Trim5-alpha/APOBEC Control of Retroviral Pathogens
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Mammals express proteins such as Trim5 alpha or APOBEC that inhibit retroviral replication.
Trim5 alpha, a splice variant of the Trim5 gene (found in a cluster with 3 other Trim genes in hominids) inhibits retroviral replication after these viruses in a species-specific manner after these have entered primate cells. The precise mechanism remains unknown, but it includes binding to the incoming retroviral capsid. Trim5 alpha from different primate species show selective restrictive activities. Human, chimpanzee and bonobo Trim5 alpha all bear the same arginine at the critical 332 position of their C-terminal B30.2 domain. These proteins are highly restrictive of chimpanzee PTERV endogenous retrovirus, possibly explaining the absence of these endogenous retroviruses in humans. Gorilla, orangutan and gibbon Trim5 alpha have the ancestral glutamine residue at the 322 position. Gorilla Trim5a shows better restriction of HIV but orang and gibbon Trim5 alpha show no restriction activity against HIV1 or PtERV.
The mutually exclusive restrictive activity against HIV or PtERV demonstrated for human Trim5 alpha may indicate trade-offs between restriction of different retroviruses. Curiously, several Trim5a from old world monkeys and new world monkeys effectively restrict HIV1 in cell culture.
Another innate antiviral mechanism involves APOBEC proteins. There are 11 human APOBEC genes. These act as “nucleic acid mutators” by editing viral single stranded DNA and thus inducing hypermutation in the genome of viruses. How this innate host defense lowers the fitness of viruses is not exactly understood, but it possibly involves hypermutational demise of the retroviral quasispecies. APOBEC enzymes act as cytidine deaminases, mutating minus strand DNA of retroviruses from C to U as these undergo reverse transcription in the host cell. This results in a G to A mutation in the genomic sense strand. HIV1 Vif protein counteracts this host defense by inducing ubiquitination of APOBEC3G, leading to its proteolytic degradation rather than incorporation into nascent virions.
Human-chimpanzee differences in Trim5 alpha and APOBEC are minimal although both loci show extensive signs of a long history of positive selection across primate species, likely due to antagonistic co-evolution with ancestral retroviral genes. Thus differences in these innate viral defense systems are unlikely to explain the apparent difference in susceptibility to HIV1, which is a human adapted form of the chimpanzee lentivirus SIVcpz.
APOBEC proteins and intrinsic resistance to HIV-1 infection., , Philos Trans R Soc Lond B Biol Sci, 2009 Mar 12, Volume 364, Issue 1517, p.675-87, (2009)
Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein., , Science, 2007 Jun 22, Volume 316, Issue 5832, p.1756-8, (2007)
Ancient adaptive evolution of the primate antiviral DNA-editing enzyme APOBEC3G., , PLoS Biol, 2004 Sep, Volume 2, Issue 9, p.E275, (2004)