Mutation in the Disordered Linker Region of Capsid Disrupts Viral Kinetics of a Neuropathogenic SIV in Rhesus Macaques

TRIM5α polymorphism in rhesus macaques (RM) limits the genetic pool of animals in which we can perform simian immunodeficiency virus (SIV) studies without first screening animals for permissive TRIM5α genotypes. We have previously shown that polymorphisms in the TRIM5α B30.2/SPRY domain impact the level of SIVsmm viremia in RM and that amino acid substitutions (P37S/R98S) in the capsid N-terminal domain (CA-NTD) enables the virus to overcome restriction in RMs with the restrictive homozygous TRIM5α(TFP/TFP) genotype. Since this genotype also negatively impacted the development of central nervous system (CNS) lesions in animals infected with the parental source of CL757, we sought to generate a TRIM5α(TFP/TFP)-resistant clone, SIV-804E-CL757-P37S/R98S (CL757-SS), using a similar strategy. Unexpectedly, viral replication of CL757-SS was impaired in RMs with either the permissive TRIM5α(TFP/Q) or the restrictive TRIM5α(TFP/TFP) genotype. Analysis of the virus which emerged in the latter animals led to the discovery of a preexisting mutation relative to other SIVs. This P146T substitution in a conserved disordered linker region in the C-terminal domain of capsid (CA-CTD) has been shown to inhibit proper formation of HIV-1 capsid particles. Restoration of this residue to proline in the context of the TRIM5α-SS escape mutations not only restored viral replication, but also enhanced the infectivity of our previously reported neurotropic clone, even in RMs with permissive TRIM5α genotypes. IMPORTANCE SIV infection of rhesus macaques has become a valuable model for the development of AIDS vaccines and antiretroviral therapies. Polymorphisms in the rhesus macaque TRIM5α gene can affect SIV replication, making it necessary to genetically screen macaques for TRIM5α alleles that are permissive for SIV replication. This limits the pool of animals that can be used in a study, thereby making the acquisition of animals needed to fulfill study parameters difficult. We have constructed a viral clone that induces neuroAIDS in rhesus macaques regardless of their TRIM5α genotype, while also highlighting the important role the disordered linker domain plays in viral infectivity.