RELATIONSHIP BETWEEN TROPISM, INFECTIVITY, AND NEUTRALIZATION IN HIV

HIV 的趋向性、感染性和中和作用之间的关系

• 批准号: 6101183
• 负责人: K PEDEN
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6101183
• 关键词: CD4 molecule; HIV envelope protein gp120; HIV envelope protein gp41; gene mutation; genetic regulatory element; genetic strain; human immunodeficiency virus 1; human immunodeficiency virus 2; tissue /cell culture; transfection; virus RNA; virus genetics; virus infection mechanism; virus replication

The identification of chemokine receptors, in addition to CD4, as coreceptors for HIV entry, not only has contributed to the understanding on viral tropism but has provided an additional target for therapeutic intervention for HIV disease. Several chemokine receptors have been shown to function as coreceptors for HIV-1 entry. The main ones are CXCR4 (for T-cell line tropic viruses) and CCR5 (for macrophage-tropic viruses). Because of the capacity of HIV to adapt when selective pressures are imposed, it is likely that any drug designed to block the interaction of HIV with, say, CCR5 will force the virus to use additional coreceptors. Thus, the determination of the complete coreceptor repertoire will be necessary. In collaboration with Dr J. Farber, NIAID, we have been studying the possible role of an orphan chemokine receptor, STRL33, as coreceptor for HIV and SIV. Because the Farber laboratory had shown that this receptor is expressed on T cells and is present in all lymphoid tissues, it seemed reasonable to test STRL33 for coreceptor activity with HIV. We demonstrated that the expression of STRL33 in Jurkat cells conferred increased permissivity to infection by the ELI1 isolate of HIV-1. Thus, STRL33 can act as an HIV-1 coreceptor in vitro. As well as testing the coreceptor activity of STRL33 with a number of HIV-1 strains of different phenotypes, we have begun studies with HIV-2 and SIV. We have shown, in an infectivity assay, that the MAL strain of HIV-1 and the mac239 isolate of SIV use STRL33 but not as well as they use CCR5. The appearance of virus only after about 30 days in culture is indicative of adaptation. To confirm this, virus emerging after about 35 days was used to infect fresh Jurkat-STRL33 as well as the parent Jurkat cells. In this second passage, virus production was seen after about 12 days, thus demonstrating that both SIVmac239 and HIV-1 MAL had adapted to use STRL33 more efficiently. Importantly, these passaged viruses were still unable to infect Jurkat cells. We are currently determining the mutations that account for the adaptation. That the passaged virus had adapted to use STRL33 was demonstrated by the fact that an antibody raised to STRL33 inhibited virus infection. We plan to expand the study to additional SIV isolates and strains and to HIV-2, as well as looking at additional coreceptors such as APJ. Once a series of SIV variants that use different coreceptors for entry has been isolated and characterized, they could be used for in vivo studies to determine which coreceptors are used for transmission via different routes of infection. Using the Jurkat-STRL33 and Jurkat-CCR5 lines and HOS.CD4 lines that express individual coreceptors, we have tested primary isolates for their corecptor use. So far most primary isolates use CCR5 and only a few can use STRL33.

趋化因子受体的鉴定，除了CD4，作为