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== Introduction ==
== Introduction ==


Since 2000, 38,1 million people were infected by the human immunodeficiency virus (HIV)<ref>[http://www.avert.org/professionals/hiv-around-world/global-statistics Global HIV and AIDS statistics]<ref/>.  
Since 2000, 38,1 million people were infected by the human immunodeficiency virus (HIV)<ref>[http://www.avert.org/professionals/hiv-around-world/global-statistics Global HIV and AIDS statistics]</ref>.  
This virus can cause the acquired immunodeficiency symptom (AIDS) which can often be lethal. The HIV belongs to the retrovirus family, more precisely to the lentivirus. This virus infects immune cells (T cells, macrophages, …) by integrating its genome in the host cell genome. Since HIV is a RNA virus, it converts its RNA into DNA thanks to the reverse transcriptase. Nevertheless, when its genome is integrated in the host genome, it can stay in latency during a long time.  
This virus can cause the acquired immunodeficiency symptom (AIDS) which can often be lethal. The HIV belongs to the retrovirus family, more precisely to the lentivirus. This virus infects immune cells (T cells, macrophages, …) by integrating its genome in the host cell genome. Since HIV is a RNA virus, it converts its RNA into DNA thanks to the reverse transcriptase. Nevertheless, when its genome is integrated in the host genome, it can stay in latency during a long time.  


The virus becomes active when the cell starts to fight another infection. The host cell transcript its own DNA and the viral DNA. This viral DNA codes for lytic proteins and viral proteins. The lytic proteins will kill the host cell, thus releasing the new viral particules. Indeed, it is the immune cells death which induces the decrease of the immune response and enhances thus the sensibility to other infections. Moreover, the viral proteins will produce new viruses which will be released and infect new cells. In this way, the knowledge of the different viral proteins, like the capsid proteins, can allows us to find new targets in order to avoid the viral dispersion/propagation ? <ref>[http://www.ncbi.nlm.nih.gov/pubmed/8493571 Weiss RA (May 1993). "How does HIV cause AIDS?". Science 260 (5112): 1273–9.Bibcode:1993 Science 260.1273W. doi:10.1126/science.8493571. PMID 8493571.]<ref/>
The virus becomes active when the cell starts to fight another infection. The host cell transcript its own DNA and the viral DNA. This viral DNA codes for lytic proteins and viral proteins. The lytic proteins will kill the host cell, thus releasing the new viral particules. Indeed, it is the immune cells death which induces the decrease of the immune response and enhances thus the sensibility to other infections. Moreover, the viral proteins will produce new viruses which will be released and infect new cells. In this way, the knowledge of the different viral proteins, like the capsid proteins, can allows us to find new targets in order to avoid the viral dispersion/propagation ? <ref>[http://www.ncbi.nlm.nih.gov/pubmed/8493571 Weiss RA (May 1993). "How does HIV cause AIDS?". Science 260 (5112): 1273–9.Bibcode:1993 Science 260.1273W. doi:10.1126/science.8493571. PMID 8493571.]</ref>




Revision as of 21:25, 28 January 2016

Structure of Human Immunodeficiency Virus monomeric capsid PDB:3H47

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Structure of Human Immunodeficiency Virus hexameric capsid PDB:3J4F

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HIV capsid hexamer

Introduction

Since 2000, 38,1 million people were infected by the human immunodeficiency virus (HIV)[1]. This virus can cause the acquired immunodeficiency symptom (AIDS) which can often be lethal. The HIV belongs to the retrovirus family, more precisely to the lentivirus. This virus infects immune cells (T cells, macrophages, …) by integrating its genome in the host cell genome. Since HIV is a RNA virus, it converts its RNA into DNA thanks to the reverse transcriptase. Nevertheless, when its genome is integrated in the host genome, it can stay in latency during a long time.

The virus becomes active when the cell starts to fight another infection. The host cell transcript its own DNA and the viral DNA. This viral DNA codes for lytic proteins and viral proteins. The lytic proteins will kill the host cell, thus releasing the new viral particules. Indeed, it is the immune cells death which induces the decrease of the immune response and enhances thus the sensibility to other infections. Moreover, the viral proteins will produce new viruses which will be released and infect new cells. In this way, the knowledge of the different viral proteins, like the capsid proteins, can allows us to find new targets in order to avoid the viral dispersion/propagation ? [2]


Function

Structural highlights

As you can see on the figure bellow, each monomer of capsid is linked to five others to form a hexamer. These hexamers (approximately 330 per virus) associates themselves to form a non-symetrical protein complex.

Interactions with others partners

Even if p24 is classified as a structural protein, it is also involved in many cellular infection processes.

You can find bellow in a non exhaustive list of p24 partners :

  • Cytoskeleton (MAP1A, MAP1S, CKAP1, WIRE).[3] [4]
  • Cyclophylin A [5]
  • Nuclear pore (certainly but not sure)[6]
  • Dynein [6]
  • Integrase ?


The HIV-1 capsid acts like a kind of "nuclear localisation signal" because it targets directly the virus toward the nucleus, where the integration takes place.

Capsid as therapeutical target

Cristal structure of PF-3450074 with N terminal domain of HIV capsid PDB:2XDE

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Here is the original spinning scene, click on me !

Thank to its central role in viral infectious process (genome protection, enveloppe cohesion, uncoating, budding), HIV capsid is a very good target for antiviral drugs. As a result, many research teams are working in this way and some molecules such as PF-3450074 [6] are very promising. By binding to a "central pocket" on P24, it was shown in vitro that this compound is inhibiting the new viruses assembly, and consequently the virus budding.

This approach is interesting because, based on structural information, we are able to build such ligands using drug design. However, we are still far away from the "miraculous HIV drug", because the pathway from design to approved drug is not an easy way at all.


References

  1. ↑ Global HIV and AIDS statistics
  2. ↑ Weiss RA (May 1993). "How does HIV cause AIDS?". Science 260 (5112): 1273–9.Bibcode:1993 Science 260.1273W. doi:10.1126/science.8493571. PMID 8493571.
  3. ↑ Fernandez J, Gärtner K, Becker A, et al. HIV-1 capsid interacts with cytoskeletal-associated proteins for intracytoplasmic routing to the nucleus. Retrovirology. 2013;10(Suppl 1):P34. doi:10.1186/1742-4690-10-S1-P34.
  4. ↑ Fernandez J, Portilho DM, Danckaert A, Munier S, Becker A, Roux P, Zambo A, Shorte S, Jacob Y, Vidalain PO, Charneau P, Clavel F, Arhel NJ. Microtubule-associated proteins 1 (MAP1) promote human immunodeficiency virus type I (HIV-1) intracytoplasmic routing to the nucleus. J Biol Chem. 2015 Feb 20;290(8):4631-46. doi: 10.1074/jbc.M114.613133. Epub 2014 Dec 11.
  5. ↑ [https://jvi.asm.org/content/84/10/5181.long Marisa S. Briones, Charles W. Dobard and Samson A. Chow. Role of Human Immunodeficiency Virus Type 1 Integrase in Uncoating of the Viral Core. Accepted manuscript posted online 10 March 2010, doi:.1128/JVI.02382-09 J. Virol. May 2010 vol. 84 no. 10 5181-5190]
  6. ↑ 6.0 6.1 6.2 HIV-1 capsid: the multifaceted key player in HIV-1 infection Nature Reviews Microbiology 13,471–483 (2015)doi:10.1038/nrmicro3503

Structural capsid image : By Thomas Splettstoesser (www.scistyle.com) (Own work) [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons

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