Abstract
BackgroundCD4 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. Together with CXCR4, CCR5 is one of the two co-receptors that interact with Env during virus entry, but the role of CCR5 in Env-induced pathogenesis is not clearly defined. We have investigated CD4 T cell depletion mechanisms caused by the Env of a highly pathogenic CXCR4/CCR5 dual-tropic HIV-1 isolate R3A.ResultsWe report here that R3A infection induced depletion of both infected and uninfected “bystander” CD4 T cells, and treatment with CCR5 antagonist 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-β 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.ConclusionWe 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 materialThe online version of this article (doi:10.1186/s12977-016-0255-z) contains supplementary material, which is available to authorized users.
Highlights
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
Supporting the functional relevance of CCR5 interaction by R3A-Env in CD4 T cells pathogenesis, we found that the inhibition of Env-CCR5 binding by CCR5 antagonistic drug TAK-779 reduced R3A-induced bystander CD4 T cells killing, whereas stimulation of the CCR5 receptor with agonistic drug
We provide the first evidence in two physiologically relevant HIV-1 infection models that shows CCR5 interaction with a dual-tropic HIV-1 Env plays a significant role in Env-induced depletion of bystander CD4 T cells
Summary
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. Multiple studies have attempted to explain the depletion of CD4 T cells during HIV-1 infection. This can be broadly categorized into killing of uninfected “bystander” CD4 T cells, and “direct” killing of HIV-infected CD4 T cells [2]. The rate of CD4 T cell decline is discordant with low level of productively infected cells in HIV-positive individuals. This suggests “direct” death of productively infected cells contributes minimally towards AIDS. HIV-1 strains can be broadly divided into two groups based on their Env tropism, each using CCR5 or CXCR4 chemokine co-receptor for viral entry. The CXCR4-tropic virus interacts with CD4 and CXCR4, infects CXCR4+ CD4 T cells, and is sensitive to CXCR4
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