TRIM34 and TRIM5a co-operatively restrict primate lentiviruses

Abstract

Human immunodeficiency virus (HIV) and other lentiviruses adapt to new hosts by evolving to evade host-specific innate immune proteins that differ in sequence and often viral recognition between host species. Understanding how these host antiviral proteins, called restriction factors, constrain lentivirus replication and transmission is key to understanding the emergence of pandemic viruses like HIV-1. One such restriction factor is TRIM5α, which blocks replication by multimerizing onto the HIV core, inducing aberrant capsid uncoating. TRIM5α-mediated restriction requires multimerization of TRIM5α monomers. Human TRIM34, a paralogue of the well-characterized lentiviral restriction factor TRIM5α, was previously identified by our lab via CRISPR-Cas9 screening as a restriction factor of certain HIV and SIV capsids. Notably, TRIM34-mediated restriction requires TRIM5α. Thus, we propose that TRIM34 requires multimerization with TRIM5α to restrict lentiviral capsids. Here, we show that diverse primate TRIM34 orthologues from non-human primates can restrict a range of Simian Immunodeficiency Virus (SIV) capsids including SIVAGM-SAB, SIVAGM-TAN and SIVMAC capsids, which infect sabaeus monkeys, tantalus monkeys, and rhesus macaques, respectively. All primate TRIM34 orthologues tested, regardless of species of origin, were able to restrict this same subset of viral capsids. We demonstrate that TRIM5α is necessary, but not sufficient, for TRIM34-mediated restriction of these capsids, and that human TRIM5α functionally interacts with TRIM34 from different species. Finally, we find that both the TRIM5α SPRY domain, in particular the v1 loop, and the TRIM34 SPRY domain are essential for TRIM34-mediated restriction. These data suggest that TRIM34 is a conserved primate lentiviral restriction factor and that TRIM34 and TRIM5α interact with each other and capsids. This supports a model in which TRIM34 is a broadly conserved primate lentiviral restriction factor that acts in tandem with TRIM5α, such that together, these proteins can restrict capsids that neither can restrict alone. The goals of this work are to define the range of primate lentiviruses against which TRIM34 is active, identify determinants of antiviral specificity for TRIM34-mediated restriction, to identify domains of TRIM34 and TRIM5α that are required for lentiviral restriction. Ultimately, these studies can help lead to a better understanding of TRIM34’s role in host-pathogen evolutionary history.