In the early stage of HIV life cycle after viral fusion, one important function of the HIV capsid is to protect the viral genome from the detection by the host innate immune system. Studies have shown that pandemic HIV-1 (M) group could evade the host innate immune sensing and effectively infect macrophages while the infections by non-pandemic HIV-1 (O) group were much repressed [1]. Sequence analysis of the capsid (CA) proteins of HIV-1 (M) and HIV-1(O) revealed two important mutations: one is Q/Y mutation at residue 50 and another one is an Arg insertion at residue 120 in HIV-1 (O) CA. The two mutations have been identified to be closely related to the different infectivity of HIV-1 (M) and HIV-1 (O) in macrophages [1].
HIV-1 (M) CA hexamer with Q50 in sequence has adopted open/close conformations at its central channel while HIV-1 (O) CA hexamer with Y50 has only open conformation. This hexamer central channel is believed to be important for transporting nucleotides into HIV cores to fuel encapsidated DNA synthesis [2]. In HIV-1(O) CA hexamer structure (3 Å) [1] and high resolution HIV-1 (O) CA N-terminal domain (CA-NTD) structure (1.47 Å, this work), Arg120 forms salt bridges with Glu98 which resides in the cyclophilin A (CypA) binding loop. In HIV-1 (M) CA, the side chain of Glu98 points to the opposite direction and interacts with His87 in the same CypA binding loop.
CypA is a well-known HIV cofactor which binds to the capsid to stabilize the capsid lattice. The complex structure of HIV-1(O) CA-NTD with human CypA in this work shows clearly the interaction between the two proteins. CypA is also known as a peptidyl-prolyl isomerase which catalyses the cis/trans interconversion of the peptide bonds preceding proline. It has indeed converted the M-G-P peptide in HIV-1 (O) CA to a cis-peptide bonding to accommodate the CA loop in the binding site of CypA.