A commonly used class of antiretroviral drugs used to treat patients with HIV, particularly in Africa, appears to speed up aging by causing natural mutations in mitochondrial DNA to accumulate faster, mirroring those present in people who age normally. You can read about the research behind this finding in this week’s online issue of Nature Genetics, where Professor Patrick Chinnery from Newcastle University in the UK, and colleagues, suggest that treatment with nucleoside analogue anti-retrovirals (NRTIs) does not accelerate aging by generating new mutations of mitochondrial DNA, but most probably by accelerating turnover of mitochondrial DNA.
Clinicians are noticing that people with HIV who are treated with antiretroviral drugs sometimes show premature signs of aging, such as increased frailty, and age-related diseases like cardiovascular disease and dementia. But they have few clues as to why, as Chinnery, who is a Wellcome Senior Fellow in Clinical Science from the Institute of Genetic Medicine at Newcastle University, told the press:
“HIV clinics were seeing patients who had otherwise been successfully treated but who showed signs of being much older than their years. This was a real mystery. But colleagues recognised many similarities with patients affected by mitochondrial diseases – conditions that affect energy production in our cells – and referred them to our clinic.”
Some of the patients referred to their clinic were being treated with a class of antiretroviral called NRTI, short for nucleoside analogue reverse-transcriptase inhibitors, the most well-known of which is Zidovudine, also known as AZT. (NRTIs are also used in the treatment of cancer).
NRTIs were the first class of drug developed to treat HIV, and at the time were regarded as a major breakthrough in anit-HIV treatment, giving patients the hope of longer life and changing our view of HIV from a terminal to a chronic condition.
But as time has gone on, higher income countries have made less use of the older NRTIs and moved onto newer, less toxic drugs with fewer side effects when taken over longer periods. But in Africa, where the older NRTIs are now off-licence and relatively cheap, they are still the main life-saver for people with HIV.
HIV spreads in the body because it inserts its genetic code into the nuclear DNA of the cells of its host. Once inside a cell, it uses its own reverse transcriptase enzyme to copy its RNA code into a double-stranded DNA which is then integrated into the DNA of the host cell. After that, when the host cell replicates, it replicates the viral DNA with it.
Mitochondria are tiny enclosed “battery” units inside cells: they make the energy that our cells need to live and work. One of the many interesting things about them is their DNA is quite separate from that in the nucleus of cells: and this mitochondrial DNA or mtDNA, is only inherited from the female parent (sperms don’t carry mtDNA).
As humans age naturally, their mtDNA accumulates mutations, however we still don’t know if mtDNA mutation cause aging or if aging cause mtDNA mutation.
When Chinnery and colleagues examined the muscle cells of the patients who had been treated with NRTIs, they found mitochondria damage similar to that found in much older healthy people: even the patients who had been treated ten years ago showed this damage.
However, they believe the NRTIs did not cause new mutations in the mtDNA, but simply accelerated the rate at which the mtDNA copies itself, thus the younger HIV patients were showing the same accumulation of copying “errors” as one might find in healthy older people:
“Ultra-deep re-sequencing by synthesis, combined with single-cell analyses, suggests that the increase in somatic mutation is not caused by increased mutagenesis but might instead be caused by accelerated mtDNA turnover. This leads to the clonal expansion of preexisting age-related somatic mtDNA mutations and a biochemical defect that can affect up to 10% of cells,” they write.
Chinnery said:
“We believe that these HIV drugs accelerate the rate at which these errors build up. So over the space of, say, ten years, a person’s mitochondrial DNA may have accumulated the same amount of errors as a person who has naturally aged twenty or thirty years. What is surprising, though, is that patients who came off the medication many years ago may still be vulnerable to these changes.”
However, the researchers urged caution: while NRTIs may have this effect, they are still important drugs and the risks should be seen as relative.
“These drugs may not be perfect, but we must remember that when they were introduced they gave people an extra 10 or 20 years when they would otherwise have died,” said HIV specialist and co-author Dr Brendan Payne from the Department of Infection and Tropical Medicine at the Royal Victoria Infirmary, Newcastle.
“In Africa, where the HIV epidemic has hit hardest and where more expensive medications are not an option, they are an absolute necessity,” he added.
Chinnery and colleagues now want to look into ways to repair or delay the damage caused by NRTIs. One option is to encourage patients to exercise more, as this appears to work for people with mitochondrial diseases.
Funds from the Wellcome Trust, the Medical Research Council, the British Infection Society, the Newcastle Healthcare Charity, and the UK NIHR Biomedical Research Centre for Aging and Age-related Disease helped pay for the study.
Brendan A I Payne, Ian J Wilson, Charlotte A Hateley, Rita Horvath, Mauro Santibanez-Koref, David C Samuels, D Ashley Price & Patrick F Chinnery.
Nature Genetics, Published online: 26 June 2011.
DOI:10.1038/ng.863
Additional source: Wellcome Trust.
Written by: Catharine Paddock, PhD