HIV infection damages mitochondria in the absence of antiretroviral therapy

Infection with HIV can cause a significant loss in the number of mitochondria in white blood cells in the first year after seroconversion, according to a study presented in the 1^st May edition of The Journal of Infectious Diseases. This could be a major factor in the development of HIV-associated complications, including peripheral neuropathy, damage to the heart muscle, wasting and kidney disease.

Mitochondria are components of human cells that release energy by breaking down food molecules. Loss of mitochondria is known to occur during treatment with nucleoside analogues (NRTIs) such as AZT (zidovudine, Retrovir) and d4T (stavudine, Zerit), and is responsible for side-effects such as peripheral neuropathy and fat loss (lipoatrophy).

However, some studies that have compared the number of mitochondria in cells of HIV-positive and HIV-negative people have suggested that HIV itself could cause loss of mitochondria. These ‘cross-sectional’ studies have suggested that the virus itself could produce similar effects to the side-effects of NRTIs.

To gain more information on the effect of HIV infection on mitochondria within individual patients, investigators from the Amsterdam Cohort Study followed 36 men with documented HIV seroconversion.

As mitochondria contain small amounts of DNA that is genetically distinct from the DNA found in the nucleus of the human cell, the investigators could estimate the number of mitochondria in each cell by measuring the relative amounts of mitochondrial and nuclear DNA in a sample of cells.

They compared the amount of mitochondrial DNA (mtDNA) per white blood cell before and after infection, discovering a significant fall in the first year after seroconversion.

“Our longitudinal study confirms the finding from earlier cross-sectional studies that HIV-1 infection, in the absence of any antiretroviral therapy, is associated with a decrease in the mtDNA content of peripheral blood mononuclear cells,” write the investigators.

The investigators isolated peripheral blood mononuclear cells from stored blood samples taken from the men a median of three years before and around one year after seroconversion. There was a significant fall in the amount of mtDNA between these two time points (median 264 vs. 234 copies/cell; p = 0.004). This was equivalent to an 11% decrease (95% confidence interval: 2 – 21%).

They also measured mtDNA levels at around five years after seroconversion in the 18 men who had still not started antiretroviral therapy and for whom samples were available. The difference from the one-year time point was not statistically significant (median 240 vs. 213 copies/cell; p = 0.894). However, the small sample size makes it impossible to draw firm conclusions from this result.

There was a significant fall in CD4 cell counts between pre-seroconversion and five years post-seroconversion (median 761 vs. 480 cells/mm³; p 3; p = 0.001).

However, the investigators found no association between these parameters or viral loads and the amount of mtDNA per cell. Age also had no significant effect on the number of mitochondria. They were unable to assess the role of other factors such as co-infection with hepatitis, due to lack of information.

The researchers offer two related explanations for their findings. Firstly, they suggest that HIV infection could cause an increase in the generation of damaging reactive oxygen species in the cells it infects. These highly reactive molecules can mutate mtDNA.

Secondly, they suggest that proteins produced by the HIV itself could have an effect on mitochondria. “HIV-1-encoded proteins, such as Vpr, have been shown to adversely affect mitochondrial integrity,” they write. “This possibility renders the normal reactive oxygen species scavenging mechanism ineffective, resulting in increased damage to mtDNA.”

Further studies are required to investigate these possible mechanisms.

The researchers conclude by predicting that the control of HIV by antiretroviral medication may remove the damaging effect of the virus on mitochondria. However, the use of NRTIs may counteract this through their own damaging effect on mtDNA, leading to further loss of mitochondria and the development of side-effects.