IUBio

Where does HIV integrate into genome and when is it activated?

Carlton Hogan carlton at walleye.ccbr.umn.edu
Mon Jul 27 15:04:07 EST 1998


In article <51853 at sci.med.aids>, WARogers  RJDuran <matilda1 at flash.net> wrote:
>Axel Boldt wrote in message <51685 at sci.med.aids>...
>>Hi,
>>
>>I have two questions about HIV:
>>
>>1) Is the HIV provirus always integrated at the same spot in the host
>>   cell's genome? If yes, where?
>
>Unfortunately, the answer to your question is a negative one.  One of the
>primary reasons that the "Vaccination" approach to containing the virus is
>not working is because the virus has no particular spot on the RNA and DNA
>chain where it goes to.  It is like a microscopic octopus that grabs hold at
>anyplace.

Actually, the biggest obstacles to immunization are the extreme antigenic
diversity of HIV strains, particularly in the env gene, the glycosylation
(sugar coating - hides the proteins from immune recognition) of surface 
proteins, and the very open question of whether antibody response is
ever enough to stop the virus. There are some new approaches to prime
the other arm of the immune system, the cell mediated immunity, to try 
and initiate a cytotoxic lymphocyte response (CTL). This approach is 
supported by findings in long term survivors, who typically have a 
very vigorous CTL response, and who secrete a still poorly characterized 
protein from their CD8 cells that stops viral replication. Where the 
provirus is integrated in host DNA is pretty irrelevant to questions
of immunization, although it is important is gene-therapy considerations.
>
>>2) What exactly causes the provirus to become active and produce new
>>   particles -- is it the activation of the T-cell by antigen?
>
>Someone please correct me if I am wrong, but I do not believe that the virus
>actually creates new particles as such.  To the best of my knowledge, the
>mature virus is composed of only a single strand of RNA.  

No, it's actually double stranded RNA

It does not have
>any DNA, like the nucleus of the T-Cell does.

This is true for the portion of the viral life cycle where it is extracellular.
But one of the first things to occur after the virus enters a cell is
the transcription of viral RNA into viral DNA (reverse transcription).
The viral DNA is then drawn into the nucleus by poorly understood processes,
where the viral integrase incorporates the viral DNA into the host DNA.

  The nucleus of the T-Cell has
>both RNA and DNA. 

All DNA that is "active" produces mRNA and cRNA transcripts, which then code 
for specific proteins. DNA in the absence of RNA is quiescent: it needs
to make RNA as a neccesary intermediate step in protein synthesis.

> To answer your question, when the virus enters the T-Cell
>with it's single strand of RNA, it does not create new particles to
>replicate itself, it simply uses the DNA genes that are already there,
>inside the T-Cell.  That's how it puts itself together.

It's actually a little more complex then that. There is a very complex 
interplay of viral and cellular enzymes and proteins that are required 
for the production of new virions. For example: without the HIV-encoded
protease enzyme, viral proteins would never be cleaved to the right 
length to create viable virions.

>
>What happens next, if I may be so bold, is that the virus, now having put
>itself together with a bunch of new genes, has killed the T-Cell.  The
>T-Cell no longer has all of it's genes, because the virus has taken them
>away

There is no evidence for that. The mechanisms of HIV-mediated cytotoxicity 
are still somewhat opaque - there are probably multiple mechanisms, including
apoptosis, and the killing of HIV "marked" T helper cells by T-killer
cells, as well as possibly others. It has nothing to do with loss of genes.

>.  Before the T-Cell disintegrates, the virus cuts itself into a whole
>bunch of little pieces. That's what's called "Reverse Transcriptase".

No, reverse transcriptase is the enzyme (actually two enzyme: a polymerase
and a robonuclease: the first "builds" the new DNA, the second degrades
the RNA post transcription) that copies viral RNA into DNA so that it can 
be incorporated into the host nucleus.

>  When
>the T-Cell disintegrates, all those pieces float free into the blood stream.
>Those little pieces are new viruses.  Then the viruses go find new T-Cells
>to attack, and the cycle starts all over again.

Although viral budding can destroy a T-cell, this is not always the case,
and 99% of the cellular debris is not viral, but simply the "pieces"
of the T-cell.

There are many great resources on the net that explain viral life cycles.
I think one of the best "plain language" expositions is in the 1988
Issue of scientific american dedicated to HIV. It's a little out of 
date now, but the basic principles of viral life cycle are still 
viable.

There are also good basic resources at 

http://www.thebody.com/whatis/underst.html

Good luck!

Carlton

 _______________________________________________________________________
 |                                                                     |
 | Carlton Hogan  (carlton at gopher.ccbr.umn.edu)                        |
 | Community Programs for Clinical Research on AIDS Statistical Center |
 | Coordinating Center for Biometric Research                          |
 | Division of Biostatistics, School of Public Health                  |
 | University of Minnesota                                             |
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>>--
>> Axel Boldt  **  axel at uni-paderborn.de  **
>math-www.uni-paderborn.de/~axel/
>




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