Guanylate binding protein 5 is an interferon-inducible inhibitor of HIV-1 infectivity
HIV is inhibited at multiple steps of its replication cycle by different cellular restriction factors, for instance APOBEC3G, Trim5-alpha or Tetherin. HIV restriction factors share common characteristics, such as interferon inducibility and evolution under positive selection pressure. In a genome wide screen, we showed that the large guanosine triphosphatase (GTPase), guanylate binding protein 5 (GBP5) shares these signatures. GTPases have been found to inhibit a wide variety of intracellular bacteria, parasites and viruses. This study shows that GBP5 potently inhibits HIV-1, by interfering with the infectivity of progeny virus. GBP5 is expressed in CD4+ T-cells as well as in macrophages, and it is further induced by interferons. It alters glycosylation and proteolytic processing of the HIV envelope protein (Env), thereby reducing Env incorporation and the fusogenic capacity of progeny virions. Mutational analyses show that GTPase activity of GBP5 is not required for its anti-HIV activity. However, the isoprenylation of GBP5 is essential for restriction of HIV. The endogenous levels of GBP5 in macrophages show a high inter-donor variation. Analysis of macrophages from 19 donors revealed a striking inverse correlation between GBP5 levels and infectious HIV-1 yield. In addition, siRNA-mediated knockdown of GBP5 in those macrophages strongly increased the infectivity of progeny virus. Notably, naturally occurring mutations in the vpu gene of HIV led to partial resistance against GBP5, due to increased Env translation in those viruses. This thesis provides a plausible explanation for the pronounced donor variation in the susceptibility of macrophages to HIV-1 replication and the high frequency of disrupted vpu genes in macrophage-tropic HIV-1 strains. In conclusion, GBP5 is a novel cellular antiviral effector of the IFN response that impairs the infectivity of retroviral particles and is evaded by mutations in vpu increasing viral envelope glycoprotein expression.
Subject HeadingsAids [GND]
Acquired immunodeficiency syndrome [MeSH]