The existence of
drug-resistant human immunodeficiency virus (HIV) viruses in patients receiving antiretroviral treatment urgently requires the characterization and development of new antiretroviral drugs designed to inhibit resistant viruses and to
complement the existing antiretroviral strategies against
AIDS. We assayed several natural or semi-synthetic
lupane-type
pentacyclic triterpenes in their ability to inhibit HIV-1
infection in permissive cells. We observed that the
30-oxo-calenduladiol triterpene, compound 1, specifically impaired R5-tropic HIV-1 envelope-mediated
viral infection and cell fusion in permissive cells, without affecting X4-tropic virus. This
lupane derivative competed for the binding of a specific anti-CCR5
monoclonal antibody or the natural
CCL5 chemokine to the CCR5 viral coreceptor with high affinity.
30-oxo-calenduladiol seems not to interact with the
CD4 antigen, the main HIV receptor, or the CXCR4 viral coreceptor. Our results suggest that compound 1 is a specific CCR5 antagonist, because it binds to the
CCR5 receptor without triggering cell signaling or receptor internalization, and inhibits
RANTES (regulated on activation normal T cell expressed and secreted)-mediated CCR5 internalization, intracellular
calcium mobilization, and cell chemotaxis. Furthermore, compound 1 appeared not to interact with
beta-chemokine receptors CCR1, CCR2b, CCR3, or CCR4. Thereby, the 30-oxo-calenduladiol-associated anti-HIV-1 activity against R5-tropic virus appears to rely on the selective occupancy of the
CCR5 receptor to inhibit CCR5-mediated HIV-1
infection. Therefore, it is plausible that the chemical structure of
30-oxo-calenduladiol or other related dihydroxylated
lupane-type triterpenes could represent a good model to develop more potent anti-HIV-1 molecules to inhibit
viral infection by interfering with early fusion and entry steps in the HIV life cycle.