HIV. Where Did All the CD4 T Cells Go? Part One
It continues to rain and rain here. Where the hell are my hip wadders?
It is well established that the development of HIV mutated viruses that preferentially find the CXCR4 receptor are an indicator of a poor prognosis, meaning AIDS.
What does this mean?
The textbook answer is that HIV strains that mutate in a certain way deplete the CD4 T cell population by promoting the fusion of HIV infected cells with normal, non-infected cells. This causes cell death and a reduction of CD4 T cell counts.
Not necessarily!!!
The CXCR4 receptor is found on almost all T cells, yet only CCR5 expressing T cells, activated/memory cells, are infected by the HIV virus. However, as the CD4 T cell count declines during HIV infections, all populations of CD4 T cells, naive and memory, decline in numbers equally. As I said, the textbook explanation for this phenomenon is that infected CD4 T cells, expressing mutated gp120 on their surface, bind to the CXCR4 receptor on naive T cells and cause their fusion. This results in cell death.
Yes, this cellular fusion does cause cell death, but there is a problem here. There are MANY HIV infected people out there, not using HIV drugs, who have VERY low or even no CD4 T cells yet they are perfectly or reasonabily healthy. What is going on?
In my opinion, these people have perfectly viable T cells but they have left the circulation and entered the tissues. This does NOT mean these cells are not functional. It means they are NOT present in the blood any longer and therefore not subject to standard CD4/CD8 T cell tests.
Some background.
The CXCR4 receptor on lymphocytes, cancer cells, and leukemia cells binds only the immune hormone SDF-1. SDF-1 is also called CXCL12. SDF-1 is a highly specific chemokine. This means it "draws" cells harboring the CXCR4 receptor to it. It's like a biological magnet. SDF-1 is secreted from stromal cells in the bone marrow and other cells that send out inflammatory signals.
In the presence of inflammation, a lesion needs to destroy mutated cells and to draw normal, progenitor cells into the lesion for wound healing. Sites of inflammation are highly associated with hypoxia or a lack of oxygen. The low oxygen tension in these damaged tissues induces the synthesis of HIF-1 or hypoxia induction factor. HIF-1 further induces the synthesis and secretion of SDF-1 from damaged endothelial (blood vessels) and other cells. The release of SDF-1 draws "healing" progenitor cells and lymphocytes into the lesion to promote wound healing.
http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&
dopt=Abstract&list_uids=15885571&itool=pubmed_docsum
http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&
dopt=Abstract&list_uids=15235597&itool=pubmed_docsum
What does this have to do with HIV infections?
Viral NEF is the only HIV protein that can cause AIDS in transgenic mice. NEF activates the membrane NADPH oxidase enzyme on numerous cells, thereby promoting the generation of superoxide anion and hydrogen peroxide. This causes tissue damage, especially vascular damage. In time, vascular damage translates to excessive blood clotting, tissue hypoxia and organ death.
Keep in mind that NEF transgenic mice express the NEF protein but NO other viral proteins.
Hypoxia increases the level of HIF-1 and HIF-1 increases the synthesis and secretion of SDF-1 from endothelial and other tissues. See previous references. This draws CXCR4 T cells into the tissue spaces.
NEF, therefore, can cause naive, non activated CD4 T cells to leave the blood by inducing vascular damage.
In a previous Blog essay, I argued that a reduction of CD4 T cell counts in the blood does NOT necessarily mean these cells are dead. Quite to the contrary, they may have migrated into the tissues spaces at an accelerated rate.
http://grouppekurosawa.com/blog/2005/12/hiv-and-cd4-t-lymphocyte-counts.htm
This is where the data gets really interesting. In the above Blog essay, I cited a long forgotten paper which argued that the migration of infected cells, primarily monocytes, out of the blood into the tissues was the beginning of clinical AIDS.
Scientists have "fixated" on the ability of CXCR4 loving viral strains to cause cellular fusion and CD4 T cell death. Although this certainly happens, does it completely explain the rapid decline in blood CD4 T cell counts associated with the development of AIDS?
I don't think so. Keep the following in mind. The formation of syncytia or giant cells due to fusion is caused by the interaction of mutated, CXCR4 loving, HIV infected cells with normal cells. The HIV gp120 protein remains in the membrane of the infected cells.
The following paper is worth its weight in Gold. It shows that FREE gp120 protein, mutated to bind the CXCR4 receptor, completely substitutes for the immune hormone SDF-1 as a chemotactic factor. Of importance, it acts on NON-activated CD4 T cells, non infected with the HIV virus, to draw them to areas of high gp120 concentrations. This means, pure and simple, that HIV synthesis in organs can release gp120 from dying virus or infected cells and "draw" CXCR4 naive T cells OUT of the blood into the tissues.
http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&
dopt=Abstract&list_uids=15585836&itool=pubmed_docsum
These cells are NOT dead nor are they infected with the HIV virus. No wonder some people with very low CD4 T cell counts are perfectly healthy. There is more to AIDS than the blood CD4 T cell count.
In the next essay, I will discuss the biochemistry of this chemotactic response.
Stay tuned...
Grouppe Kurosawa, Medicine in the Public Interest
(http://www.grouppekurosawa.com)
It is well established that the development of HIV mutated viruses that preferentially find the CXCR4 receptor are an indicator of a poor prognosis, meaning AIDS.
What does this mean?
The textbook answer is that HIV strains that mutate in a certain way deplete the CD4 T cell population by promoting the fusion of HIV infected cells with normal, non-infected cells. This causes cell death and a reduction of CD4 T cell counts.
Not necessarily!!!
The CXCR4 receptor is found on almost all T cells, yet only CCR5 expressing T cells, activated/memory cells, are infected by the HIV virus. However, as the CD4 T cell count declines during HIV infections, all populations of CD4 T cells, naive and memory, decline in numbers equally. As I said, the textbook explanation for this phenomenon is that infected CD4 T cells, expressing mutated gp120 on their surface, bind to the CXCR4 receptor on naive T cells and cause their fusion. This results in cell death.
Yes, this cellular fusion does cause cell death, but there is a problem here. There are MANY HIV infected people out there, not using HIV drugs, who have VERY low or even no CD4 T cells yet they are perfectly or reasonabily healthy. What is going on?
In my opinion, these people have perfectly viable T cells but they have left the circulation and entered the tissues. This does NOT mean these cells are not functional. It means they are NOT present in the blood any longer and therefore not subject to standard CD4/CD8 T cell tests.
Some background.
The CXCR4 receptor on lymphocytes, cancer cells, and leukemia cells binds only the immune hormone SDF-1. SDF-1 is also called CXCL12. SDF-1 is a highly specific chemokine. This means it "draws" cells harboring the CXCR4 receptor to it. It's like a biological magnet. SDF-1 is secreted from stromal cells in the bone marrow and other cells that send out inflammatory signals.
In the presence of inflammation, a lesion needs to destroy mutated cells and to draw normal, progenitor cells into the lesion for wound healing. Sites of inflammation are highly associated with hypoxia or a lack of oxygen. The low oxygen tension in these damaged tissues induces the synthesis of HIF-1 or hypoxia induction factor. HIF-1 further induces the synthesis and secretion of SDF-1 from damaged endothelial (blood vessels) and other cells. The release of SDF-1 draws "healing" progenitor cells and lymphocytes into the lesion to promote wound healing.
http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&
dopt=Abstract&list_uids=15885571&itool=pubmed_docsum
http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&
dopt=Abstract&list_uids=15235597&itool=pubmed_docsum
What does this have to do with HIV infections?
Viral NEF is the only HIV protein that can cause AIDS in transgenic mice. NEF activates the membrane NADPH oxidase enzyme on numerous cells, thereby promoting the generation of superoxide anion and hydrogen peroxide. This causes tissue damage, especially vascular damage. In time, vascular damage translates to excessive blood clotting, tissue hypoxia and organ death.
Keep in mind that NEF transgenic mice express the NEF protein but NO other viral proteins.
Hypoxia increases the level of HIF-1 and HIF-1 increases the synthesis and secretion of SDF-1 from endothelial and other tissues. See previous references. This draws CXCR4 T cells into the tissue spaces.
NEF, therefore, can cause naive, non activated CD4 T cells to leave the blood by inducing vascular damage.
In a previous Blog essay, I argued that a reduction of CD4 T cell counts in the blood does NOT necessarily mean these cells are dead. Quite to the contrary, they may have migrated into the tissues spaces at an accelerated rate.
http://grouppekurosawa.com/blog/2005/12/hiv-and-cd4-t-lymphocyte-counts.htm
This is where the data gets really interesting. In the above Blog essay, I cited a long forgotten paper which argued that the migration of infected cells, primarily monocytes, out of the blood into the tissues was the beginning of clinical AIDS.
Scientists have "fixated" on the ability of CXCR4 loving viral strains to cause cellular fusion and CD4 T cell death. Although this certainly happens, does it completely explain the rapid decline in blood CD4 T cell counts associated with the development of AIDS?
I don't think so. Keep the following in mind. The formation of syncytia or giant cells due to fusion is caused by the interaction of mutated, CXCR4 loving, HIV infected cells with normal cells. The HIV gp120 protein remains in the membrane of the infected cells.
The following paper is worth its weight in Gold. It shows that FREE gp120 protein, mutated to bind the CXCR4 receptor, completely substitutes for the immune hormone SDF-1 as a chemotactic factor. Of importance, it acts on NON-activated CD4 T cells, non infected with the HIV virus, to draw them to areas of high gp120 concentrations. This means, pure and simple, that HIV synthesis in organs can release gp120 from dying virus or infected cells and "draw" CXCR4 naive T cells OUT of the blood into the tissues.
http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&
dopt=Abstract&list_uids=15585836&itool=pubmed_docsum
These cells are NOT dead nor are they infected with the HIV virus. No wonder some people with very low CD4 T cell counts are perfectly healthy. There is more to AIDS than the blood CD4 T cell count.
In the next essay, I will discuss the biochemistry of this chemotactic response.
Stay tuned...
Grouppe Kurosawa, Medicine in the Public Interest
(http://www.grouppekurosawa.com)
1 Comments:
Dr. Steve,
Great article on the pathogenesis of HIV disease. I look forward to reading more about this subject.
Thank you,
Tom
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