Why does the number of CD4 T cells decrease gradually in AIDS patients?

The number of CD4 T cells in HIV infected individuals decreases gradually, which takes place spanning a decade so, or even longer.  Why will that be the case?  How does it work?  Are all CD4 T cells supposed to be killed after activation by HIV as generally considered currently?  Are any CD4 T cells getting killed after activation by HIV?  These questions can easily be asked by any seasoned immunologist, since we do not have any general information on this issue, other than CD4 T cells are killed after activation by HIV.  Even though AIDS has been around almost three decades and we have known that HIV is a causative viral agent, this apparent phenomenon is not clearly explained and even not clearly understood to investigators of HIV pathogenesis.  Here, the possible mechanism that can explain this apparent phenomenon will be discussed.  
One of the earlier proposals to explain the gradual decline of total number of CD4 T cells was the "bathtub theory", one or two decades ago.  Bathtub theory states that CD4 T cells are repeatedly attacked and killed off by HIV without supplying and replenish them fast enough from the thymus. Therefore, the total number of CD4 T cells eventually drained lie the water level in a bathtub with slower water supply but a full drain.  This hypothesis may have been proposed even before the significance of R5 tropic virus depleting all CD4 T cells found in mucosal effector sites.  Other than bathtub theory, there is not many alternative explanations to explain the gradual decline of total CD4 T cells, an important indicator of the progression of AIDS.
This is one of the hypothesis that I come up with why it takes so long to kill off all the CD4 T cells, if HIV infects and kills only activated CD4 T cells.


Highlights of the theory
The bottom line of this theory is that HST (CD4 T cells that are susceptible to R5-tropic HIV) are all killed within a few weeks by R5-tropic HIV after infection.  None of the non-HST are direct targets for R5-tropic HIV, unless they express CCR5.  However, there is a possibility that R5 tropic HIV can gain tropism for CXCR4 and become an R5/X4 dual tropic HIV.  In addition, not only R5-tropic HIV, but also X4 tropic HIV is also co-infected an individual.  I have to emphasize that infection of X4 tropic HIV will not cause AIDS.  

• HST are infected by the R5-tropic HIV and depleted rapidly.
• The loss of HST will lead to the failure in a maturation of antigen presenting cells (APCs), such as dendritic cells.
• The lack of mature APCs fail to activate naive CD4 T cells, which were developed in the thymus and migrated to the lymphoid organs.
• Since naive T cells cannot survive forever and have a life span as a quiescent stage, the number of these population will gradually decrease, leading to the decline in total number of CD4 T cells.
• The proposal suggests a three step process for the gradual decrease in a total number of CD4 T cells.  
1. the loss of HST
2. Failure to activate antigen presenting cells due to the loss of HST
3. Failure to activate naive T cells within their life-span

Studies supporting above hypothesis:  (Many of them are for professionals only)

• HST (CCR5+ CD4 T cells) are depleted within a matter of weeks (by many reviews written by many authors, such as Picker L, Douek D, Silvestri G etc.).  This is a well established phenomenon.
• Effector memory T cells (TEM) are professional CD40 ligand expressing CD4 T cells (by Sallusto's group in JEM).  HST share the majority of phenotypes with TEM. 
• APCs becomes fully matured by interactions of CD40L-CD40.  This is well established among immunologists for two decades.
• Several recent studies and concept of naive T cells suggest that naive T cells are in the stage of quiescence, just like many stem cells.  They are live, but in a stage of quiescence, just surviving without much expenditure of energy.
• Certain molecules are involved in maintaining quiescence.  Those are, Foxo proteins, transcription factors KLF2, Id2, etc.  
• The lack of these proteins in mouse lacking genes encoding these proteins usually lose naive T cell population, without leaving behind effector memory T cells at the mucosal effector sites.
• Dipeptidyl Peptidase 2 (DPP2), by Dr. B. Huber of Tufts, has been linked to the survival of quiescent cells. Partial deficiency of DPP2 by knockdown expression of a gene encoding DPP2 resulted in the generation of Th17 cells, suggesting Th17 cells are not derived from naive T cells.  This hypothesis needs several leaps of imagination.

Key words:

HIV, AIDS, CD4 T cells, CCR5 tropic, CXCR4 tropic, HST (CD4 T cells that are susceptible to R5-tropic HIV infection), antigen presenting cells, naive T cells, effector memory T cells, Picker, Douek, Silvestri, Sallusto, Huber, Th17, quiescent, stem cells, FOXO, KLF2, Id2,