体外模型在代表肿瘤病变方面的局限性。这些发现可能导致 KS 的诊断和治疗标志物的确定，并为进一步研究涉及病毒和细胞基因的功能的机制研究提供基础。
