CD8+ive T cell death in HIV infection

[Naomi Gayle Housman]

On Tue, 21 Mar 1995, Laszlo Radvanyi wrote:

> 
> 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.

This may be true, however, it is clear from Fauci et al's data that HIV 
does have the ability to infect CD4+8+(double positives) in vitro.  
Additionally, Fauci et al have shown that HIV replicates like mad in 
lymph nodes and spleen during all stages of the diseases.  From an 
immunological stand point, it is not at clear how and where CD4+ T cells 
develop in the mature adult (that is post- thymus involution).  However, 
if we take the recent data presented by George Shaw et al, and David Ho 
et al, with regards to HIV replication and steady state models, it is 
clear that CD4+ T cells are constantly being renewed (although I'm not so 
sure at the rate that they discuss).  So the question remains, where are 
these CD3+4+ T cells coming from and is there a pool(s) of precursor 
lymphocytes, perhaps, double positives, that exists that becomes depleted as the 
disease progresses?  My own personal bias is that there is a pool of 
precursor lymphocytes, perhaps located in the gut, lymph nodes, and 
spleen, a part of which may be double-positives. 

> 
> 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.
> 
Again, viral replication in lymph nodes, spleen, and even thymus is an 
ongoing event throughout HIV infection, not just late stage.  In fact, 
there have been several reports of SIV replication in thymus in monkey 
studies, early in infection.  In terms of virion detection, with the 
rapidly advancing technologies available, it has become clear that HIV 
replication is tremendous and quite detectable in peripheral blood 
mononuclear cells.  Again, this is not a late stage phenomenon.  In terms 
of AIDS cachexia and cytokine involvement, the late stage development of 
these symptomologies may have more to due with the viral persistence in 
macrophages that are disseminated throughout the body by that time.  Some 
studies, in vitro albeit, have suggested that TNF provides an autocrine 
loop-feedback system that promotes HIV's ability to infecte macrophages.  
This may explain the late stage wasting.


> 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.  

Although I would agree with the assertion that HIV does not appear to 
kill the very cells it infects, this is tentative and by no means 
conclusive yet. It remains to be seen, even in the recent studies you 
have sighted in Nature Medicine (Finkel, T and Ruprecht, R et al, 1995) 
their data is limited by the number of microscopic fields in which they 
looked.  It would be of interest to know if we would see the same type of 
occurrences in vitro with primary isolates.  I think an interesting 
paper was published by Essex et al (P.N.A.S. in Oct or Nov of 1994) on 
the ability of a primary macrophage tropic isolate to kill fresh PBL's in 
culture.  The data there is striking, however, whether or not the 
mechanisms involved are direct or indirect remain to be seen.  This is 
something that we are currently working on utilizing flow cytometry and 
the appropriate monoclonals.  In addition, the manner in which those 
bystander T-cells were undergoing apoptosis is of extreme importance.  I 
wonder if it involves the type of programmed cell death that is seen with 
antigen responding cells in vitro?

>      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?
> 
> 
I'm not much for attenuated vaccines as prophyllactic measures.  I 
wouldn't take it would you??  Attenuated how?  I hope not with nef, as 
Ruprecht, R. et al have already stated that even severely crippled SIV's 
when injected into, interestingly enough, newborn macaques eventually 
revert.  So what's the likelihood of maintaining the attenuation of HIV 
in vivo?  Not much.  By the way she has said that this data will be 
published some time soon in Science.  Additionally, it is not clear that 
HIV does not infect professional APC's in the early stages of the 
infection/disease.  In fact, it seems that HIV preferentially infects 
macrophages (do they qualify as prof. APC's?) upon transmission of the 
virus, a selection for which determinants have yet to be elucidated.  Yet 
I would agree that the nature of dendritic cell involvement seems crucial 
to AIDS pathogenesis and development.  This was presented at a recent 
meeting in Baltimore, Md by Fauci as his group has been analyzing lymph 
nodes from so-called non-progressors or long-term survivors. They have 
found that the level of replication and tissue destruction varies 
directly with the progression of the disease.  
However, they have not determined what separates some people whose lymph
node cytoarchitectural organization remains intact from those whose nodes 
fall apart with active viral replication.

Yes indeeed, virologists are not cell biologists but I would suggest that 
they need not have to be.  It seems to me that cell biologists need to 
start listening to the virologists, and the virologists definitely need 
to begin to listed more acutely to the cell biologists if we are going to 
make any headway with this thing.  I'm interested in your comments, 
rebuttals, etc....



Chad Womack
Centers for Disease Control and Prevention
National Centers for Infectious Diseases
Division of HIV/AIDS, Immunology Br
Atlanta, GA



> 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
> 
>