- Intrinsic immunity
Intrinsic immunity refers to a set of recently discovered
cellular based anti-viral defense mechanisms, notably genetically encodedproteins which specifically targeteukaryotic retroviruses. Unlike adaptive and innate immunity effectors, intrinsic immune proteins are always expressed at a constant level, allowing a viral infection to be halted quickly.Background
Eukaryotic organisms have been exposed to viral infections for millions of years. The development of the innate and adaptive immune system reflects the evolutionary importance of fighting
infection . Some viruses, however, have proven to be so deadly or refractory to conventional immune mechanisms that specific, genetically encoded cellular defense mechanisms have evolved to combat them. Intrinsic immunity comprises cellular proteins which are always active and have evolved to block infection by specific viruses or viraltaxa [cite journal|last=Bieniasz|first=Paul D|title=Intrinsic immunity: a front-line defense against viral attack|journal=Nature Immunology|volume=5|issue=11|url=http://www.nature.com/ni/journal/v5/n11/full/ni1125.html|year=2004|month=November|pages=1109–1115|doi=10.1038/ni1125] .The recognition of intrinsic immunity as a potent anti-viral defense mechanism is a recent discovery and is not yet discussed in most
immunology courses or texts. Though the extent of protection intrinsic immunity affords is still unknown, it is possible that intrinsic immunity may eventually be considered a third branch of the traditionally bipartiteimmune system .Relationship to the Immune System
Intrinsic Immunity combines aspects of the two traditional branches of the immune system - adaptive and innate immunity – but is mechanistically distinct. Innate cellular immunity recognizes viral infection using
toll-like receptors (TLRs), orpattern recognition receptors , which sensepathogen associated molecular patterns (PAMPs), triggering the expression of nonspecific antiviral proteins. Intrinsic immune proteins, however, are specific both in virus recognition and their mechanism of viralattenuation . Like innate immunity, however, the intrinsic immune system does not respond differently upon repeat infection by the same pathogen. Also, like adaptive immunity, intrinsic immunity is specifically tailored to a single type or class of pathogens, notablyretroviruses .Unlike adaptive and innate immunity, which must sense the infection to be turned on (and can in the case of adaptive immunity, take weeks to become effective) intrinsic immune proteins are constitutively expressed and ready to shut down infection immediately following viral entry. This is particularly important in retroviral infections since viral integration into the host
genome occurs quickly after entry andreverse transcription and is largely irreversible.Because the production of intrinsic immune mediating proteins cannot be increased during infection, these defenses can become saturated and ineffective if a cell is infected with a high level of virus.
Antiviral Activities of Canonical Intrinsic Immune Proteins
* TRIM5α (Tripartite interaction motif five, splice variant α) is one of the most studied intrinsic immune proteins due to its connection with
human immunodeficiency virus (HIV) andsimian immunodeficiency virus (SIV). This constitutively expressed protein recognizes thecapsid proteins of entering retroviruses and prevents viral uncoating and reverse transcription through an unknown mechanism. Therhesus monkey TRIM5α variant is able to recognize and prevent HIV infection, whereas thehuman TRIM5α protein can prevent SIV infection. This variation helps explain why HIV and SIV infect humans and monkeys respectively, and probably reflects a previousepidemic of what we now call HIV among ancestors of current rhesus monkey populations [cite journal|last=Stremlau|first=Matthew, et al.|title=The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys|journal=Nature|volume=427|url=http://www.nature.com/nature/journal/v427/n6977/abs/nature02343.html|year=2004|month=February|pages=848–853|doi=10.1038/nature02343] ..
*APOBEC3G (Apolipoprotein editing complex 3 G) is another intrinsic immune protein which interferes with HIV infection. APOBEC3G is acytidine deaminase against single strandedDNA which introducestransversion mutations into the HIV genome during reverse transcription by randomly changingcytidine basepairs intouracil . Thought this will not necessarily stop viral integration, the resulting progeny viral genomes are too riddled withmutations to be viable. APOBEC3G expression is disrupted by the HIV vif protein which induces its degradation through theubiquitin /proteasome system. If an HIVΔvif deletion mutant is created it will be able to infect a cell, but will produce non-viable progeny virus due to the action of APOBEC3G [cite journal|last=Sheehy|first=Ann M. et al.|title=Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein|journal=Nature|volume=418|url=http://www.nature.com/nature/journal/v418/n6898/full/nature00939.html|year=2002|month=August|pages=646–650|doi=10.1038/nature00939] .Other intrinsic immune proteins have been discovered which block
Murine leukemia virus (MLV),Herpes simplex virus (HSV), andHuman Cytomegalovirus (HCMV). In many cases, such as that of APOBEC3G above, viruses have evolved mechanisms for disrupting the actions of these proteins. Another example is the cellular proteinDaxx , which silences viral promoters, but is degraded by an active HCMV protein early in infection [cite journal|last=Saffert|first=Ryan T, et al.|title=Inactivating a Cellular Intrinsic Immune Defense Mediated by Daxx Is the Mechanism through Which the Human Cytomegalovirus pp71 Protein Stimulates Viral Immediate-Early Gene Expression|journal=Journal of Virology|volume=80|issue=8|url=http://jvi.asm.org/cgi/content/full/80/8/3863?ck=nck|year=2006|month=January|pages=3863–3871|doi=10.1128/JVI.80.8.3863-3871.2006] .References
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