Lisco Andrea, Grivel Jean-Charles, Biancotto Angélique, Vanpouille Christophe, Origgi Francesco, Malnati Mauro S, Schols Dominique, Lusso Paolo, Margolis Leonid B
Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, NIH, Bldg. 10, Rm. 9D58, 9000 Rockville Pike, Bethesda, MD 20892, USA.
J Virol. 2007 Jan;81(2):708-17. doi: 10.1128/JVI.01367-06. Epub 2006 Oct 25.
Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens that affect the clinical course of HIV disease. Here, we identified another virus, human herpesvirus 7 (HHV-7) that interferes with HIV type 1 (HIV-1) replication in human lymphoid tissue, where critical events of HIV disease occur. Like the closely related HHV-6, HHV-7 suppresses the replication of CCR5-tropic (R5) HIV-1 in coinfected blocks of human lymphoid tissue. Unlike HHV-6, which affects HIV-1 by upregulating RANTES, HHV-7 did not upregulate any CCR5-binding chemokine. Rather, the inhibition of R5 HIV-1 by HHV-7 was associated with a marked downregulation of CD4, the cellular receptor shared by HHV-7 and HIV-1. HHV-7-induced CD4 downregulation was sufficient for HIV-1 inhibition, since comparable downregulation of CD4 with cyclotriazadisulfonamide, a synthetic macrocycle that specifically modulates expression of CD4, resulted in the suppression of HIV infection similar to that seen in HHV-7-infected tissues. In contrast to R5 HIV-1, CXCR4-tropic (X4) HIV-1 was only minimally suppressed by HHV-7 coinfection. This selectivity in suppression of R5 and X4 HIV-1 is explained by a suppression of HHV-7 replication in X4- but not in R5-coinfected tissues. These results suggest that HIV-1 and HHV-7 may interfere in lymphoid tissue in vivo, thus potentially affecting the progression of HIV-1 disease. Knowledge of the mechanisms of interaction of HIV-1 with HHV-7, as well as with other pathogens that modulate HIV-1 replication, may provide new insights into HIV pathogenesis and lead to the development of new anti-HIV therapeutic strategies.
人类免疫缺陷病毒（HIV）感染常伴有其他病原体感染，这些病原体可影响HIV疾病的临床进程。在此，我们鉴定出另一种病毒——人类疱疹病毒7型（HHV - 7），它能在发生HIV疾病关键事件的人类淋巴组织中干扰1型人类免疫缺陷病毒（HIV - 1）的复制。与密切相关的HHV - 6一样，HHV - 7在人类淋巴组织共感染组中抑制CCR5嗜性（R5）HIV - 1的复制。与通过上调调节活化正常T细胞表达和分泌的趋化因子（RANTES）来影响HIV - 1的HHV - 6不同，HHV - 7不会上调任何与CCR5结合的趋化因子。相反，HHV - 7对R5 HIV - 1的抑制与CD4的显著下调有关，CD4是HHV - 7和HIV - 1共有的细胞受体。HHV - 7诱导的CD4下调足以抑制HIV - 1，因为用环三氮二磺酰胺（一种特异性调节CD4表达的合成大环化合物）使CD4发生类似程度的下调，会导致HIV感染受到抑制，这与在HHV - 7感染组织中观察到的情况相似。与R5 HIV - 1相反，CXCR4嗜性（X4）HIV - 1仅受到HHV - 7共感染的轻微抑制。对R5和X4 HIV - 1抑制的这种选择性是由HHV - 7在X4共感染组织而非R5共感染组织中的复制受到抑制所解释的。这些结果表明，HIV - 1和HHV - 7可能在体内的淋巴组织中相互干扰，从而可能影响HIV - 1疾病的进展。了解HIV - 1与HHV - 7以及其他调节HIV - 1复制的病原体的相互作用机制，可能为HIV发病机制提供新的见解，并引领新的抗HIV治疗策略的开发。
