P35.02
Background: Maraviroc (MVC) is a CCR5 antagonist currently used for the treatment of HIV-1 and is being tested as a Pre-exposure prophylaxis prevention strategy. MVC resistance can occur, however the mechanisms behind its development are unclear. Elucidating these mechanisms will assist in the design of improved CCR5 antagonists for use in prevention and therapy.
Methods: Envs were cloned from plasma from two phase III MOTIVATE clinical trial participants, who developed phenotypically verified MVC resistance in vivo. Both participants were male with a similar duration of infection (14yrs). MVC resistance was characterised by measuring the maximal percent inhibition (MPI) and the ability of the Envs to recognise the MVC-bound confirmation of CCR5 (Affinofile assay). Tropism alterations for the infectivity of CD4+ T cell subsets and macrophages were characterised and CCR5 engagement of resistant Envs was tested for neutralization by sulfated peptide fragments of the CCR5 N-terminus.
Results: The MPI values and affinity profiling showed that these Envs displayed a divergent ability to recognise MVC-bound CCR5, characterised by either a relatively efficient (MPI ∼10%, less CCR5-dependant) or inefficient (MPI ∼90%, more CCR5-dependant) recognition. Only the MVC-resistant Env with efficient recognition of MVC-bound CCR5 (MPI ∼10%) displayed a tropism shift for CD4+ T cells characterized by a significant expansion of infected CM T cells, potentially affecting the HIV reservoir size and no change in macrophage infectivity. Interestingly, both resistant Envs were susceptible to neutralization by a sulphated peptide fragment of the CCR5 N-terminus.
Conclusions: Our results suggest that the pattern of HIV tropism alterations for susceptible cells can vary depending on the magnitude of MVC resistance. Despite divergent phenotypes of resistance, both Envs showed an increase reliance on sulfated CCR5 N-terminus residues, which could provide a new avenue to block HIV-1 entry through CCR5 N-terminus sulfopeptidomimetic drugs.
