MRC-University of Glasgow Centre for Virus Research

Intrinsic immunity to virus infection

Entry of HSV-1 genomes (red) into the infected cell nucleus triggers recruitment of cellular proteins, including PML (green) and Sp100 (blue), into closely associated foci.

The cellular mechanisms that confer intrinsic resistance to herpes simplex virus (HSV) and cytomegalovirus (CMV) are closely related and a number of cellular proteins are involved in defence against both viruses. Intrinsic resistance to HSV and CMV infection represses viral gene expression, resulting in the viral genome being retained in a quiescent state in the infected cell. CVR scientists have identified a group of proteins that contribute to intrinsic resistance to HSV and CMV; including PML, Sp100, hDaxx and ATRX. The repressive effects of these proteins are overcome by HSV-1 protein ICP0 and the combined effects of CMV proteins pp71 and IE1. Current studies are investigating the mechanisms underlying hDaxx and ATRX mediated repression of HSV and CMV infection; the attributes of PML and Sp100 that contribute to the repression of HSV gene expression; the molecular mechanisms underlying ICP0 mediated targeting of PML and other proteins for degradation; and detailed analyses of the E3 ubiquitin ligase activity of ICP0 and related orthologues.

Intrinsic immunity to retroviral infection occurs at several stages of the replicative cycle: entry is targeted by tripartite motif-containing proteins such as TRIM5; hypermutation of the viral genome during reverse transcription is mediated by the APOBEC family of cytidine deaminases; and the release of nascent virus particles is prevented by BST-2/tetherin. CVR researchers are studying the role of intrinsic factors in host intrinsic immunity to retroviral infection in ovids and felids:

  • Sheep harbour at least 27 copies of endogenous betaretroviruses (enJSRVs), highly related to the oncogenic Jaagsietke sheep retrovirus (JSRV). JSRV late restriction (JLR) acts to repress viral replication and is due to the dominant negative action of two enJSRV proviruses.
  • Feline immunodeficiency virus (FIV) invaded the domestic cat population relatively recently, lions and pumas are thought to have co-existed with FIV for hundreds of thousands of years and thus offer an insight into the likely endpoint for lentivirus-host co-evolution and the future for the global AIDS epidemic. Novel approaches to anti-lentiviral gene therapy are being evaluated with the synthesis of a feline TRIM5-cyclophilin A gene fusion (TRIMCyp), a potent inhibitor of HIV-1 and FIV infection.