Background CD4 T cell depletion during HIV-1 infection is associated with AIDS disease progression, and the HIV-1 Env protein plays an important role in the process

Background CD4 T cell depletion during HIV-1 infection is associated with AIDS disease progression, and the HIV-1 Env protein plays an important role in the process. TAK-779 inhibited R3A-induced bystander CD4 T cell depletion without affecting virus replication. To further define the role of Env-CCR5 interaction, we utilized an Env-mutant of R3A, termed R3A-5/6AA, which has lost CCR5 binding capability. Importantly, R3A-5/6AA replicated to the same level as wild type R3A by using CXCR4 for viral infection. We found the loss of CCR5 interaction resulted in a significant reduction of bystander CD4 T cells death during R3A-5/6AA infection, whereas stimulation of CCR5 with MIP1- increased bystander pathogenesis induced by R3A-5/6AA. We confirmed our findings using a humanized mouse model, where we observed similarly reduced pathogenicity of the mutant R3A-5/6AA in various lymphoid organs in vivo. Conclusion We provide the first evidence that shows CCR5 interaction with a dual-tropic HIV-1 Env played a significant role in Env-induced depletion of CD4 T cells. Electronic supplementary material The online version of this article (doi:10.1186/s12977-016-0255-z) contains supplementary materials, which is open to certified users. tropism, each using CXCR4 or CCR5 chemokine co-receptor for viral admittance. The CCR5-tropic HIV-1 Env interacts with CCR5 and Compact disc4, infects CCR5+ Compact disc4 T macrophages and cells, and is delicate to CCR5 antagonists such as for example TAK-779. Likewise, the CXCR4-tropic disease interacts with CXCR4 and Compact disc4, infects CXCR4+ Compact disc4 T cells, and it is delicate to CXCR4 antagonists such as for example AMD-3100 [7, 8]. Furthermore, dual-tropic HIV-1 strains have already been reported which are competent to utilize both CXCR4 and CCR5 for entry [9C12]. R5-tropic HIV-1 dominates through the early stages of HIV-1 infection. In later stages of infection, X4-tropic viruses emerge and are thought to be responsible for the accelerated decline of CD4 T cells and AIDS progression [13]. The highly pathogenic phenotype of late stage X4-viruses has been related to the abundant expression of CXCR4 in virtually all CD4 T cells, whereas CCR5-expressing CD4 T cells are mostly memory T cells [14]. However, in a significant proportion ( 50?%) of AIDS patients, there is no co-receptor switch detected and their AIDS associated viruses are exclusively R5-tropic [15, 16]. Therefore, CCR5-tropic HIV-1 viruses can lead to AIDS progression but the mechanism remains unclear. Previous reports have studied the pathogenic effect of HIV-1 Env binding to CCR5 by overexpression of R5-tropic Env on cell surface or by using recombinant R5-tropic gp120 proteins [4, 5, 17]. However, the pathogenic effect of R5-tropic Env has not been studied in HIV-1 infection models, or directly compared to HIV-1 viral load. In this report, we studied the Env pathogenicity of a highly pathogenic dual-tropic HIV-1 strain (R3A) derived from a rapid progressor [9]. The gene of R3A is highly pathogenic and has been used for HIV-1 pathogenesis studies [9C11]. The interaction of the V3 region of R3A-Env with the co-receptors and its specificity for either CCR5 or CXCR4 has been elucidated in a previous study [8]. We took advantage of a mutant R3A strain termed R3A-5/6AA from the study, Zinquin which has lost the ability to bind and utilize CCR5 but can still use CXCR4 for viral infection, therefore not affecting viral replication capability. Interestingly, the mutant R3A-5/6AA is less pathogenic then the wild type R3A substantially, as evidenced from the reduced CD44 amount of virus-mediated bystander Compact disc4 T cells depletion. Assisting the practical relevance of CCR5 discussion by R3A-Env Zinquin in Compact disc4 T cells pathogenesis, we discovered that the inhibition of Env-CCR5 binding by CCR5 antagonistic medication TAK-779 decreased R3A-induced bystander Compact disc4 T cells eliminating, whereas stimulation from the CCR5 receptor with agonistic medication MIP-1 improved the pathogenesis impact. We verified our results in vivo utilizing a humanized mouse model, and we noticed decreased bystander pathogenesis from the mutant R3A-5/6AA set alongside the crazy type R3A Zinquin disease in Compact disc4 T cells within the bloodstream, spleen and bone tissue marrow. We offer the first proof in two physiologically relevant HIV-1 disease models that presents CCR5 discussion having a dual-tropic HIV-1 Env takes on a.

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