R5 (CCR5) tropic vs. X4 (CXCR4) tropic HIV

R5-tropic HIV is the dangerous one since the loss of CCR5 expressing CD4 T cells (HST) by R5-tropic virus infection leads to AIDS.  On the other hand, X4-tropic HIV is frequently found in a latent stage of HIV infected individuals in a variety of cell types including CD4 T cells and hematopoietic stem cells.  Accumulated data suggest that an onset of AIDS will not occur without R5-tropic HIV infection since the loss of HST is the main cause of AIDS and sparing HST (or providing a mutant form of HST) will be able to cure AIDS.  CD4 T cells, which were reconstituted by a bone marrow transplant in the Berlin patient have a potential to become CXCR4+ after activation and can readily be infected by X4-tropic, but not by R5-tropic HIV.  The Berlin patient has a low titer of HIV and is free from AIDS symptoms, which suggests that infection by X4-tropic HIV can be taken care of by a host protective immune system and will not cause an onset of AIDS.

R5-tropic HIV
Originally called M-tropic virus, meaning that macrophages are the major target cells for R5-tropic HIV.  I am not so certain whether it holds true until now.  The significance of the R5-tropic HIV is that they infect CCR5 expressing CD4 T cells mainly found at the mucosal effector sites, such as gut, vagina and lung.  The loss  of those cells is the main culprit for HIV pathogenesis and directly associated with an onset of AIDS.

X4-tropic HIV
X4-tropic HIV seems to be easily be taken care of by a protective immune system without causing a lethal disease.  The main target cells for the X4-tropic HIV could be activated CD4 T cells and remain as latent form when they are rested.  It is also possible that X4-tropic HIV can become R5-tropic or R5-tropic HIV can become X4-tropic HIV by a notorious rapid mutation rate of retrovirus.  It is a common occurrence that later stage of AIDS patient has a dual tropic (R5X4-tropic) HIV.  Nevertheless, X4-tropic HIV may not be a main HIV that causes an onset of AIDS.

My personal thoughts: HST could be a different type of CD4 T cell that shares certain similarities to macrophages, such as those expressing several molecules expressed on macrophages.  This important issue has never been noticed and deeply investigated.  Since HST could be a totally different type of T cells with paramount significance in a protective immunity, protecting HST from R5-tropic HIV infection could be an ultimate goal of HIV vaccine.
If we were able to look at an outside of the box, we may have a new insight on HIV pathogenesis and AIDS.

Relevance to HIV vaccine development:
Since R5-tropic HIV is the major AIDS causing virus and they destroy HST rapidly, this concept has to be established in advance even before trying a variety of expensive and extensive HIV vaccine trials.

Key words:
CCR5, CXCR4, M tropic, T tropic, HST, HIV, AIDS, vaccine, CD4, macrophage,

http://soonhong-hivandaids.blogspot.com/2012/04/lacking-hst-leads-to-aids-and-providing.html

SAV001 (Canadian) HIV vaccine trials

Human trials for HIV vaccine approved by FDA (SAV001)

http://www.youtube.com/watch?feature=player_embedded&v=1NohdDy2J54#!
http://www.youtube.com/watch?feature=endscreen&NR=1&v=jFpwHe6KjDA

What could happen for this trial?  Will it work this time?

If yes, what is the difference?  Why will it be different from previous numerous unsuccessful trials?

If it fails, why will it be the case?  

I wish I can be more enthusiastic and positive this time than many previous trials.  However, there is a concern as usual.  This trial is different from others in that it uses inactive form of whole HIV as immunogen, while many previous trials use a piece of HIV gene (or combination of HIV genes) using various delivery system (different virus as a vector).  Nevertheless, there is no differences in terms of leaving HST unprotected from infection and depletion by HIV.
During vaccination, *HST will expand as I outlined previously (http://soonhong-hivandaids.blogspot.kr/2012/04/r5-tropic-hiv-susceptible-cd4-t-cells.html).  Even with multiple failures of generating HIV vaccine, it never seems to ring the bell.  It is even more so to whom his (her) interests are geared towards infectious agents, such as HIV itself.  Early expansion of HST immediate after infection is critical for protective immunity for any pathogens.  However, unfortunately, it has not provided any protection from HIV infection in all cases of HIV vaccine trials up to now.  Instead of protecting it, the expanded HST becomes preferable and ample targets for HIV for their maximum expansion.  This should be the main concern for any HIV vaccine trials, whether it is based on live recombinant, attenuated or chemical and radiation inactivated (killed) recombinant HIV, as in SAV001.  Unfortunately, this issue has never been brought up in any of HIV vaccine trials.  It is probably due to the lack of current immunological understanding on HST even among the top-notch immunologists.  HIV, especially CCR5 (R5)-tropic HIV, is unique among any pathogens known to man by infecting and depleting CCR5 expressing CD4 T cells (HST).  As I outlined elsewhere (http://soonhong-hivandaids.blogspot.kr/2012/04/lacking-hst-leads-to-aids-and-providing.html), presence or absence of HST determines the outcome of the HIV infection, getting AIDS or not.  
There is always a possibility that it may work this time, like a magic as had been the case in polio and smallpox about decades and century ago.  In a very fortuitous situation, there will be abundant high affinity, pre-made broad neutralizing antibodies against the surface antigen of HIV and it will immediately cover up the incoming HIV, before they infect widely available HST.  It is also highly likely that killed HIV vaccination will generate cytotoxic T cells specific for any HIV antigen.  But the boosting anti-HIV immune response has never been the problem during the stage of HIV vaccine trials.

The foremost problem lies in the specificity of target cells for HIV, unlike any other pathogens known.  HIV is unique pathogen known, which attacks and depletes HST.  By immunization, we provide more target cells (HST) for HIV to attack and propagate.  At the same time, it generates more soldiers (both antibodies and T cells) to fight against HIV.  

At the moment, the pendulum of the field of HIV vaccine development swings in favor of the antibody mediated protection against HIV infection from the cell mediated protection mediated by CD8 T cells.  This is mainly due to the fact that T cell based STEP trials had just failed in recent years.  We will see what will happen within a few years. If we failed antibody based HIV vaccine trials, will it swing back to T cell based vaccine development?  It has been back and forth by the same (handful) group of investigators.  At least, UWO is the newcomer for our endeavor of obtaining an HIV vaccine.  In addition, killed whole HIV immunization is something that we have not tried, even though the idea are nothing new.  At he moment, we are not in position to discriminate one method or another to fight against HIV and AIDS.

There is an innate problem on the SAV001 trial as well.  It is expected and hoped that the whole HIV vaccination (minus nef, vpu and signal peptide) approach will cover not only antibody mediated, but also T cell mediated immune responses against HIV.  As shown by Klatt et al (Klatt, et al. SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination Blood 2011 118:5803-5812) in non-human primate model, lacking HST affects both types of immune responses.   This suggests that follicular helper T cells (TFH), which helps B cell maturation and differentiation, could be derived from HST.  If that will be the case, generating an HIV vaccine is almost an impossible task without any major breakthrough in human intelligence.

It seems that we are desperate to generate HIV vaccine ASAP.  At the same time, we have too many unknowns at the moment.  We need a big scale collaboration from all over the field (and world), basic immunologists, virologists and vaccinologists!!

Wish I were more positive on this urgent issue as an immunologist!!

I would welcome any comments, suggestions and corrections in English.

The following is cited from an original report from The University of Western Ontario:

"Before it can be commercialized, the SAV001 vaccine must go through three phases of human clinical trials:

• Phase I, set to begin in January 2012, will double check the safety of the vaccine in humans, involving only 40 HIV-positive volunteers.
• Phase II will measure immune responses in humans, involving approximately 600 HIV-negative volunteers who are in the high-risk category for HIV infection.
• Phase III will measure the efficacy of the vaccine, involving approximately 6,000 HIV-negative volunteers who are also in the high-risk category for HIV infection."

Key words:
HST, AIDS, HIV, AIDS vaccine, SAV001, STEP, T cell, B cell, antibody, immunology, virology, vaccinology, nef, vpu, clinical trial

Why does the lack of HST lead to AIDS?

Why does the lack of HST result in the loss of systemic immune responses leading to AIDS?

This is the very fundamental immunological question of HIV pathogenesis and answering this will provide theoretical foundation for developing an effective vaccine against HIV.  If one assumes HST as just one type of effector memory T cells, as currently being regarded, the correct answer would not be achieved.  It has been the case until now.  In my previous post, I defined the HST as CD4 T cells that are susceptible for CCR5 (R5)-tropic HIV.  Accumulating data obtained from both with individuals infected with HIV and with non-human primates infected with SIV, support that the lack of HST will lead to AIDS and providing HST will cure AIDS, even though we need more cases on curing AIDS by providing HST with homozygous CCR5 mutation.  Nevertheless, it is a dramatic and breathtaking positive result (A German-Patient case).  Likewise, sparing HST from experimental SIV infection do not lead to AIDS like syndrome in non-human primates (similar to HIV in human, SIV depletes HST in pathogenic infection, but in non-pathogenic infection).  (many thanks to Dr. Guido Silverstri for his contribution on this part, http://www.yerkes.emory.edu/research/divisions/microbiology_immunology/silvestri_guido.html)

From now on, I will share my theory that are different from current immunological paradigms in several ways.  The crux of my theory is that HST are different but unique type of T cells from the rest of T cells (non-HST) in several ways.  Considering the HST as one of many T cells will create a major obstacle to solving problems of HIV infection and AIDS.

The following segment may require advanced-level of immunological knowledge with cutting edge (up to date) immunology information.  If you have any question, pleasae do not hesitate contact me. I will do my best to explain them.

1. HST could be the source for a variety of effector T cells.  

If that were the real case, the loss of HST by HIV infection will result in deficiency in systemic immune responses, but not just an antigen specific T cell response.  This hypothesis is supported by numerous reports.  It has been shown that HIV infected individuals lose Th17 cells, lose of B cell function possibly due to the lack of follicular helper T cells, and also lose secretion of IFN-g at an early stage.  

2. HST could be the T cells that can exclusively activate antigen presenting cells.  This hypothesis is deviation from a current immunological paradigm but makes perfect sense, since activation of an antigen specific T cells require professional antigen presenting cells that were preactivated.  This hypothesis is supported by a work of Sallusto’s group published in JEM. It is possible that effector memory T cells that they were referred in that paper could be the HST.  HST and effector memory T cells share many similarities.  If this will be the real case, HST could be a specific T cells that can activate antigen presenting cells by exclusively expressing CD40L.
3. HST can become polyfunctional effector T cells.  Polyfunctionality of T cells are considered as T cells that are missing in HIV infected individuals and AIDS patient.  Therefore, the generation of polyfunctional T cells has been used to gauge the HIV vaccine efficacy.  However, it cannot be simulated a condition where HST are missing by HIV infection, this current method of examining vaccine efficacy may not be an ideal method.
4. HST could proliferate much faster than non-HST.  This hypothesis is based on my personal instinct and observation made by a group of Silvestri.  It means that HST could be an early sentinels at the gut and other mucosal effector sites.  Therefore, the lack of these HST could open the door for the subsequent fall of protective immunity as seen in AIDS patient.  There is a strong possibility that HST could be T cells that are involved in innate immune responses, instead of adaptive cell mediated immunity.
5. HST could be the TRM, effector memory T cells reside in mucosal effector sites. Effector T cells found in mucosal effector sites had been considered for a,long period of time that they were moved to the site and a specific environment made TRM with their distinct phenotypes. With recent correction by the same group of investigator (Masopust's), it should be considered that TRM are different from other memory T cells found in lymphoid tissue.

I will expand this later

October 17th 2012

Lacking HST leads to AIDS and providing HST cures AIDS.

Lacking *HST leads to AIDS and providing HST cures AIDS.  
What and how can it be simpler than this?
(http://www.youtube.com/watch?v=A44LyMpnnmU).

*HST (CD4 T cells that are susceptible to CCR5 (R5)-tropic HIV).

It is now clear that *HST, CCR5+ CD4 T cells (also called Effector memory T cells: TEM), mainly reside in the gut mucosal area and other effector sites are the first targets for R5- tropic HIV infection and are depleted within a few days after infection.  The lack of the HST is the main cause for the ensuing pathogenesis mediated by HIV infection leading to AIDS.  It has been shown that providing CD4 T cells with a mutant form of CCR5 (CCR5delta32) can cure AIDS, as shown in a Berlin patient (a patient from New Jersey treated in Berlin, Germany) by bone marrow transplant (http://bloodjournal.hematologylibrary.org/content/117/10/2791.full) (http://www.youtube.com/watch?v=A44LyMpnnmU).  The patient had suffered not only from AIDS, but also from leukemia.  To cure leukemia (and AIDS as secondary), he was treated with bone marrow stem cell (BMSC) transplantation.  Donor BMSC contains a homozygous mutation of CCR5 (CCR5delta32), which prevents them from being infected by R5-tropic HIV.  Donor derived cells not only expanded, but also reconstituted recipient’s immune system.  It also showed that CD4 T cells were able to express CXCR4, another co-receptor for HIV.  Presence of CXCR4 expressing CD4 T cells did not affect the outcome of disease, suggesting the presence of CXCR4 (X4)-tropic HIV virus may not be as critical as R5-tropic HIV in inducing AIDS.  This clinical outcome provides one of the most compelling evidence that saving HST should be an ultimate goal for the HIV vaccine, since providing HST was able to reconstitute the mucosal immune system and cured AIDS.  However, it may require more than one clinical case to be generalized, to be sure.  

We need in depth knowledge of HST even before trying out extensive and expensive HIV vaccine trials.  Underlying scientific basis for almost all current HIV vaccine trials are in essence similar to those for smallpox vaccine or influenza vaccine.  Vaccination has been usually successful in most cases, with an exception of HIV and AIDS.  One clear difference between HIV and other pathogens are their target cells. HIV attacks and destroys HST while others not.  

Lacking HST leads to AIDS and providing HST cures AIDS.  
What and how can it be simpler than this?

This is my current hypothesis why the loss of HST could be the main reason for breaking down of systemic immune responses which eventually leads to AIDS.  It is not a breakdown of an antigen specific immune responses.  

To prove this hypothesis, it would require reevaluation of current understanding of immunological knowledge (paradigm) to interpret abundant information (data) gathered from HIV infected individuals or from SIV infected non-human primates.  I will explain those issues in other section.

Key words:
HST, AIDS, HIV, AIDS vaccine, CCR5, Berlin patient, bone marrow transplant, stem cells, CXCR4, CXCR4-tropic HIV,

I will update this with adding scientific papers, figures and better words. Any idea would be greatly appreciated if you can help (correct) me to expand this.

What is the HIV vaccine supposed to do?

Vaccination, including the HIV vaccine, will result in an expansion of effector memory CD4 T cells, also called *HST here, right after the vaccination.  Contrary to our current understanding, vaccination would result in rapid expansion of HST at the mucosal non-lymphoid tissues.  These expanded HST would leave the non-lymphoid tissues, such as gut mucosal effector sites, and move to adjacent lymph nodes.  Simultaneously, antigen presenting cells (APC) present in non-lymphoid tissues, pick up antigens and move to the adjacent lymph nodes.  At the lymph nodes, expanded HST will activate antigen presenting cells that were migrated from the non-lymphoid tissues after picking up antigens.  Mature antigen presenting cells with the help of HST will activate  antigen specific naïve T cells, both CD4 and CD8 T cells, and they finally become activated.  Since a limited number of antigen specific naïve T cells are present in the lymph nodes, it will take a while (2 to 3 weeks) to have enough antigen specific T cells, which require multiple cell divisions.  

Based on an above scheme, vaccination will do the following:

1. Expansion of HST at the mucosal effector sites (this is different from current paradigm)
2. Migration of HST to the lymph nodes (this is different from current paradigm)
3. Migration of antigen presenting cells (APC) to the lymph nodes
4. HST activates APC at the lymph nodes and APC become matured (this is different from current paradigm)
5. Mature APCs activate antigen specific naive T cells

As explained above the presence of HST and their unique role needs to be clarified to fully understand the HIV PATHOGENESIS AND HIV VACCINE DEVELOPMENT.

During and after HIV infection:
Immediately after HIV infection, HIV infects and depletes the majority of the HST within a few days or weeks. The lack of HST in HIV infected individuals will not be able to initiate T cell mediated immune responses based on an above scheme.  How can you mimic this situation during vaccine development and clinical trials? To simulate that you will need to deplete all the HST present since real HIV infection will infect and deplete those present.  

This is impossible to consider at the present time. The first step is to gain a correct understanding of the presence of HST as unique type of CD4 T cells. The second step is to obtain comprehensive immunological understanding of HST.

Issues of facing current HIV and AIDS vaccine trials:
It is difficult to simulate the absence of HST and predict immune responses when HST are missing by HIV infection and destruction. That is the major problem facing our current HIV and AIDS vaccine trials whether this situation is being considered or not. During vaccination, HST will expand dramatically and boost a variety of immune responses. However, expansion of HST would provide more target cells that HIV can infect, feed on and prosper, no matter what the methods of vaccination were. Therefore, the repeated failures of HIV vaccine trials are not too surprising and actually are expected. Saving HST even in the presence of HIV infection should be the major goal and the focus of the research. It is a very difficult and challenging task without correct immunological understanding of HST.

What about the antibody mediated immune responses?
Recently, a group of investigators in Vaccine Research Center (VRC) of NIH reported that possible connection of HST to the antibody mediated immune responses (Klatt, et al. SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination Blood 2011 118:5803-5812).  Their work hinted that loss of HST will not only affect T cell mediated immune responses, but also on B cell mediated antibody responses.  I will discuss this issue separately later.  
It seems that the lack of HST would prevent antibody mediated immune responses due to failure of generating follicular helper T cells (TFH), which could be derived from HST.  


*HST: CD4 T cells that are susceptible to CCR5 (R5)-tropic HIV.  The majority, if not all, would show effector memory T cell phenotypes.

Key words:
Vaccination, HIV, HIV vaccine, effector memory T cells, HST, non-lymphoid tissues, lymph nodes, antigen presenting cells (APC), mature APC, naive T cells, CD4, CD8, antigen specific naive T cells, follicular helper T cells (TFH), B cell, antibody mediated immune responses

Reasons for struggle of obtaining an effective HIV (AIDS) vaccine

Current HIV vaccine trials are based on an assumption that immunization with HIV-derived antigen will result in immunological memory responses, whether they are cell mediated or antibody mediated.  Many HIV vaccine trials are unique in terms of choice of HIV-derived antigen used and (or) choice of viral vectors that deliver antigens. Some trials apply the pre-immunization with a piece of DNA derived from HIV genes or some uses whole killed HIV.  However, they are essentially all similar in a big picture of our current understanding of immunology. They only differ antigens delivered or vehicles to deliver antigens, hoping that different HIV epitopes or different viral vectors will do some magic.

On immunization, HIV-derived peptide will be presented to antigen presenting cells. Antigen presenting cells will activate HIV-peptide specific CD4 or CD8 T cells via MHC class II or class I molecules. After initial activation, a small number of T cells will remain as memory T cells and act quickly on their second encounter of the same antigen. This is the immunological basis for the cell mediated (T cells mediated) vaccine. Antibody mediated HIV vaccine is dependent upon generating memory B cells that were pre-exposed to external HIV epitopes, although it requires several critical steps for B cell maturation, which is helped by follicular helper CD4 T cells in several steps.

It is anticipated that pre-clinical experimental trials result in successful boosting of immune responses, whether they are T cell mediated, antibody mediated, or both.  If it were not the case, further trials would have been halted at that stage. Due to impressive immune boosting effects during pre-clinical trials, there were high hope that we will be able to obtain a successful HIV vaccine within a few short period of time. Why then, is it so difficult to generate HIV vaccine even after repeated and well-designed trials by many excellent groups for almost two decades? What is (are) the missing element(s)? Can we keep applying the same (or similar) strategy, just changing the minor components, and hope to get a vaccine within a next several decades?

During pre-clinical trials, when the host was not infected by HIV (SIV), all components necessary for an appropriate immune response to any pathogen (including the experimental SIV) remains intact. Once infected with HIV, the normal protective immune response becomes non-functional leading to a systemic immunodeficiency. There could be millions of reasons that can contribute to this. To find a reason or reasons could be very difficult, confusing and time-consuming. At the same time, it will provide a once in a lifetime chance to understand an underlying mechanism(s) on how does an immune system works and how does a vaccine works. I propose here one very apparent reason why do we encounter repeated failures of generating an HIV vaccine. This proposed explanation is well supported by ample experimental data, but not by a current theoretical basis. Our current immunological paradigm could prevent us from moving forward towards generating an effective HIV vaccine. Therefore, the problem could be our knowledge (or misunderstanding, or misconception), instead of the lack of knowledge. It usually takes a lot more time to unlearn, instead of just to learn. We may have to go through both, unlearning and learning.

One very apparent reason:
One of the critical steps for the successful vaccination requires the generation of memory T cells, whether the effect of vaccine is mediated by cytotoxic T cells or by broad neutralizing antibody. The generation and presence of memory T cells enable immune system to react to the previously exposed antigen quickly on the second or repeated exposure of the same antigen. The problem is that the process of generating immunological memory requires effector memory CD4 T cells (I will call them HIV Susceptible CD4 T cells, or HST, which designate CD4 T cells that are susceptible to CCR5 (R5)- tropic HIV).  However, during an early period of HIV infection, HIV selectively infect HST and deplete them all in a rapid pace.  Therefore, HIV infected individuals will permanently lose HST.  Without HST, there is no hope that immune response could be restored.  That could have been the case.  It is highly likely that HST could expand during vaccination.  Expanded HST become ideal and ample targets for CCR5 tropic HIV infection and expansion of virus very early on.


Key words:
HST, AIDS, AIDS vaccine, HIV, cell mediated immune responses, antibody mediated immune responses, viral vectors, immunological memory, CCR5, CCR5-tropic HIV

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