Urgent immunological questions regarding AIDS and HIV

Urgent Immunological questions:

1. What is the real nature of HIV target cells, *HST?
2. What could be the consequence of lacking HST?
3. Can many of the pathologies triggered by HIV be explained by the lack of HST?
4. How do CD8 T cells become defective when an individual is infected with HIV?
5. What is the real nature of exhaustive CTLs?
6. How do Th17 cells become depleted in HIV infected individuals or SIV infected Rhesus macaque?
7. Do regulatory T (Treg) cells play a critical role in HIV pathogenesis?  If so, how do they work?
8. Why are Treg cells in lamina propriae (LP) of intestine depleted while those present in peripheral blood and lymph nodes remain intact?
9. Is it possible to generate effective HIV (AIDS) vaccine without the help of HST?
10. How can you explain the chronic immune activation seen in HIV infected individuals?
11. How Sooty mangabey is not subject to the SIV mediated pathology, while Rhesus macaque is?
12. Antibody mediated immune responses will be discussed later.

*HST: CD4 T cells that are susceptible to CCR5 (R5)-tropic HIV. I will use the word HST in all of my blog.

Personal view on above issues:

1. HST are different type of T cells from non-HST, in their origin, effector function, life expectancy, requirements for their activation, dependency on commensal microbiota etc.  Thorough comprehension of HST could be the key to understand HIV pathogenesis.
2. Lack of immune tolerance at the mucosal effector sites, lack of effector function when necessary (such as after infection or overgrowth of commensals, etc) and systemic immunodeficiency.  HST could be responsible for both immune tolerance and protective immunity, particularly at the non-lymphoid tissues.
3. Certainly.  The majority, if not all, are the consequences of lacking HST.  For example, chronic immune activation and lack of protective immunity.
4. One of the main functions of HST could be to induce maturation of antigen presenting cells.  Without HST, not only CD4 T cells, but also naive CD8 T cells are not getting appropriate signals for the proper activation.  It will lead to the generation of anergic CD8 T cells.  It is expected that not only the number of CD4 T cells but also that of antigen specific CD8 T cells wold be diminished in chronically HIV infected individuals.
5. My current hypothesis on this issue is provocative.  But there seem to be any good alternative explanation on this issue.  Exhaustive CTLs could be derived from HST (yes, CD4-positive HST becomes CD8 T cells).  Once an effector function is done, HST should die out to prevent unnecessary damage to the host to prevent autoimmune disease.  It will be the case in an healthy individuals.  In the case of HIV infection or other chronic viral infection, HST will remain survived, but without function.  However, they lost their expression of CD4 and would gain CD8 expression.  It is also likely that HST express CD8 molecule in the first place.  Therefore the majority of CD8 T cells will be non-functional CD8 T cells with the phenotype of exhaustive CTLs.
6. Th17 cells, unlike conventional antigen specific Th1 or Th2 effector T cells, could be derived from HST, but not from naive T cells.  Therefore, the lack of HST in HIV infected individuals will lose Th17 cells as well.
7. Yes.  However there will be two different types of Treg cells, one susceptible to R5-tropic HIV and the other not.  The loss of Treg cells susceptible to R5-tropic HIV, as in FoxP3-negative HST, would occur in non-lymphoid tissue.  Therefore, the majority of Treg cells in  lymphoid tissues is not affected by HIV infection for a long period of time after initial HIV infection.  The loss of Treg cells in non-lymphoid tissue would impact on immune tolerance at the mucosal effector sites.
8. It is possible that origin and the function of Treg cells in LP of gut and those in lymphoid tissue could be different.  It is also likely that Treg cells in LP is plastic in nature , while those in lymphoid tissues are not.
9. No.
10. It is due to the loss of HST, both FoxP3-negative (probably IL-10 producing Tr1) and FoxP3-positive IL-10 producing Treg cells.  Microbial translocation could be the consequences of losing HST, which will lead to chronic immune activation.
11. The prevalence of HST after SIV infection.
12. To be continued

Key words:
AIDS, HIV, effector memory T cells, Th17, CTL, chronic immune activation, exhaustive CTL, HST, SIV, sooty mangagey, Treg, regulatory T cells,  HIV pathogenesis, CCR5, R5-tropic HIV