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