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THEORY: What causes the loss of CD4 T cells in people infected with HIV?

A Theory for HIV infection: What causes the loss of CD4 T cells in people infected with HIV? Guest Contributor: Dr Clovis Palmer, Brunet Institute, Melbourne Australia | 18th Jul 2014 HIV infection causes dysfunction and destruction of CD4 T cells that, without antiretroviral therapy (ART: a cocktail of drugs that interrupts the HIV life cycle), result in AIDS and eventual death within 7 to 10 years).Scientists believe that most CD4 T cells die, not because of direct infection by HIV of these cells, but through a process called inflammation, by which immune cells secrete toxic molecules to get rid of the virus.However, the logic behind how inflammation causes cell death has been a mystery for decades.But now, research conducted by scientists at the Burnet Institute in Melbourne, Australia, and published in the premiere HIV/AIDS Journal, AIDS in 2014, shows for the first time that HIV infection not only disturbs the functions of CD4 T cells but affects how these cells use energy (1). The team, led by chief investigator Dr Clovis Palmer, proposed a new model of how CD4 T cells are destroyed in people infected with HIV.In healthy persons, immune cells such as CD4 T cells take up low levels of glucose through a protein known as Glucose transporter 1 (Glut1). By a series of steps the glucose is broken down to produce pockets of energy called adenosine triphosphate (ATP) to maintain the general wellbeing of the cells The Burnet team showed that the Glucose transporter (Glut1) level is increased on CD4 T cells in people infected with HIV, and that this causes more glucose to enter the cells. This is a survival mechanism because the CD4 T cells need more energy to divide and manufacture antiviral and inflammatory molecules to fight the infection. This is what is called CD4 T cell activation or immune activation. In this activated state, instead of breaking down glucose to form energy pockets (ATP), glucose is broken down into a substance called lactic acid through a process called aerobic glycolysis. Glycolysis is only moderately efficient in energy production and, as a result, the CD4 T cells die of exhaustion. The researchers called this process ‘metabolic exhaustion’ Dr Palmer believes that this finding could lead to new drugs that delay the start of anti-retroviral therapy and will strengthen the immune systems of HIV-positive people.Healthy adults have between 600 to 1,200 CD4 T cells in their blood but up to 30 percent of HIV infected adults have a CD4 cell count consistently less than 350, well below the normal range despite being on ART and having undetectable viral load. The team showed that glycolysis remains elevated in CD4 T cells from these persons and that this could explain why they are unable to reconstitute their normal CD4 T cell levels. These low levels of CD4 T cells put HIV-positive people on ART at higher risk of cardiovascular disease, liver disease, kidney failure and other life-threatening diseases.The results from this study suggest that CD4 T cells in HIV infected people cannot replenish themselves because they exhaust their energy reserves through their high metabolic activity. What’s exciting about this is a very real scenario where, by returning metabolic activity to normal, these cells could be re-energised to fight the infection by themselves.Dr Clovis Palmer heads the immunometabolism group at the world renowned Burnet Institute of Medical Research in Melbourne, Australia. Dr Palmer is a reviewer for several top ranked international journals including Hepatology, AIDS and Antioxidants and Redox Signalling. He is the chief scientific editor for Natural Immunity-Health, Australia (www.naturalimmunity.com.au). References1. Palmer C, Ostrowski M, Gouillou M, Tsai L, Yu D, Zhou J, Henstridge D, Maisa A, Hearps AC, Lewin S, Landay A, Jaworowski A, Mccune J, Crowe SM (2014). Increased glucose metabolic activity is associated with CD4+ T cell activation and depletion during chronic HIV infection. AIDS. 28:297-309

A Theory for HIV infection: What causes the loss of CD4 T cells in people infected with HIV?

Guest Contributor: Dr Clovis Palmer, Brunet Institute, Melbourne Australia | 18th Jul 2014

HIV infection causes dysfunction and destruction of CD4 T cells that, without antiretroviral therapy (ART: a cocktail of drugs that interrupts the HIV life cycle), result in AIDS and eventual death within 7 to 10 years).

Scientists believe that most CD4 T cells die, not because of direct infection by HIV of these cells, but through a process called inflammation, by which immune cells secrete toxic molecules to get rid of the virus.

However, the logic behind how inflammation causes cell death has been a mystery for decades.

But now, research conducted by scientists at the Burnet Institute in Melbourne, Australia, and published in the premiere HIV/AIDS Journal, AIDS in 2014, shows for the first time that HIV infection not only disturbs the functions of CD4 T cells but affects how these cells use energy (1). The team, led by chief investigator Dr Clovis Palmer, proposed a new model of how CD4 T cells are destroyed in people infected with HIV.

In healthy persons, immune cells such as CD4 T cells take up low levels of glucose through a protein known as Glucose transporter 1 (Glut1). By a series of steps the glucose is broken down to produce pockets of energy called adenosine triphosphate (ATP) to maintain the general wellbeing of the cells

The Burnet team showed that the Glucose transporter (Glut1) level is increased on CD4 T cells in people infected with HIV, and that this causes more glucose to enter the cells. This is a survival mechanism because the CD4 T cells need more energy to divide and manufacture antiviral and inflammatory molecules to fight the infection. This is what is called CD4 T cell activation or immune activation.

In this activated state, instead of breaking down glucose to form energy pockets (ATP), glucose is broken down into a substance called lactic acid through a process called aerobic glycolysis. Glycolysis is only moderately efficient in energy production and, as a result, the CD4 T cells die of exhaustion. The researchers called this process ‘metabolic exhaustion’

Dr Palmer believes that this finding could lead to new drugs that delay the start of anti-retroviral therapy and will strengthen the immune systems of HIV-positive people.

Healthy adults have between 600 to 1,200 CD4 T cells in their blood but up to 30 percent of HIV infected adults have a CD4 cell count consistently less than 350, well below the normal range despite being on ART and having undetectable viral load. The team showed that glycolysis remains elevated in CD4 T cells from these persons and that this could explain why they are unable to reconstitute their normal CD4 T cell levels. These low levels of CD4 T cells put HIV-positive people on ART at higher risk of cardiovascular disease, liver disease, kidney failure and other life-threatening diseases.

The results from this study suggest that CD4 T cells in HIV infected people cannot replenish themselves because they exhaust their energy reserves through their high metabolic activity. What’s exciting about this is a very real scenario where, by returning metabolic activity to normal, these cells could be re-energised to fight the infection by themselves.

Dr Clovis Palmer heads the immunometabolism group at the world renowned Burnet Institute of Medical Research in Melbourne, Australia. Dr Palmer is a reviewer for several top ranked international journals including Hepatology, AIDS and Antioxidants and Redox Signalling. He is the chief scientific editor for Natural Immunity-Health, Australia (www.naturalimmunity.com.au).

References

1. Palmer C, Ostrowski M, Gouillou M, Tsai L, Yu D, Zhou J, Henstridge D, Maisa A, Hearps AC, Lewin S, Landay A, Jaworowski A, Mccune J, Crowe SM (2014). Increased glucose metabolic activity is associated with CD4+ T cell activation and depletion during chronic HIV infection. AIDS. 28:297-309