Ex vivo modeling of the effects of mycophenolic acid on HIV infection:: Considerations for antiviral therapy
Ex vivo modeling of the effects of mycophenolic acid on HIV infection:: Considerations for antiviral therapy
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DOI：
10.1089/aid.2005.21.116
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发表时间：
2005-02-01
影响因子：
1.5
通讯作者：
Margolis, D
中科院分区：
文献类型：
--
作者：
Kaur, R;Klichko, V;Margolis, D
霉酚酸酯（Mycophenolatemofetil，MMF）是霉酚酸（Mycophenolicacid，MPA）的生物可利用形式，已被提议作为人类免疫缺陷病毒1型（humanimmunodeficiencyvirustype 1，HIV-1）感染的辅助治疗。MPA可以抑制病毒复制，并可能钝化病毒诱导的免疫病理学。然而，这种抑制剂的其他作用可能对HIV感染患者有害。因此，我们研究了MPA对选定的与HIV感染相关的细胞过程的影响。我们发现，MPA并没有改变的主要HIV辅助受体CCR 5的表达在初级静息淋巴细胞，但适度增加CCR 5的表达后激活。相反，MPA适度降低静息淋巴细胞中CCR 5配体RANTES的分泌，但激活后无影响。研究表明，使用宿主核苷代谢抑制剂可能会增强HIV-1核苷逆转录酶抑制剂（NRTI）诱导的临床毒性。我们没有发现证据表明MPA诱导线粒体功能障碍或增强线粒体毒性的HepG 2细胞系模型中NRTI诱导的功能障碍。此外，MPA没有选择性地增强HIV-1感染的淋巴细胞的凋亡。我们的研究结果支持测试的霉酚酸酯，以加强抑制病毒复制。然而，需要进行仔细的研究，以证明当不使用抗逆转录病毒治疗时，MMF对抑制残余复制或清除潜伏感染的非活化细胞池是有益的。
Mycophenolate mofetil (MMF), the bioavailable form of mycophenolic acid (MPA), has been proposed as adjuvant therapy for human immunodeficiency virus type 1 (HIV-1) infection. MPA can inhibit viral replication and might blunt virus-induced immunopathology. However, other effects of this inhibitor might be detrimental in an HIV-infected patient. We therefore studied the effect of MPA on selected cellular processes of relevance to HIV infection. We found that MPA did not alter the expression of the primary HIV coreceptor CCR5 on primary resting lymphocytes, but modestly increased CCR5 expression after activation. Conversely, MPA modestly decreased the secretion of the CCR5 ligand RANTES in resting lymphocytes, but had no effect after activation. It has been suggested that the use of inhibitors of host nucleoside metabolism may enhance clinical toxicities induced by HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs). We found no evidence that MPA induced mitochondrial dysfunction or enhanced dysfunction induced by NRTIs in an HepG2 cell line model of mitochondrial toxicity. Further, MPA did not selectively enhance apoptosis in HIV-1-infected lymphocytes. Our findings support the testing of MMF to augment suppression of viral replication. However, careful study will be required to demonstrate that MMF is beneficial when used without antiretroviral therapy, to inhibit residual replication, or to deplete the pool of latently infected nonactivated cells.