Combined antiretroviral therapy (cART) for HIV-1 dramatically slows disease progression among HIV⁺ individuals. Currently, lymphoma represents the main cause of death among HIV-1-infected patients. Detection of p17 variants (vp17s) endowed with B-cell clonogenic activity in HIV-1-seropositive patients with lymphoma suggests their possible role in lymphomagenesis. Here, we demonstrate that the clonogenic activity of vp17s is mediated by their binding to PAR1 and to PAR1-mediated EGFR transactivation through Gq protein. The entire vp17s-triggered clonogenic process is MMPs dependent. Moreover, phosphoproteomic and bioinformatic analysis highlighted the crucial role of EGFR/PI3K/Akt pathway in modulating several molecules promoting cancer progression, including RAC1, ABL1, p53, CDK1, NPM, Rb, PTP-1B, and STAT1. Finally, we show that a peptide (F1) corresponding to the vp17s functional epitope is sufficient to trigger the PAR1/EGFR/PI3K/Akt pathway and bind PAR1. Our findings suggest novel potential therapeutic targets to counteract vp17-driven lymphomagenesis in HIV⁺ patients.

针对 HIV-1 的联合抗逆转录病毒疗法 (cART) 显着减缓 HIV ⁺个人。目前，淋巴瘤是 HIV-1 感染患者死亡的主要原因。在 HIV-1 血清阳性淋巴瘤患者中检测到具有 B 细胞克隆形成活性的 p17 变体 (vp17s) 表明它们可能在淋巴瘤发生中发挥作用。在这里，我们证明 vp17s 的克隆形成活性是通过它们与 PAR1 的结合和通过 Gq 蛋白与 PAR1 介导的 EGFR 反式激活介导的。整个 vp17s 触发的克隆形成过程依赖于 MMP。此外，磷酸化蛋白质组学和生物信息学分析强调了 EGFR/PI3K/Akt 通路在调节促进癌症进展的几种分子中的关键作用，包括 RAC1、ABL1、p53、CDK1、NPM、Rb、PTP-1B 和 STAT1。最后，我们显示对应于 vp17s 功能表位的肽 (F1) 足以触发 PAR1/EGFR/PI3K/Akt 途径并结合 PAR1。我们的研究结果提出了新的潜在治疗靶点来对抗 HIV 中 vp17 驱动的淋巴瘤形成⁺患者。