Dr Richard Hunt

VIDEO LECTURE

VIROLOGY - CHAPTER   SEVEN    PART TEN

HUMAN IMMUNODEFICIENCY VIRUS AND AIDS  

LINKS  TO OTHER HIV AND AIDS SECTIONS ARE AT THE BOTTOM OF THIS PAGE

  Syncytia formation

   Infected cells are destroyed by cytotoxic T cells

Figure 27 - Some possible mechanism for the loss of T4 cells after HIV infection

Why, when only 1 in 10,000 (early) or 1 in 40 (later) cells show productive infection, do all of the T4 cells disappear? It is still unclear why the CD4⁺ cells all disappear but there are a number of possibilities:

 a) In an activated, infected CD4 cell, huge numbers of virions are synthesized. These bud from the cell and result in punctured membranes (figure 27). But the cell needs to be infected for this to happen and most CD4 cells are not infected.

 b) Since the membrane of HIV fuses with the membrane of the cell to be infected by a pH-independent mechanism, syncytia formation can occur leading to the spread of virus to uninfected cells (figure 27). But syncytia are not very common.

 c) Infected cells that are producing viral proteins (but not those in the latent state)  will present those proteins on the cell surface in association with class I MHC histocompatibility antigens. The infected cell, like other virally-infected cells, will be destroyed by cytotoxic T cells (figure 27). Again this only happens in cells that are infected by HIV.

d) Gp120 is linked to the Gp41 on the virus surface by non-covalent interactions and is frequently shed from infected cells or from virus particles. This binds to uninfected cells via CD4 antigen. As a result, they appear to be infected and destroyed by the immune system.

e) There have been reports of AIDS-related cytotoxic antibodies in infected patients that may react with a specific antigen on the surface of activated but uninfected T4 cells.

  The cells contact one-another and TNF-alpha and the receptor interact. Apoptosis ensues

  Macrophages internalize T cell

Figure 28 - Induction of apoptosis in T8 cells

f) AIDS may have an auto-immune component. In a normal antigenic response carried out by T4 cells, CD4 antigen interacts with MHC type II histocompatibility antigens. Since Gp120 also binds to CD4, the Gp120 can mimic MHC class II antigens since both  have a CD4-binding site; indeed, there appear to be regions of similar sequence in the two proteins. Thus anti-Gp120 antibodies may turn out to be anti-MHC antibodies as well. (This might spell trouble for vaccine production).

g) It is possible that HIV might infect  a subset of T4 cells that is vital to propagation of entire population of T4 cells

h) HIV proteins may alter T4 cell function. There is some evidence for this.

i)  Presently, the most actively studied possibility for the loss of the entire CD4+ and CD8+ cell population is that HIV initiates apoptosis in these cells (Such apoptosis is a normal process in  T4 cells to overcome autoimmunity and to terminate an immune response) (figure 28).  This is now thought to be a major factor in the loss of CD4 cells during the progression of the disease

Some of the above may explain why only a minority of T4 cells appear to be infected at a given time yet all disappear in the later stages of the disease. It could also be that the virus switches from one T4 cell population to another as it switches its co-receptor (see above).

CD8⁺ cells are not infected by HIV (because they do not have the CD4 receptor) and their numbers remain high during the course of the disease for many years. And then, until recently inexplicably, they rapidly die off.  It appears that some of the HIV subtypes that occur late in infection prompt a mass apoptosis of CD8 cells. Although CD8 cells are CD4^-, they do have CXCR4 co-receptor and HIV can bind to this (only the later syncytium-inducing strains of HIV do this). Since no CD4 antigen is present there is no infection but binding to CXCR4 sends a signal to the cell, the signal for apoptosis and mass CD8⁺ cell suicide ensues. Interestingly, the CD8 cells only die when macrophages are present.
 

How does this happen?   It is now known that binding of strains of HIV that arise later in infection to the CXCR4 receptor sets in motion the tumor necrosis-alpha death transducing pathway (figure 28). In macrophages, binding of a ligand to CXCR4 receptor on the cell surface induces the expression of TNF-alpha. In CD8+ T cells, the same binding triggers the expression of TNF-alpha receptor II. 

When such a macrophage and CD8+ T cell come in contact, the TNF-alpha on the macrophage binds to the TNF-alpha receptor on the CD8+ T cell. This triggers  an apoptosis signal in the CD8+ T cell resulting in the vesiculation of the CD8+ T cell (figure 28). Macrophages then phagocytose the remains of the T cell. This explains why macrophages have to be present for the CD8+ cells to die. Why would this happen naturally? Why do chemokines act as death signals for CD8+ T cells? These cells are killer cells and may cause serious trouble if they end up in the wrong place. It is thought that chemokines direct CD8+ T cells to the fate of macrophage-mediated death unless they reach their appropriate location.
 

PART I HUMAN IMMUNODEFICIENCY VIRUS AND AIDS

PART II HIV AND AIDS, THE DISEASE

PART III COURSE OF THE DISEASE

PART IV PROGRESSION AND COFACTORS

PART V STATISTICS

PART VI  SUBTYPES AND CO-RECEPTORS

PART VII  COMPONENTS AND LIFE CYCLE OF HIV

PART VIII  LATENCY OF HIV

PART IX GENOME OF HIV

PART X  LOSS OF CD4 CELLS

PART XI  OTHER CELLS INFECTED BY HIV AND POPULATION POLYMORPHISM

APPENDIX I  ANTI-HIV VACCINES

APPENDIX II  DOES HIV CAUSE AIDS?

APPENDIX III  ANTI_HIV CHEMOTHERAPY

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