Solunsisäisen luonnollisen immuniteetin osuudesta

TRIM-geenejä on on 77 ja näitä immunofiliinejä on  19  koodaavaa syklofili9iniä ja liuta pseudogeenejä sekä  FKBP-. ryhmää 18 geeniä sekä niitä parvuliineja 3.
TRIM ja cyklofiliinit sekä APOBEC kuuyluvat luonnollisen immuniteetin  solunsisäiseen komponenttiin, jolla pitäisi olla myös tehoa  kaikenlaista retromateriaalia vastaan.  vaikutta siltä että  suuret geeniresurssit ovat  ihmiskunnan genomissa  suurelta osin uinuvia ja sitten tulee niitä vaiheita että immunivaste ei pysty räätälöimään kokoon  hengissäpysyttävää  suojaa .
 Yhden  syklofiliinin huomasin muodostavan  RING-proteiinin kanssa  yhteisen  rakenteen , mutta kuuluu   UBOX-ryhmään E3 ubikitiiniligaaseja, jolla taas  ei ole sinkkiä.
 Antiretroviraaliseen  solunsisäiseen  luonnollisen immuniteetin  kilpeen kuuluu TRIM-proteiinit, APOBEC-proteiinit ja syklofiliinit.
 Näistä on paljon  artikkeleita netissä. Otan tähän linkkejä: 


(1)
 Intrinsic immunity (2004)
https://www.nature.com/articles/ni1125

Published: 20 October 2004 Intrinsic immunity: a front-line defense against viral attack
Paul D Bieniasz
Nature Immunology volume 5, pages1109–1115(2004) 

 

Abstract

In addition to the conventional innate and acquired immune responses, complex organisms have evolved an array of dominant, constitutively expressed genes that suppress or prevent viral infections. Two major cellular defenses against infection by retroviruses are the Fv1 and TRIM5 class of inhibitors that target incoming retroviral capsids and the APOBEC3 class of cytidine deaminases that hypermutate and destabilize retroviral genomes. Additional, less well characterized activities also inhibit viral replication. Here, the present understanding of these 'intrinsic' immune mechanisms is reviewed and their role in protection from retroviral infection is discussed.

 (2) Intrinsic immunity (2011)
  In:  Molecular Biosafety Margy S. Lambert BIOSHERM, Madison, Wisconsin
https://journals.sagepub.com/doi/pdf/10.1177/153567601001500210

The two main types of mammalian immune system mechanisms are innate and adaptive. Innate immunity is also found widely in other species including plants and non-mammalian animals. Antiviral innate defenses in humans are mediated by interferons, macrophages, and natural killer cells. Innate defenses against other types of pathogens involve numerous additional components such as neutrophils, eosiniphils, inflammatory media-tors, complement, mast cells, etc. Adaptive immunity comes into play when innate immunity is not sufficient to eradicate invading pathogens and involves protection through the development of a vast array of non-self receptors and antibodies (Mangeat & Trono, 2005). Mammalian immune systems are further complicated by many interactions between the two types of mechanisms, often with elements of innate immunity working in concert with adaptive effectors. 
Viral replication requires a number of host factors. Just as the characteristics of the virus impact tropism (e.g., which envelope gene is present in a retrovirus/ lentivirus determines which host and which cell types will be infected), species-specific host factors affect which hosts and which tissues of the host are infected. 
 Host factors that restrict viral replication are termed restriction factors (Strebel et al., 2009), and the antiviral systems mediated by some of these restrictive factors are termed intrinsic immunity (Takeuchi & Matano, 2008).
Intrinsic Immunity and the APOBEC Enzyme Family.  One of the most studied types of antiviral intrinsic immunity involves the APOBEC family. These cytidine deaminases have RNA and DNA editing enzyme functions and have been found to inhibit replication of retroviruses such as HIV (Izumi et al., 2008). These enzymes are being explored as potentially effective weapons against retroviruses and as targets for developing antiviral therapies. The APOBEC family of enzymes is able to inhibit retroviral replication in several ways, including through hypermutation of the virus via its enzymatic function and through inhibition of movement of reverse transcriptase along the template RNA (Aguiar & Peterlin, 2008; Newman et al., 2005)...
How these enzymes can inhibit non-retroviruses is not fully understood but is likely to be related to the enzyme’s activity against ss (single-stranded)-DNA since HBV and parvovi-ruses have ss-DNA intermediate forms during the replication process. Different APOBEC family members show specificity against different types of viruses. In addition, APOBEC enzymes have been shown to protect the mammalian cell not only from retroviruses but also against the mobilization of endogenous retroviral elements, protecting the host genome (Aguiar & Pe-terlin, 2008; Goila-Gaur & Strebel, 2008). 

Intrinsic Immunity, Tripartite Motif (Trim) Proteins, and Cyclophilin A.  Besides the APOBEC family, Trim5 has been shown to be a restriction factor against retroviral infection (Towers, 2005). Trim5’s antiviral activity appears to be mediated by rapid degradation of viral cores (Towers, 2007). Cyclophilin A is essential for HIV-1 replication and is associated with viral tropism (Takeuchi & Matano, 2008). Cyclophilin A binds HIV-1 capsid, increasing infectivity of HIV-1 in humans but promoting anti-HIV-1 restriction activity in non-human primates (Sokolskaja & Luban, 2006). Like the APOBEC family, Trim5 and cyclophilin effects are species-specific with a family of Trim proteins that show species-specific restriction activity against viruses. Even non-primate Trim-like proteins with antiviral activity have been discovered (Ylinen et al., 2006). Also similar to APOBEC-mediated intrinsic immunity, Trim proteins have been shown to have antiviral activity not only against retroviruses but also against certain viruses such as herpes simplex virus (Reszka et al., 2010). One factor indicative of the key role played in antiviral immunity by Trim proteins is their rapid evolution to parry the rapid emergence of viral defenses against the host’s immunity mechanisms (Johnson & Sawyer, 2009).
Intrinsic Immunity and Interferon (IFN).   Interferons play a key role in the outcome of viral infections (Malmsgaard, 2004). Interferons induce expression of a number of APOBEC proteins involved in antiviral immunity (Argyris et al., 2007) and many Trim proteins (Carthagena et al., 2009). Besides species-specific induction of antiviral immunity, interferons also play a role in tissue-specific immunity. Interferon signifi-cantly enhances the expression of APOBEC-3G/3F in the human blood-brain barrier, drastically inhibiting HIV-1 entry into the central nervous system (Argyris et al., 2007). 

...The potential for therapeutic interventions based on intrinsic immunity is immense—notably the possibility of greatly increasing host protections against a broad range of viruses. The mammalian immune system is very complex, however, and includes the rapidly evolving host defenses necessary to protect against the continually emerging mechanisms of viruses to successfully infect and replicate in those hosts. Caution is therefore merited in any research in this field, both in terms of pre-venting negative consequences to host immune mechanisms and in terms of preventing the expansion of host and/or tissue tropism of viral pathogens.

(3)  Man made intrinsic immunity therapy: Fusion peptide of TRIM and CypA.
https://patents.google.com/patent/US8835617B2/en
(Current assignee)

Polynucleotides encoding a human TRIM-Cyp fusion polypeptide, compositions thereof, and methods of using same

Abstract  A nucleic acid is provided which encodes a human TRIM-cyclophilin A fusion sequence encoding a human TRIM-CypA fusion protein which is active as an anti-viral agent, and in particular antiretroviral. Also provided is a nucleic acid encoding a polypeptide having both TRIM activity and cyclophilin activity. Also provided is an isolated polynucleotide encoding a human TRIM-CypA fusion protein, or variants thereof retaining the TRIM and cyclophilin A activities. Also provided are compositions thereof, antibodies that specifically bind thereto, and vectors and host cells comprising the nucleic acid or polypeptide. In addition, methods are provided for treating or preventing viral infection, or reducing viral load in a subject comprising administering the nucleic acid, polypeptide, vector, or composition to the subject in an amount effective to treat or prevent the viral infection. In some embodiments, the viral infection is HIV-I infection, hepatitis C infection, pox virus infection, vaccinia virus infection, or HTLV infection.

 BACKGROUND Several million people die each year as a consequence of HIV-1 infection ( pandemic retrovirus) . Currently used antiviral therapies suppress HIV-1 replication and resultant disease but these antiviral therapies are plagued with complications and cannot eliminate the virus. Gene therapy is an alternative to life-long pharmacotherapy. Ideally, gene therapy should potently suppress HIV-1 replication without eliciting viral resistance. While all steps of the viral life cycle are potential gene therapy targets, blocking the virus before reverse transcription (RT) would preclude the genetic diversity that permits emergence of viral resistance. Additionally, targeting the virus before HIV-1 cDNA is ligated into host chromosomal DNA would prevent the virus from becoming a heritable genetic element in that cellular lineage. The discovery that certain TRIM5 (T5) orthologues inhibit HIV-1 infection immediately after the virus enters otherwise susceptible cells raised the prospect that these host factors might be exploited in HIV-1 gene therapy.

HIV-1 infection is a serious problem throughout the world and there is a great need for a composition that will prevent infection of a subject by HIV-1 and for a composition that treats or ameliorates the effects of HIV-1 infection in humans. There is a need for life-long anti-HIV-1 pharmacotherapy, and therapies that treat or prevent HIV-1 associated morbidity and mortality.