The Persistence of HIV Diversity, Transcription, and Nef Protein in Kaposi's Sarcoma Tumors during Antiretroviral Therapy.
The Persistence of HIV Diversity, Transcription, and Nef Protein in Kaposi's Sarcoma Tumors during Antiretroviral Therapy.
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DOI：
10.3390/v14122774
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发表时间：
2022-12-13
期刊：
影响因子：
--
通讯作者：
McGrath MS
中科院分区：
文献类型：
--
作者：
Nolan DJ;Rose R;Zhang R;Leong A;Fogel GB;Scholte LLS;Bethony JM;Bracci P;Lamers SL;McGrath MS
流行性卡波西肉瘤 (KS) 的定义是人类疱疹病毒 8 (HHV-8) 和人类免疫缺陷病毒 (HIV) 的共同感染，是撒哈拉以南非洲地区的一个主要原因。抗逆转录病毒治疗 (ART) 显着降低发生 KS 的风险，对于 KS 患者，肿瘤通常仅通过 ART 即可消退。然而，由于未知的原因，大量 KS 病例并未得到缓解，甚至可能进展至死亡。为了探索 HIV 如何在 KS 肿瘤微环境中对 ART 做出反应，我们对 ART 治疗 180-250 天后出现无反应或进行性 KS 的 4 名乌干达研究参与者进行了 ART 前后从血浆、外周血单核细胞和肿瘤活检中分离的 DNA 和 RNA 中发现的 HIV env-nef 测序。我们进行了免疫组织化学实验，以检测匹配的福尔马林固定肿瘤活检中的病毒蛋白。我们的测序结果表明，尽管血浆病毒载量无法检测到，但 KS 肿瘤中的 HIV 多样性和 RNA 表达在 ART 后得以维持。 ART 后 KS 肿瘤中剪接的 HIV 转录本的存在与转录活性病毒库一致。免疫组织化学染色发现 KS 肿瘤中 HIV Nef 蛋白和组织驻留巨噬细胞共定位。总体而言，我们的结果表明，即使在 ART 将血浆 HIV 病毒载量降低至不可检测的水平并恢复免疫功能后，KS 肿瘤中的 HIV 仍然具有转录和翻译活性，这可能会影响肿瘤的维持和进展。
Epidemic Kaposi’s sarcoma (KS), defined by co-infection with Human Herpes Virus 8 (HHV-8) and the Human Immunodeficiency Virus (HIV), is a major cause of mortality in sub-Saharan Africa. Antiretroviral therapy (ART) significantly reduces the risk of developing KS, and for those with KS, tumors frequently resolve with ART alone. However, for unknown reasons, a significant number of KS cases do not resolve and can progress to death. To explore how HIV responds to ART in the KS tumor microenvironment, we sequenced HIV env-nef found in DNA and RNA isolated from plasma, peripheral blood mononuclear cells, and tumor biopsies, before and after ART, in four Ugandan study participants who had unresponsive or progressive KS after 180–250 days of ART. We performed immunohistochemistry experiments to detect viral proteins in matched formalin-fixed tumor biopsies. Our sequencing results showed that HIV diversity and RNA expression in KS tumors are maintained after ART, despite undetectable plasma viral loads. The presence of spliced HIV transcripts in KS tumors after ART was consistent with a transcriptionally active viral reservoir. Immunohistochemistry staining found colocalization of HIV Nef protein and tissue-resident macrophages in the KS tumors. Overall, our results demonstrated that even after ART reduced plasma HIV viral load to undetectable levels and restored immune function, HIV in KS tumors continues to be transcriptionally and translationally active, which could influence tumor maintenance and progression.
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