We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Characterization of a CXCR4 antagonist TIQ-15 with dual tropic HIV entry inhibition properties.
- Authors
Zhou, Zheng; Guo, Jia; Hetrick, Brian; Tiwari, Sameer; Haikerwal, Amrita; Han, Yang; Bond, Vincent C.; Huang, Ming B.; Mankowski, Marie K.; Snyder, Beth A.; Hogan, Priscilla A.; Sharma, Savita K.; Liotta, Dennis C.; Reid, Terry-Elinor; Wilson, Lawrence J.; Wu, Yuntao
- Abstract
The chemokine co-receptors CXCR4 and CCR5 mediate HIV entry and signal transduction necessary for viral infection. However, to date only the CCR5 antagonist maraviroc is approved for treating HIV-1 infection. Given that approximately 50% of late-stage HIV patients also develop CXCR4-tropic virus, clinical anti-HIV CXCR4 antagonists are needed. Here, we describe a novel allosteric CXCR4 antagonist TIQ-15 which inhibits CXCR4-tropic HIV-1 infection of primary and transformed CD4 T cells. TIQ-15 blocks HIV entry with an IC50 of 13 nM. TIQ-15 also inhibits SDF-1α/CXCR4-mediated cAMP production, cofilin activation, and chemotactic signaling. In addition, TIQ-15 induces CXCR4 receptor internalization without affecting the levels of the CD4 receptor, suggesting that TIQ-15 may act through a novel allosteric site on CXCR4 for blocking HIV entry. Furthermore, TIQ-15 did not inhibit VSV-G pseudotyped HIV-1 infection, demonstrating its specificity in blocking CXCR4-tropic virus entry, but not CXCR4-independent endocytosis or post-entry steps. When tested against a panel of clinical isolates, TIQ-15 showed potent inhibition against CXCR4-tropic and dual-tropic viruses, and moderate inhibition against CCR5-tropic isolates. This observation was followed by a co-dosing study with maraviroc, and TIQ-15 demonstrated synergistic activity. In summary, here we describe a novel HIV-1 entry inhibitor, TIQ-15, which potently inhibits CXCR4-tropic viruses while possessing low-level synergistic activities against CCR5-tropic viruses. TIQ-15 could potentially be co-dosed with the CCR5 inhibitor maraviroc to block viruses of mixed tropisms. Author summary: HIV uses the chemokine co-receptors CXCR4 or CCR5 for cell fusion and entry. While the CCR5-tropic viruses predominate early in HIV infection, the emergence of the CXCR4-tropic viruses at later stages in 50% of patients is associated with rapid disease progression. The CCR5 antagonist maraviroc has been approved for treating HIV infection. However, currently, there is no clinical anti-HIV CXCR4 inhibitor. Here we report a novel CXCR4 antagonist TIQ-15 that potently blocked CXCR4-tropic HIV infection of human CD4 T cells. TIQ-15 in combination with maraviroc also demonstrated synergistic activities against CCR5-tropic viruses and could be potentially used with maraviroc to block viruses of mixed tropisms.
- Subjects
CXCR4 receptors; HIV infections; CD4 antigen; CHEMOKINE receptors; VIRUS diseases
- Publication
PLoS Pathogens, 2024, Vol 20, Issue 8, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1012448