Do all CD4 T cells become targets for HIV infection after activation?

Do all CD4 T cells become targets for HIV infection?

This is a simple but important question that can easily be answered and the outcome would benefit tremendously to understand the HIV pathogenesis correctly.  If I ask this question to many current immunologists who have spent the majority of their professional lives on CD4 T cell, they would not be able to give you a correct answer, let alone from virologists working on HIV pathogenesis.  Therefore, I decided to describe our current consensus (understanding) on this issue and will add my own version to this.

Current views:

• Not all CD4 T cells are readily infected by HIV.
• CCR5 expressing CD4 T cells can only be infected by R5-tropic HIV.
• CXCR4 expressing CD4 T cells can only be infected by X4-tropic HIV.
• R5/X4-tropic HIV can infect CD4 T cells that express either CCR5 or CXCR4.

What is not clear:

• Do all CD4 T cells have potential to express CCR5 and/or CXCR4?
• Can a specific group of CD4 T cells express either CCR5 or CXCR4?
• What is the general tendency of expression of these molecules among all CD4 T cells?

My version:

• Only a specific group of CD4 T cells is able to express CCR5 (HST)
• The majority of CD4 T cells is able to express CXCR4, especially after activation.
• There is a possibility that CCR5 expressing CD4 T cells (HST) can express CXCR4 before or after activation.  But this may not be an important issue.
• The loss of CXCR4 expressing CD4 T cells are not as critical as the loss of CCR5 expressing CD4 T cells.  (Evidence: Berlin patient)

Significance:

• Infection of CD4 T cells by X4-tropic HIV infection may not be as critical as that of R5-tropic HIV infection, since the loss of CCR5 expressing CD4 T cells undoubtedly leads to AIDS.
• The loss of a small population of activated CD4 T cells by X4-tropic HIV infection would leave a small hole in our protective immunity.  Fox example, the loss of certain flu-peptide specific CD4 T cells is not life threatening or leads to systemic immunodeficiency as the loss of HST (HST: CD4 T cells that are susceptible to R5-tropic HIV).  
• But that is not the case, when we are infected with R5-tropic HIV.  They wipe off all CCR5 expressing CD4 T cells and undoubtedly will lead to an onset of AIDS.
• Without the presence of R5-tropic HIV, there may not be AIDS.
• Therefore, it could be very important to be able to separate R5-tropic vs. X4-tropic HIV infection.
• Why does the loss of CCR5 expressing CD4 T cells lead to AIDS?
• Why does the loss of total CD4 T cells happen gradually, while the HST are depleted within a matter of weeks after R5-tropic HIV infection?
• The above questions are apparent ones that are in need of immediate answers.

Relevant publication:

The following is a very specialized issue for advanced immunologists:  It will probably get you bored from the get-go.

Low levels of SIV infection in sooty mangabey central memory CD4⁺ T cells are associated with limited CCR5 expression

Paiardini, Silvestri and their colleagues from around the world (published in the Nature medicine).  

http://www.nature.com/nm/journal/v17/n7/full/nm.2395.html (Nature Medicine 2011). Their abstract is as follows,

"Naturally simian immunodeficiency virus (SIV)-infected sooty mangabeys do not progress to AIDS despite high-level virus replication. We previously showed that the fraction of CD4⁺CCR5⁺ T cells is lower in sooty mangabeys compared to humans and macaques. Here we found that, after in vitro stimulation, sooty mangabey CD4⁺ T cells fail to upregulate CCR5 and that this phenomenon is more pronounced in CD4⁺ central memory T cells (T_CM cells). CD4⁺ T cell activation was similarly uncoupled from CCR5 expression in sooty mangabeys in vivo during acute SIV infection and the homeostatic proliferation that follows antibody-mediated CD4⁺ T cell depletion. Sooty mangabey CD4⁺ T_CM cells that express low amounts of CCR5 showed reduced susceptibility to SIV infection both in vivo and in vitro when compared to CD4⁺ T_CM cells of rhesus macaques. These data suggest that low CCR5 expression on sooty mangabey CD4⁺ T cells favors the preservation of CD4⁺ T cell homeostasis and promotes an AIDS-free status by protecting CD4⁺ T_CM cells from direct virus infection."

My personal view on this paper: This is an excellent paper on one of the most important issues in HIV and AIDS research.  Why sooty mangabey is not getting an AIDS-like syndrome even with high titers of SIV?  As usual, they did a very good job.  One of the issues that I do not totally agree with them are marked as a bold/underlined above.  Their experiment is based on an assumption that CCR5 is expressed on the 'so called' effector memory CD4 T cells (T_EM), and they are derived from the central memory T cells (CD4⁺ T_CM cells).  That is our current common understanding and paradigm, especially to several investigators for HIV pathogenesis.  However, there is a strong possibility that there is a separate lineage of CD4 T cells that are exclusively able to express CCR5 molecules.  Instead of upregulation as they have claimed, a small number of those cells could be differentially expanded.  I will leave detailed discussion to the current professionals.  Nonetheless, it is one of the essential and basic knowledge to be resolved to design an effective vaccine against HIV.

Key words:
CD4 T cell, HIV, immunologist, virologist, CCR5, CXCR4, R5-tropic, X4-tropic, AIDS, HST, Paiardini, Silvestri, Nature Medicine, SIV, sooty magabey, central memory T cells, effector memory T cells, homeostatic proliferation, rhesus macaque