CD8+ive T cell death in HIV infection

Laszlo Radvanyi radvanyi at oci.utoronto.ca
Tue Mar 21 00:18:29 EST 1995


Christopher;

     I read your suggestion that CD4+8+ cells may be targets of HIV 
infection.  There are a number of problems with this hypothesis:

1.  Very few CD4+8+ T cells reside in the periphery, especially in 
adults.  There are a significant number of immature double positive 
thymocytes that escape into the periphery, but usually this is found only 
during the period shortly after birth- a number of studies  
peripheral immune system development in mice have shown this.

2.  Infection of the thymus by HIV is generally considered a late stage 
event in the pathophysiology of HIV-AIDS.  In fact, due to the failure of 
the primary immune response to adequately keep the virus in check, the 
virus replicates in the lymph nodes during the so-called "latent phase" 
of the disease.  This often lasts for years.  During this time free 
virion is virtually undetectable in the peripheral blood.  Following the 
latent phase, virus begins to spill over into the peripheral blood and 
also infects other lymphoid organs, especially the thymus.  By this time, 
the patient is nearing, or already undergoing, the full-blown AIDS stage of 
the disease.  The body seems to attempt one final assault so to speak 
through a chronic immune response due to the now widespread dissemination 
of the virus, again failing.  This may explain AIDS 
cachexia (high circulating TNF, IL-1 etc.,i.e., inflammatory cytokines) 
found during this time.

3.  The fact is HIV does not seem to kill the cells it infects.  That is 
what recent research is uncovering.  Even in an evolutionary sense it does not 
make sense for a virus to kill its host cell- this is obviously not 
conducive to viral replication!!  In fact, the most "clever" viruses 
(e.g., adenovirus, human papillomavirus, Hepatitis B, EBV, small pox virus 
etc.) have evolved genetic elements coding for proteins that actually 
ensure cell survival by preventing apoptosis during productive 
infection!!  I predict that HIV 
will be found to do the same, we simply haven't looked hard enough at the 
problem yet.  Unfortunately, virologists are not cell biologists.  As 
AIDS is now FINALLY being recognized as an immune problem not a viral 
problem per se, and more attention (and more funding) is being paid to the 
cell biology of the problem (apoptosis etc.), I'm sure answers will be 
forthcoming.  A recent paper published in Nature Medicine actually 
found that HIV-infected T cells in lymph node follicles were 
the ones NOT undergoing apoptosis.  I think the record has to be set 
straight on this once and for all.  
     More pertinent questions to ask are; how does HIV infect antigen 
presenting cells (APCs), the actual orchestrators of the immune response?  
What is the nature of HIV infection of dendritic cells in the lymph node 
follicles?  If HIV does not infect professional APCs very well during the 
initial course of infection, then why not?  Should a successful vaccine 
entail an attenuated virion which prefentially infects APCs for Th1 
triggering, and how can this be achieved?


Laszlo


Laszlo Radvanyi
Ontario Cancer Institute,
Princess Margaret Hospital
Toronto, Ontario M4X 1K9
tel: 416-924-0671 ext. 4994
fax: 416-926-6529
e-mail: radvanyi at oci.utoronto.ca



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