human biology - Why is there an extended delay before G.M. liver cells are attacked by the immune system?

In this BBC article a trial is described where patients with B-Haemophillia are infected with modified Adeno-associated Virus 8 which contained the genes for Factor IX clotting protein. Trials seemed to be successful, however the article later mentions

There was an immune response against the infected liver cells around seven to nine weeks after the virus was injected.

I am interested to know why there was a delay period of such length? Would this be true of all cells and is it due to a long duration of clonal selection in the humoral immune response or is something else at play? Also, I'm presuming that the Adeno Virus would be attacked long before the cells it has infected?

Answer

The delay in immune attack is common for many viral infectious deceases where auto-immune response plays substantial to significant role in pathogenesis of the decease. The classical example here are the viral hepatitis B, C and D where it is auto-immune attack that causes the massive death of liver cells (hepatocytes).

The delay in immune attack is explained by the following mechanisms:

The immune attack is developed against the surface antigen, in case of hepatitis it is the HbS Antigen. "Surface" means that this antigen has to appear on the cell surface in order to elicit immune response: the virus itself as well as the parts of destroyed cells are not immunogenic enough for this.

The second point explaining why the attack takes so long to develop is that it is primarily cell-mediated attack, the humoral factors play the secondary role here.

So, the usual "workflow" in this case is the following:

1. Contamination with hepatitis virus.


2. Virus propagation to hepatic cells and their infection.


3. Processing of the viral DNA (either as DNA or first reversed-transcripted from RNA) so that it is integrated into cell normal processing pathways.


4. Expression of viral proteins (=antigenes) and their anchoring in the cell membrane.


5. Surface antigenes are detected by macrophagues, processed and expressed on their membrane for T-helpers ... (continuation of the usual cell-mediated immune response via T4 and T8 lymphocytes).

Every stage takes some time, the total duration can sum up to 4 to 12 weeks depending upon the viral activity and the immune system status.