Abstract
We have studied the effects associated with two single amino acid substitution mutations in HIV-1 capsid (CA), the E98A and E187G. Both amino acids are well conserved among all major HIV-1 subtypes. HIV-1 infectivity is critically dependent on proper CA cone formation and mutations in CA are lethal when they inhibit CA assembly by destabilizing the intra and/or inter molecular CA contacts, which ultimately abrogate viral replication. Glu98, which is located on a surface of a flexible cyclophilin A binding loop is not involved in any intra-molecular contacts with other CA residues. In contrast, Glu187 has extensive intra-molecular contacts with eight other CA residues. Additionally, Glu187 has been shown to form a salt-bridge with Arg18 of another N-terminal CA monomer in a N-C dimer. However, despite proper virus release, glycoprotein incorporation and Gag processing, electron microscopy analysis revealed that, in contrast to the E187G mutant, only the E98A particles had aberrant core morphology that resulted in loss of infectivity.
Highlights
The HIV-1 capsid protein (CA, p24) is the building block of the conical core structure of the virus. It is initially produced as a part of the Gag precursor (p55) and during or concomitant with the virus release, p55 is cleaved sequentially into the matrix (MA; p17), capsid, nucleocapsid (NC; p7) and p6 proteins [1,2]
Several studies have shown that mutations within the gag gene disrupt virus replication or infectivity [4,5,6,7,8] and the infectivity of HIV-1 is critically dependent on proper CA
Much of the assembly properties of HIV-1 CA were based on x-ray crystallographic data, NMR and in vitro assembly models, the importance of major homology region [10], the binding site for cyclophilin A (CypA) [11,12], and the CA dimer interfaces [13,14] are some of the functions in CA that have been characterised using mutational analysis
Summary
The HIV-1 capsid protein (CA, p24) is the building block of the conical core structure of the virus. In contrast to the E187G and wild-type, we found that the E98A virions were non-infectious in permissive CD4 positive H9 cells (Fig. 2B), despite being competent for particle assembly, normal processing of Gag and incorporating viral envelope glycoproteins.
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