The structure of simian immunodeficiency virus (SIV) matrix and the role of a suppressed membrane component myristyl switch mechanism

Examining the differences and similarities between HIV and SIV retroviral replication systems is important in light of the fact that SIV animal models are used in the development and testing of HIV eradicating drugs and vaccines. One such difference may be the efficiency of Gag directed viral assembly. Studies with HIV-1 Gag have shown that during the late phase retroviral replication, 1,500-5,000 copies of Gag are targeted to lipid raft sites on the plasma membrane for new virus production.2; 3; 4 The role of MA as a domain of Gag/Gag-Pro-Pol is crucial for viral particle assembly and budding through the synergistic properties of the myristate group and positively charged basic residues of the N-terminus.;Work done by Tang et al.5 demonstrated myristylated [myr(+)] HIV-1 MA exists in an equilibrium between a monomeric and trimeric state. Concentration dependent assays done with 2D 1H, 15N-HSQC NMR showed the chemical shift progression of myr(+) HIV-1 MA towards the unmyristylated [myr(-)] HIV-1 MA structure with increasing concentrations of myr(+) MA. Analytical ultracentrifugation data revealed that myr(-) HIV-1 MA exists as a monomer while the myr(+) HIV-1 MA construct fits a monomer-trimer equilibrium. Together these data demonstrate that myr(+) HIV-1 MA exists in a monomer-trimer equilibrium that is shifted towards the myr(e) state as myr(+) HIV-1 MA becomes more concentrated.;More recently Saad et al.6; 7 has published two structures showing myr(+) HIV-1 and HIV-2 MA proteins complexed with a PI(4,5)P2, a phosphoinositide found in the plasma membrane. 6; 7 Interestingly however, PI(4,5)P2 was shown to induce myristate exposure for HIV-1, but not for HIV-2. Furthermore, myr(+) HIV-2 MA was found not to have a concentration dependent mechanism for myristate exposure unlike HIV-1 MA.7 Based on the myr(+) HIV-1 MA/di-C 4-PI(4,5)P2 structure, a trimeric membrane model was proposed that suggested that the myristate group and PI(4,5)P2 act to anchor Gag into the plasma membrane during viral assembly.6;In our analysis of the SIV MA structure, we have found that SIV MA shows the same behavior as HIV-2 rather than HIV-1 MA protein. While the pathogenicity and overall structure remains similar to HIV-1, myr (+) SIV MA does not undergo either a concentration dependent or PI(4,5)P2 induced myristyl switch. Such differences are important in determining what other structural or cellular factors may be important for efficient viral Gag assembly.