AZT resistance suppression mutations can also reduce tenofovir resistance, test tube study shows (corrected)

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This is a corrected version of an article originally published on aidsmap.com on Friday, 19 November 2004.

Mutations in HIV that suppress AZT (zidovudine, Retrovir) resistance, can also reduce resistance to tenofovir (Viread), according to the results of a test tube study presented this week at the Seventh International Congress on Drug Therapy in HIV Infection in Glasgow.

Both tenofovir and AZT work by preventing HIV from copying its genetic material within cells by mimicking one of the building blocks of DNA. These drugs are ‘chain terminators’, meaning that their chemical structure allows them to be incorporated into a DNA molecule, but prevents the next link in the chain from being added. This effectively stops the production of DNA and the production of new HIV particles.

Glossary

deoxyribonucleic acid (DNA)

The material in the nucleus of a cell where genetic information is stored.

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

concentration (of a drug)

The level of a drug in the blood or other body fluid or tissue.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

HIV that is resistant to AZT can overcome this by developing mutations that allow the virus to remove the AZT from the end of the growing DNA chain. These mutations are called thymidine analogue mutations (TAMs). This allows the virus to continue copying DNA and for viral loads to begin to rise within the body.

Furthermore, mutations within HIV's reverse transcriptase gene can reverse the effect of AZT resistance mutations. These 'suppression mutations' can decrease the level of resistance to AZT.

Investigators from the Karolinska Institute in Stockholm wished to assess the effect of three of the suppression mutations for AZT on tenofovir resistance: M184V, a 3TC (lamivudine, Epivir) resistance mutation, and Y181C and L100I, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations.

They used a biochemical assay to assess the replication rate of HIV in the presence of tenofovir, comparing normal, or ‘wild type’ reverse transcriptase with mutant reverse transcriptase. One mutant contained five TAMs: M41L, D67N, K70R, L210W and T215Y and the other, termed ‘69S-SG’, contained TAMs and a T69S-SG insertion. Both mutants were constructed with and without the three suppression mutations.

When they added the M184V mutation to wild type HIV, the investigators found that they needed only 50% of the concentration of tenofovir to produce the same amount of inhibition. Similarly, when this mutation was added to HIV with TAMs, it required 54% of the concentration of tenofovir for the same anti-viral effect, and 27% when it was added to 69S-SG virus, meaning that the degree of tenofovir resistance had been reduced.

The investigators also analysed the effect of adding the Y181C and L100I mutations to the 69S-SG mutant. These reduced the required concentration of tenofovir by 75% and 72%, respectively.

“The M184V, Y181C and L100I mutations reduce the ATP mediated excision of incorporated tenofovir” state the study’s investigators. “This indicates that there would be a benefit with tenofovir therapy combined with therapy rendering these suppression mutations.”

Narges Hassani Espili, presenting, confirmed that patients with suppression mutation for AZT resistance may show reduction in tenofovir resistance, and that maintaining therapy generating suppression mutations in such patients may increase tenofovir’s effectiveness. However, she warned that the clinical relevance of these in vitro findings must await investigation in future clinical studies.

References

Hassani Espili N et al. Effects of mutations associated with suppression of zidovudine resistance in HIV-1 reverse transcriptase on removal of tenofovir from blocked primer/template. Seventh International Congress on Drug Therapy in HIV Infection, Glasgow, abstract PL5.4, 2004.