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Excess DNA mutations seen in babies whose HIV-infected mothers took antiretroviral drugs

Susman, Ed

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Excess DNA mutations seen in babies whose HIV-infected mothers took antiretroviral drugs

In areas of the world in which antiretroviral drugs are readily available and can be used to treat pregnant women, the incidence of mother-to-child-transmission of HIV has fallen to vanishingly low levels.

However, researchers have begun to notice that these children who are born without infection appear to have a higher burden of DNA mutations. In the short term that finding has little consequence, but doctors worry that it might cause problems in the future.

`We really don't know what this means as far as the future risk of cancer', said Vernon Walker, research scientist at the Lovelace Respiratory Research Institute, Albuquerque, New Mexico. ‘However, it does indicate that warnings about future health problems that were promulgated by the Food and Drug Administration about the use of these drugs in pregnant women were justified.'

In a report at the annual meeting of the American Association for the Advancement of Science in Boston, MA, USA, Walker noted that there are no cases in which cancer related to the changes in drug use have been reported in children [1].

`All children are born with a few DNA mutations', he said. In his study, the average number of mutations among 68 children born to mothers who were unexposed to nucleoside reverse transcriptase inhibitors occurred at the rate of 1.3 per million cells. Of the 71 babies whose mothers took zidovudine to prevent transmission of the virus, there were an average of 2.6 mutations per million cells – approximately twice as many.

Walker said that approximately 3% of the unexposed children had mutations that indicated that an abnormal protein was created by the DNA damage; among children who took zidovudine alone or in a combination of zidovudine and lamuvidine these types of mutation occurred in 9–14% of babies. ‘Both those figures are significantly greater than the unexposed children', Walker said.

`DNA damage accumulates through a person's lifetime', Walker said. ‘These babies whose mothers received zidovudine and lamivudine have the accumulated DNA mutations one would expect to see in teenagers.'

Although raising some alarms, Walker insisted that because the antiretroviral drugs prevent transmission, the benefit of giving birth to a child not infected with HIV outweighs the possibility that cancer might develop years later. Children whose mothers originally took zidovudine in clinical trials are now approximately 6–7 years of age.

Nkosi honored

Nkosi Johnson, the 12-year-old South African child who gave children with AIDS a voice that reached around the world, was posthumously awarded the Children's Nobel Prize, awarded by the Swedish organization The Children's World, supported by the Swedish International Development Cooperation Agency.

Nkosi, who died in June 2001, electrified the 13th International AIDS Conference in Durban in 2000 when he pleaded with the reluctant South African government to provide antiretroviral therapy to pregnant women infected with HIV. ‘I just wish the government can start giving AZT to pregnant HIV mothers to help stop the virus being passed on to their babies. I don't want babies to die!'

`Nkosi is a worthy recipient of the Children's Nobel Prize because of his magnificent contributions towards raising awareness of the terrible disaster of the HIV/AIDS pandemic', said Jerry Coovadia, professor of HIV/AIDS Research at the University of Natal and chair of the Durban conference. ‘He lived through considerable difficulties as a child yet contributed more during his lifetime than many adults. Let us hope this award will rivet the world's attention and help mobilize the action so long delayed that will prevent the birth of more Nkosis.'

Only days after he was honored in Stockholm, the government of South Africa agreed to dispense antiretroviral drugs to rape victims and to pregnant women infected with the virus. The government of President Thabo Mbecki had long refused to distribute the drugs, claiming that their safety had not been proved.

`It's good news beyond belief', said Zackie Achmat, chairman of the South African AIDS activist group Treatment Action Campaign, ‘common sense has prevailed. We applaud the government for doing the right thing.'

HIV ‘rafts’ into cells

In order to enter cells, HIV must latch onto solid ‘raft-like’ cholesterol-rich regions of a cell's mainly fluid membrane, researchers at the National Institute of Allergy and Infectious Diseases have discovered. So, scientists postulate, cholesterol-lowering therapy might have an impact on HIV replication.

`Our research raises the intriguing possibility that widely used cholesterol-lowering drugs might have an effect in humans similar to what we have found in these initial laboratory studies', says Eric O. Freed, PhD, an investigator in NIAID's Laboratory of Molecular Microbiology [2].

When Freed and colleagues removed cholesterol from the cells, HIV lost much of its ability to produce new virus particles and infect additional cells. In order to navigate through a cell's outer membrane, HIV hops a ride on cholesterol-rich ‘rafts', which are more solid than the surrounding membrane and are able to move about like a raft on water.

The scientists said that rafts appear to be a mechanism that helps HIV spread. They speculate that even a modest degree of disruption could slow the spread of the virus because it would hinder the ability of the virus to enter and leave its host cells.

Scientists have known for some time that an HIV protein called Gag must attach to the inner surface of the cell membrane before new viruses can be produced.

Dr Freed established that Gag does indeed attach to rafts. Then they determined that removing cholesterol from the cell abolishes the ability of HIV to replicate.

`Our findings are clear evidence that Gag–raft association is a critical step in HIV replication', says Dr Freed. ‘Additional experiments are needed to determine whether this interaction can be interrupted therapeutically to treat HIV-infected people.'

HAART halts progression of AIDS dementia in some but not all patients

Patients with AIDS-related dementia tend to progress despite highly active antiretroviral therapy (HAART) if the patients are injection drug users, researchers reported at the 54th annual meeting of the American Academy of Neurology in Denver, CO, USA [3].

`We saw a trend toward improvement of HIV- associated dementia in patients who were able to maintain low viral loads', Dr Ryan Dougherty, MD, an internal medicine specialist at Johns Hopkins University School of Medicine said. ‘But we identified a strong association toward progression if the patient was an injection drug user. Why there is a difference is not clear, but it may be because the injection drug users also have numerous other comorbidities such as hepatitis.'

In his study, Dr Dougherty identified 30 patients since 1996 who have been started on HAART after HIV-associated dementia. Neurological outcomes were assessed by The Memorial Sloan–Kettering dementia severity score and the HIV Dementia Scale.

`Sixty percent of patients improved neurologically and 40 progressed', he said. Almost three-quarters of the patients who progressed had a history of injection drug use, compared with 17% of the patients who improved.

`Although the number of patients is low, the study suggests that neurological improvement correlates with virological suppression achieved with HAART', he said.

References

1. Walker VE, et al. Overview of antiretroviral nucleoside analogs: clinical use and toxicities. In:2002 American Association for the Advancement of Science Annual Meeting and Science Innovation Exhibition. Boston, MA, USA, 2002 [Abstract page A7].
2. Ono A, Freed EO. Plasma membrane rafts play a critical role in HIV-1 assembly and release.Proc Natl Acad Sci U S A 2001, 98:13925–13930. DOI: 10.1073/pnas.241320298.
3. Dougherty RH, McArthur JC. Progression of HIV-associated dementia treated with highly active antiretroviral therapy [Abstract P06.035]. Neurology 2002, 58 (Suppl. 3) : A441.A441.

Web sites

African Treatment Action Campaign http://www.tac.org.za
    of the National Academy of Sciences http://www.pnas.org
      Respiratory Research Institute http://www.lrri.org
        Nkosi Johnson AIDS Foundation http://nkosi.iafrica.com
          © 2002 Lippincott Williams & Wilkins, Inc.