Question

The author’s state, “the compound inhibited R5 HIV-1 replication”. Does the evidence the authors present justify this conclusion? Why or why not?

study comes from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC21923/

Answer 1

Yes the evidence the authors present justifies the conclusion. The compound specifically inhibits the R5 HIV-1 replication.

The inhibition of chemokine receptors by TAK-779 appears to be specific to CCR5 because it was highly inhibitory to the binding of [125I]-RANTES to CHO/CCR5 cells and, to a less extent, to the binding of [125I]-monocyte chemotactic protein-1 to CCR2b. Furthermore, chemokine binding to neither CCR1, CCR3, CCR4, nor CXCR4 was inhibited by the compound. The inhibitory effect of TAK-779 was shown to be selective for CCR5 and not for RANTES because the compound had no effect on [125I]-RANTES binding to CCR1 and RANTES-induced Ca2+ mobilization in CHO/CCR1 cells. The specificity of TAK-779 to CCR5 seems extremely important from a chemotherapeutic viewpoint because nonspecific inhibition of β-chemokine receptors may generate serious side effects associated with chemokine dysregulation. Although some HIV-1 isolates can use CCR3 as an alternative coreceptor for their entry into the host cells, in particular, macrophages and microglia, the contribution of CCR3 to HIV-1 infection and pathogenesis in vivohas not fully been elucidated.

Unlike RANTES and aminooxypentane-RANTES, TAK-779 did not induce the internalization of CCR5. However, TAK-779 could suppress the binding of the anti-CCR5 mA 45531.111 (R & D Systems) to CHO/CCR5 cells, suggesting the direct interaction between the compound and CCR5. Because the monoclonal antibody was directed to the second extracellular loop of seven-transmembrane receptor CCR5, TAK-779 may have interaction with this extracellular loop. Alternatively, TAK-779 may induce a conformational change of the second extracellular loop after binding to a different part of CCR5. Of interest, TAK-779 did not inhibit the binding of another anti-CCR5 mAb, 2D7 (PharMingen), to CHO/CCR5 cells (experiments and data not shown), although 2D7 also recognizes the second extracellular loop of CCR5. The exact site on CCR5 molecule targeted by the compound remains to be determined.