Abstract
CXC chemokine receptor 4 (CXCR4) is a co-receptor for HIV-1 entry into target cells. Its natural ligand, the chemokine SDF-1, inhibits viral entry mediated by this receptor. However, the broad expression pattern of CXCR4 and its critical roles in various physiological and pathological processes indicate that the direct application of SDF-1 as an entry inhibitor might have severe consequences. Previously, we constructed an effective SDF-1 mutant, SDF-1/54, by deleting the α-helix of the C-terminal functional region of SDF-1. Of note, SDF-1/54 shows remarkable decreased chemotoxic ability, but maintains a similar binding affinity to CXCR4, suggesting SDF-1/54 might better serve as a CXCR4 inhibitor. Here, we found that SDF-1/54 exhibited potent antiviral activity against various X4 HIV-1 strains, including the infectious clone HIV-1 NL4-3, laboratory-adapted strain HIV-1 IIIB, clinical isolates and even drug-resistant strains. By using time-of-addition assay, non-infectious and infectious cell–cell fusion assay and CXCR4 internalization assay, we demonstrated SDF-1/54 is an HIV-1 entry inhibitor. A combination of SDF-1/54 with several antiretroviral drugs exhibited potent synergistic anti-HIV-1 activity. Moreover, SDF-1/54 was stable and its anti-HIV-1 activity was not significantly affected by the presence of seminal fluid, vaginal fluid simulant and human serum albumin. SDF-1/54 showed limited in vitro cytotoxicity to lymphocytes and vaginal epithelial cells. Based on these findings, SDF-1/54 could have a therapeutic potential as an HIV-1 entry inhibitor.
Highlights
37 million people are currently living with human immunodeficiency virus type I (HIV-1)and approximately 2.1 million new infections per year continue to fuel the HIV-1 pandemic [1].Current anti-retroviral (ARV) therapies for HIV/AIDS containing three or more drugs from at least two different ARV categories are usually recommended for use in combination to better suppress virus replication and to minimize drug resistance
The potency and efficacy of stromal cell-derived factor-1 (SDF-1)/54 against CXC chemokine receptor 4 (CXCR4) tropic HIV-1 strains were determined in single-cycle infection assays and multiple-cycle infection assays, respectively
Because SDF-1/54 targets the co-receptor CXCR4, which is essential for viral entry, we validated its role as an HIV-1 entry inhibitor by a time-of-addition assay in which we studied the inhibitory activity of SDF-1/54 against CXCR4-tropic HIV-1 IIIB when it was added to cells at different intervals post-infection
Summary
37 million people are currently living with human immunodeficiency virus type I (HIV-1)and approximately 2.1 million new infections per year continue to fuel the HIV-1 pandemic [1].Current anti-retroviral (ARV) therapies for HIV/AIDS containing three or more drugs from at least two different ARV categories are usually recommended for use in combination to better suppress virus replication and to minimize drug resistance. 37 million people are currently living with human immunodeficiency virus type I (HIV-1). Approximately 2.1 million new infections per year continue to fuel the HIV-1 pandemic [1]. Current anti-retroviral (ARV) therapies for HIV/AIDS containing three or more drugs from at least two different ARV categories are usually recommended for use in combination to better suppress virus replication and to minimize drug resistance. Due to the long-term toxicity, high cost, drug-resistance and cross-resistance, HIV-1-infected patients might not be capable to keep a lifelong ARV treatment. There is an urgent need to develop new, efficient, safe and cheap anti-HIV-1 drugs. These entry inhibitors can be subdivided into three different classes, including (i) adhesion inhibitors, targeting the gp120-CD4 binding; (ii) co-receptor antagonists targeting
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