Krambovitis Elias, Spandidos Demetrios A
Department of Applied Biochemistry and Immunology, Institute of Molecular Biology and Biotechnology, Vassilika Vouton, Heraklion 711 10, Crete, Greece.
Int J Mol Med. 2006 Jul;18(1):3-8.
The long asymptomatic phase of HIV infection is critical in the progression to AIDS. It probably reflects an ancestral relationship with lentiviruses stemming from the primate-simian immunodeficiency virus evolutionary pathway leading to an idiosyncratic immune tolerance, which needs to be understood if effective vaccines are to be rationally designed. The majority of CD4+ T cells that die due to HIV-1 in the asymptomatic phase are not infected with the virus. Transmission of the predominant HIV-1 R5 variants to T cells is mediated by infected monocyte-derived macrophages. The two cell populations come into intimate contact mainly in the lymph nodes during antigen presentation where there is also active viral replication. We propose that HIV exploits antigen presentation to access target T cells and evade immune surveillance. This is achieved at the assembly point of an immunological synapse between an antigen presenting, HIV-1-infected macrophage and a responding effector/memory CD4+ T cell. Viral envelope gp120 glycoproteins proximal to MHC II molecules cross-link with T cell CD4 molecules, thus establishing a supra molecular immuno-viral synapse. The interaction results in conformational changes of gp120 exposing its V3 domain. Ionic interaction of this domain with the synapse-recruited chemokine receptor CCR5 dimerizes the receptor triggering intracellular signals that contribute to T cell receptor transactivation pathways and subsequent enhancement of T cell activation. HIV-downregulated MHC II gives weak immune complexes. Disruption of the immuno-viral synapse before completion of cell entry is a frequent outcome condemning the responding T cell to a premature activation-induced T cell death. Information on the assembly, mechanistic and functional interactions at the immuno-viral synapses may well assist in elucidating new strategies to combat HIV infection.
HIV感染的长期无症状期在艾滋病进展过程中至关重要。这可能反映了与慢病毒的祖先关系，该关系源于灵长类动物 - 猿猴免疫缺陷病毒的进化途径，导致了一种特殊的免疫耐受，若要合理设计有效的疫苗，就需要了解这种耐受。在无症状期因HIV - 1死亡的大多数CD4 + T细胞并未感染该病毒。主要的HIV - 1 R5变体向T细胞的传播是由受感染的单核细胞衍生的巨噬细胞介导的。这两种细胞群体主要在淋巴结中抗原呈递过程中密切接触，而淋巴结中也存在活跃的病毒复制。我们提出，HIV利用抗原呈递来接触靶T细胞并逃避免疫监视。这是在抗原呈递的、被HIV - 1感染的巨噬细胞与应答效应/记忆CD4 + T细胞之间的免疫突触组装点实现的。靠近MHC II分子的病毒包膜gp120糖蛋白与T细胞CD4分子交联，从而建立超分子免疫病毒突触。这种相互作用导致gp120构象改变，暴露出其V3结构域。该结构域与突触招募的趋化因子受体CCR5的离子相互作用使受体二聚化，触发细胞内信号，这些信号有助于T细胞受体反式激活途径及随后T细胞活化的增强。HIV下调的MHC II产生较弱的免疫复合物。在细胞进入完成之前免疫病毒突触的破坏是常见的结果，这会使应答T细胞过早发生活化诱导的T细胞死亡。关于免疫病毒突触的组装、机制和功能相互作用的信息很可能有助于阐明对抗HIV感染的新策略。
