Marshall W L, Brinkman B M, Ambrose C M, Pesavento P A, Uglialoro A M, Teng E, Finberg R W, Browning J L, Goldfeld A E
Center for Blood Research and Division of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
J Immunol. 1999 May 15;162(10):6016-23.
The level of ongoing HIV-1 replication within an individual is critical to HIV-1 pathogenesis. Among host immune factors, the cytokine TNF-alpha has previously been shown to increase HIV-1 replication in various monocyte and T cell model systems. Here, we demonstrate that signaling through the TNF receptor family member, the lymphotoxin-beta (LT-beta) receptor (LT-betaR), also regulates HIV-1 replication. Furthermore, HIV-1 replication is cooperatively stimulated when the distinct LT-betaR and TNF receptor systems are simultaneously engaged by their specific ligands. Moreover, in a physiological coculture cellular assay system, we show that membrane-bound TNF-alpha and LT-alpha1beta2 act virtually identically to their soluble forms in the regulation of HIV-1 replication. Thus, cosignaling via the LT-beta and TNF-alpha receptors is probably involved in the modulation of HIV-1 replication and the subsequent determination of HIV-1 viral burden in monocytes. Intriguingly, surface expression of LT-alpha1beta2 is up-regulated on a T cell line acutely infected with HIV-1, suggesting a positive feedback loop between HIV-1 infection, LT-alpha1beta2 expression, and HIV-1 replication. Given the critical role that LT-alpha1beta2 plays in lymphoid architecture, we speculate that LT-alpha1beta2 may be involved in HIV-associated abnormalities of the lymphoid organs.
个体内持续的HIV-1复制水平对HIV-1发病机制至关重要。在宿主免疫因子中，细胞因子肿瘤坏死因子-α（TNF-α）先前已被证明可在各种单核细胞和T细胞模型系统中增加HIV-1复制。在此，我们证明通过肿瘤坏死因子受体家族成员淋巴毒素-β（LT-β）受体（LT-βR）进行的信号传导也调节HIV-1复制。此外，当不同的LT-βR和肿瘤坏死因子受体系统同时被其特异性配体激活时，HIV-1复制受到协同刺激。而且，在生理共培养细胞测定系统中，我们表明膜结合的TNF-α和LT-α1β2在调节HIV-1复制方面与其可溶性形式的作用几乎相同。因此，通过LT-β和TNF-α受体的共信号传导可能参与了HIV-1复制的调节以及随后单核细胞中HIV-1病毒载量的确定。有趣的是，LT-α1β2的表面表达在急性感染HIV-1的T细胞系上上调，这表明HIV-1感染、LT-α1β2表达和HIV-1复制之间存在正反馈回路。鉴于LT-α1β2在淋巴结构中所起的关键作用，我们推测LT-α1β2可能参与了HIV相关的淋巴器官异常。
