Guanylate binding protein 5: Impairing virion infectivity by targeting retroviral envelope glycoproteins

Abstract

Guanylate binding proteins (GBPs) are interferon-inducible cellular factors that belong to the superfamily of guanosine triphosphatases (GTPases) and play important roles in the cell-intrinsic defense against bacteria, protozoa and viruses. In a recent report in Cell Host & Microbe, we identify GBP5 as novel restriction factor of HIV-1 that reduces the infectivity of progeny virions by interfering with processing and incorporation of the viral envelope (Env) glycoprotein. The inhibitory activity of GBP5 requires C-terminal isoprenylation, mediating Golgi-association, but not its GTPase function. Notably, GBP5 expression levels vary considerably in human macrophages and inversely correlate with infectious virus yield. We demonstrate that GBP5 can be evaded by an unusual tradeoff mechanism: Naturally occurring mutations in the start codon of the viral accessory gene vpu attenuate GBP5 inhibition by increasing Env expression at the cost of Vpu function. Whether direct counteraction mechanisms or more subtle changes balancing Vpu and Env expression also affect HIV-1 inhibition by GBP5 remains to be clarified. Other open questions are whether GBP5 restricts HIV-1 in CD4⁺ T cells and if other GBP family members also decrease infectivity of HIV and/or additional enveloped viruses.

Keywords: Env; GBP5; HIV-1; IFN; restriction factor; vpu.

Figure 1.

Antiviral factors targeting the Env glycoprotein. GBP5 and 90K reduce the infectivity of progeny virions by impaired processing of the gp160 precursor, resulting in reduced incorporation of mature gp120/gp41. The membrane-associated protein MARCH8 downmodulates Env from the cell surface, thereby preventing its incorporation into budding virions.

Figure 2.

Regulation of env expression. Simplified depiction of the HIV-1 genome highlighting different regulatory mechanisms (red stars) to modulate env expression from bicistronic vpu/env mRNAs: (1) The non-coding rev1-vpu intergenic region determines the strength of the vpu Kozak sequence and balances vpu and env expression. (2) The minimal open reading frame (ORF) upstream of the vpu start codon contributes to efficient downstream env translation. (3) A defective vpu start codon allows immediate translation of env. (4) The Kozak consensus upstream of the env start codon determines transcription efficiency. (5) A positively charged amino acid at position 12 of the Env signal peptide (SP) is associated with efficient Env production and trafficking in transmitted-founder viruses.