Pathogenic effects of human herpesvirus 6 in human lymphoid tissue ex vivo
Pathogenic effects of human herpesvirus 6 in human lymphoid tissue ex vivo
复制标题
DOI：
10.1128/jvi.77.15.8280-8289.2003
复制
发表时间：
2003-08-01
影响因子：
5.4
通讯作者：
Lusso, P
中科院分区：
文献类型：
--
作者：
Grivel, JC;Santoro, F;Lusso, P
人疱疹病毒6 （HHV-6）是一种潜在的免疫抑制剂，已被认为是人类免疫缺陷病毒疾病进展中的辅助因子。然而，缺乏合适的实验模型阻碍了对hhv -6介导的免疫抑制机制的阐明。本研究利用离体淋巴组织研究HHV-6的细胞趋向性和致病机制。属于HHV-6亚群（A和B）的病毒株能够在没有外源刺激的情况下有效感染人类扁桃体组织片段。大多数表达病毒抗原的细胞是表达非幼稚表型的CD4(+) T淋巴细胞，而CD8(+) T细胞仅被HHV-6A有效感染。因此，HHV-6A感染导致CD4（+）和CD8(+) T细胞的耗竭，而在hfuv - 6b感染的组织中，CD4(+) T细胞主要耗竭。在HHV-6感染的组织中，不同细胞抗原的表达显著改变：CD4上调，CD46（作为HHV-6的细胞受体）和CD3下调。然而，CD3下调仅限于感染细胞，而CD46表达缺失是普遍存在的。此外，HHV-6感染显著增强了CC趋化因子RANTES的产生，而其他细胞因子和趋化因子仅轻微影响。这些结果在生理学相关的研究模型中首次提供了证据，证明HHV-6可以通过直接感染T淋巴细胞和调节关键膜受体和趋化因子严重影响次要淋巴器官的生理。
Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of human immunodeficiency virus disease. However, the lack of suitable experimental models has hampered the elucidation of the mechanisms of HHV-6-mediated immune suppression. Here, we used ex vivo lymphoid tissue to investigate the cellular tropism and pathogenic mechanisms of HHV-6. Viral strains belonging to both HHV-6 subgroups (A and B) were able to productively infect human tonsil tissue fragments in the absence of exogenous stimulation. The majority of viral antigen-expressing cells were CD4(+) T lymphocytes expressing a nonnaive phenotype, while CD8(+) T cells were efficiently infected only with HHV-6A. Accordingly, HHV-6A infection resulted in the depletion of both CD4(+) and CD8(+) T cells, whereas in HFUV-6B-infected tissue CD4(+) T cells were predominantly depleted. The expression of different cellular antigens was dramatically altered in HHV-6-infected tissues: whereas CD4 was upregulated, both CD46, which serves as a cellular receptor for HHV-6, and CD3 were downmodulated. However, CD3 downmodullation was restricted to infected cells, while the loss of CD46 expression was generalized. Moreover, HHV-6 infection markedly enhanced the production of the CC chemokine RANTES, whereas other cytokines and chemokines were only marginally affected. These results provide the first evidence, in a physiologically relevant study model, that HHV-6 can severely affect the physiology of secondary lymphoid organs through direct infection of T lymphocytes and modulation of key membrane receptors and chemokines.