Entry of Retroviruses

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Entry of Retroviruses

• Nucleic Acids
• Pankaj Jain
• 04/19/2007

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Roadmap

• Retroviruses
• General entry
• Resistance
• Detailed entry mechanism
• Conclusions

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Retroviruses

• Retroviruses are RNA viruses. They use the enzyme
  reverse transcriptase for the formation of DNA

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Importance

• Retroviruses are responsible for causing
  various deadly diseases, AIDS being the most
  common.
• Retroviruses are used as vectors in various gene
  therapies

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Why are we not able to fight viruses?

• Viral enzymes undergo a large error rate during
  their production
• Mutations are random and the virus can not
  figure out what types of mutations are going to
  resist medication
• Just one mutation is enough to develop resistant
  strains for NNRTIs

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• Series of mutations need to take place to develop
  resistance against the protease
• inhibitors
• Missing the doses of drugs leads to development
  of more mutations
• Selective Pressure develops in resistant
  strains
• More than 3/4 of the HIV positive patients in USA
  show resistance to commonly used drugs

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Ways to tackle viruses in the current scenario

• Studying the entry mechanism

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Entry mechanism for viruses
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Important steps after viral entry

• Formation of reverse transcription complex
• Formation of the pre integration complex
• Transport of pre integration complex to the
  nucleus
• Crossing of this complex through the nuclear pore
  and integration

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• Viral DNA is associated with viral and cellular
  proteins in a large nucleoprotein complex.
• Integration of viral DNA copy is a vital step in
  viral replication cycle.
• For integration to occur the complex must be
  transported from the cytoplasm to the nucleus and
  should be able to cross the nuclear envelope.

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Reverse transcription complex

• It is nucleoprotein complex formed from the core
  of infecting virion.
• Little is understood about the properties and
  contents of this complex.
• Main components include RT, IN, CA, MA and Vpr.

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Pre-integration complex

• Newly synthesized viral DNA, the viral and the
  cellular proteins form the main components of PIC
• PIC is present in the cytoplasm and should be
  carried to the nucleus and must cross the nuclear
  envelope

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How PIC targets the nucleus

• Most viruses use motor proteins to propel PIC
  through the intracellular network of
  cytoskeleton.
• Studies show the accumulation of HIV-1 PICs at
  the MT- organizing centers.

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PIC targeting contd

• Actin aids in the movement of PICs very close to
  the nucleus
• Association of MT with NPCs is not understood,
  interaction of Gag proteins with motor proteins
  may account for specific routing along MTs.

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Entry into the nucleus

• PIC is large nucleoprotein complex, much larger
  than the nuclear pore
• Some retroviruses wait for the nuclear envelope
  to break during mitosis
• Lentiviruses can infect both the dividing and the
  non dividing cells

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Attack of virus on dividing and non-dividing cells
http//www.scielo.br/img/revistas/gmb/v29n2/a27fig
02.gif
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• Entry into the nucleus is a critical step in
  pathogenesis of HIV-1.HIV-PIC is more than 50nm
  in diameter.
• Some karyophilic signals aid in nuclear import.

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• Suzuki and Craigie Nature Reviews Microbiology 5,
  187196 (March 2007)

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Karyophilic agents

• Matrix proteins (MA) contains a short amino acid
  sequence at the N terminus that closely resembles
  the nuclear localization signal
• Vpr an accessory protein

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• IN also has Karyophilic properties
• Poly purine tract prevents the protosomal
  degradation of IN

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• http//www.medscape.com/content/1998/00/41/73/4173
  10/art-m3151.fig1.jpg

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http//www.medscape.com/content/1998/00/41/73/4173
10/art-m3151.fig5.jpg
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Conclusions

• Actin aids the PIC into nucleus so this could be
  a target for drugs.
• Study concludes that cellular proteins play an
  important role in transport of PIC into the
  nucleus.

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• Modulation of the cellular proteins abundance
  can disrupt various cell pathways thus affecting
  viral replication.
• This information helps in the discovery of novel
  anti-viral drug targets and designing better
  retroviral drugs.

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References

• 1. S.Youichi C.Robert Nature reviews
  microbiology 5, 187-196 (march 2007)
• 2. Khiytani.DK, Dimmoch NJ J Gen virol 83,
  2523-32 (Oct 2002)
• 3. Jeffrey Daniel Dvorin Trafficking nuclear
  impact of HIV-1 Pre Integration complex 2002
• 4. Limon.A Devroe.E Lu.R et al J virol
  76(21) 10598-607 (Nov 2002)
• 5. Dilller.SL caly.L Jan DA Current drug
  targets 4(5) 409-29 (Jul 2003)

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