Retrovirus Part 1 Flashcards
Retroviridae subfamily
Subfamily: oncovirinae: tumor virus
lentivirinae: slow virus: related to AIDS virus
Spumavirinae: non oncogenic: Human Foamy Retrovirus, (HFV) produced progressive degenrative disease in CNS and striated muscle of transgenic mice, can pass pathological phenotype to offpsring, possible cause of human disease.
Retroviridae Structural
Complex: helical nucleocapsid plus icosahederal or cylindrical outer capsid.
Genome: SS RNA, 2 identical 35S RNAs joined by specific tRNAs; diploid genome.
Enzymatic complex consisting of RNA dependent - DNA polyermase (reverse transcriptase), DNA polymerase and RNAse H and integrase encoded by “pol” gene, PRO gene encodes the protease and is either part of pol gene or adjacent to it
Retroviridae structural 2
Envelop: cell membrane derived via budding
3 envelope protines (ENV)
4 internal capsid proteins (GAG gene)
RNA genome= GAG- Pol - Env - ONC (+/-); chronic leukemia viruses lack ONC; acute leukemia/ Sarcoma viruses usually lack env, but possesses oncogenes; exception Rous Sarcoma, which has full complement of genes.
HIV RNA genome: GAG Pol ENV plus other encoding region (nef, tat, Rev, etc., topic of future lecture.)
Replication
Cytoplasm and nucleus
general scheme= + RNA genome > +RNA -DNA > -DNA +DNA (provirus) > integration provirus DNA at many sites within chromosomal DNA; provirus integration is integrase mediated.
Pro virus formation takes place in cytoplasm which is then transported to the nucleus where integration occurs
the conversion of genomic RNA to proviral DNA produces a long terminal repeat (LTRs) which are located at each end of the provirus; LTR has regulatory regions within it.
Transription from provirus yield two or three mRNAs: 35s mRNA, 28s mRNA, and 21s mRNA.
Translation of mRNAs
- 35s mRNA GAG or GAG - POL polyprotein; Gag mRNA predominates
- 28s Env polyprotein; polyprotein proteolytically cleaved into smaller proteins
- 21s ONC protein; present in acute leukemia/ sarcoma virus
- Proteolytic cleavage of polyprotein precursors to yield actual viral proteins, viral proteases encoded by PRO gene involved in specific cleavage.
Unlike DNA tumor viruses, which transform cells or cause lytic infection with virus production, retroviruses can transform cells and produce progeny virus, also cause tumors in vivo
Oncornavirinae classified as type B, C, D based on host range, antigenicity, virus morphology (location of core relative to virus structure)
Avian subgroup Chronic leukemia viruses
In vitro: no transformation
No SrC gene or oncogene
In vivo leukemia after long latent period; activate protooncogene that is already present in cell DNA
nondefective for envelope.
Avain subgroup Acute leuemia-sarcoma viruses
In vitro: Rous sarcoma virus transforms cells and produces virus (exception); other strains do transform but no virus is produced
SRC or other oncogene is present
Sarcoma in vivo
usually defective (lack of Env gene) for replication except for Rous Sarcoma virus
Require helper virus for replication (leukemia virus supply env proteins for envelopment.
Avian subgroup Animal factors
genetic strain of mice
hormonal factors: estrogen enhances tumor formation, LTR has receptors for horome
AGE: newborns are very susceptible by various routes of infection, adults require massive doses of virus to produce tumors
Oncogenes
cellular equivalent to viral oncogenes called “protooncogenes” or cellular oncogenes (c-onc), retorviruses may have acquired oncogenes from cells- designated by 3 letters (src, myc, ras, sis over 30 protooncogenes, also found in human tumors; viral oncogene (v-onc))
protooncogenes are nromally repressed and are inactive in cell DNA; for different reasons they are activated and can encode transforming proteins. Even though tumor cells may have 20 or more protooncogenes only one or a few is activated.
Possible modes of protooncogene activation
- chemical carcinogen causes mutation in repressor gene. repressor protein no onger repressed protooncogene– protooncogene itself may be point mutated before causing tumors, eg. ras
- insertion of a leukemia provius near a rpotooncogene, LTR of leukemia virus “turns on” expression of protooncogene or endogenous virus.
- translocation of protooncogenes from normal position on a chromosome to a position on another chromosome.
Places protooncogene under the influence of an enhancer or promoter which activates transcription of the protooncogene, eg. for Burkitts lymphoma myc translocated to position under control of Ig enhancer.
4, Sarcoma or acute leukemia viruses may introduce oncogene (provirus) into a cell DNA which “overdoses” the cell with the oncogene protein; some oncogene products may appear as fused proteins: gaga- myc.
Function of transforming protein encoded by protooncogene-diverse
phosphorylation of cell proteins specficially at tyrosines- protein kinase activity may phosphorylate many possible proteins.
phosphorylation of vinculin - protein which binds actin bundles to plasma membranes - disorganization of cytoskeletal system may result
enzymes involved in glycolysis, increased glycolysis results
membrane associated kinase may mimic receptors for growth factors - phosphorylation effects a pathway which stimultes cell replication or acts like growth hormone
nuclear acting proteins - control of gene expression by influencing the promoters or enhancers.
phosophorylation changes activity of many proteins - growth hormone receptor change activity – continously turned on.
Function of transforming protein encodeed by non ONC gene
leukemia provirus integrates into cell DNA and the control region of its LTR ativates an endogenous provirus or a protooncogene
the endogenous provirus has an oncogene which codes for a transforming protein
side note: certain endogenous viruses have been linked to neurological diseases such as multiple sclerosis. Human endogenous retrovirus W (HERV -W) encode for a protein that induces an inflammatory response that involves the cells of the nervous system.
