AIDS-Acquired Immuno Deficiency SyndromeThis is a featured page



Targeting HIV replication

The replication of HIV 1 is a multi-stage process.

Each step is crucial to successful replication and is therefore a potential target of antiretroviral drugs.

Step one is the infection of a suitable host-cell, such as a CD4-positive T-lymphocyte.

Entry of HIV into the cell requires the presence of certain receptors on the cell surface, CD4 -- receptors and co-receptors such as CCR5 or CXCR4.

These receptors interact with protein-complexes, which are embedded in the viral envelope.

These complexes are composed of two glycoproteins:

an extracellular gp 120 and
a transmembrane gp 41

When HIV approaches the target cell gp120 binds to the CD4-receptors. This process is termed attachment.

It promotes further binding to a co-receptor. Co-receptor binding results in a conformational change in gp120.

This allows gp41 to unfold and insert its hydrophobic terminus into the cell membrane.

Gp 41 then folds back on itself.

This draws the virus towards the cell and facilitates the fusion of their membranes.

The viral nucleocapsid enters the host cell and breaks open releasing two viral RNA-strands and 3 essential replication enzymes:

Integrase, Protease and Reverse Transcriptase.

Reverse Transcriptase begins the reverse transcription of viral RNA.

It has two catalytic domains:

The Ribonuclease-H active site

And the polymerase active site

Here single stranded viral RNA is transcribed into an RNA-DNA double helix. Ribonuclease- H breaks down the RNA.

The polymerase then completes the remaining DNA-strand to form a DNA -- double helix.

Now Integrase goes into action.

It cleaves a dinucleotide from each 3-prime end of the DNA creating two sticky ends.

Integrase then transfers the DNA into the cell nucleus and facilitates its integration into the host cell genome.

The host cell genome now contains the genetic information of HIV.

Activation of the cell induces transcription of proviral DNA into messenger RNA.

The viral messenger RNA migrates into the cytoplasm where building blocks for a new virus are synthesised.

Some of them have to be processed by the viral protease.

Protease cleaves longer proteins into smaller core proteins.

This step is crucial to create an infectious virus.

Two viral RNA-strands and the replication enzymes then come together and core proteins assemble around them forming the capsid.

This immature particle leaves the cell acquiring a new envelope of host and viral proteins.

The virus matures and becomes ready to infect other cells.

HIV replicates billions of times per day destroying the hosts` immune cells and eventually causing disease progression.

Drugs which interfere with the key steps of viral replication can stop this fatal process.

Entry into the host cell can be blocked by fusion inhibitors for example.

Inhibition of reverse transcriptase by nucleoside inhibitors or by non-nucleoside Reverse Transcriptase- inhibitors is part of standard antiretroviral regimens.

The action of Integrase can be blocked.

Protease inhibitors are also part of standard antiretroviral therapy.

Each blocked step in viral replication is a step towards better control of HIV disease.




Script, Storyboard, Art Direction by: Frank Schauder, MD
Animation: MACKEVISION
Publicity: Dr.A.Rufus Rajadurai, MD., D.DENS.,



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Anonymous Thanks 3 May 15 2009, 3:29 PM EDT by dr.rufusrajadurai
 
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excellent!!it really helped me a lot with my study..well done
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