Computational modeling of drug resistance to guide treatment decisions for HIV patients

September 20, 2017, Agency for Science, Technology and Research (A*STAR), Singapore
Computational modeling of drug resistance to guide treatment decisions for HIV patients
The Antibody and Product Development group is led by Samuel Ken-En Gan (back row, second from the left). Postdoctoral fellow Chinh Tran-To Su (back row, second from right) was the first author of this study. Credit: A*STAR Bioinformatics Institute

A bioinformatic examination of HIV mutations documented in clinics could help guide the selection of antiretroviral therapies.

Through structural modeling and computational analyses, A*STAR researchers have shown how changes in the HIV genome that make the virus resistant to one can often induce resistance more broadly to other drugs of the same class. The findings suggest that some of these drugs—known as protease inhibitors because they block critical viral proteases—should be prescribed before others.

Such a strategy could help "delay the onset of , thereby prolonging effectiveness, improving quality of life and lowering treatment costs," says Samuel Ken-En Gan, the study's senior author from the A*STAR Bioinformatics Institute.

Gan and his team modeled the structures of more than two dozen mutated proteases that clinicians found made HIV resistant to any one of seven different protease-blocking drugs. These mutations arose in patients who were taking just one of these drugs, but they impacted the efficacy of other protease inhibitors, too. The A*STAR team showed that cross-resistance can develop easily across five of the seven protease inhibitors, but less so for the other two.

That kind of information, says Chinh Tran-To Su, a postdoctoral fellow in Gan's lab, "could help guide the selection of drugs for the first and subsequent lines of treatment."

Take the lopinavir, for example. The analysis found that resistance to any other protease inhibitor would probably induce resistance to lopinavir as well. That means it's not very useful if taken by patients after other drugs have started to fail. However, since resistance to lopinavir does not seem to affect how well the other six protease inhibitors will work, Gan and Su conclude that lopinavir should be considered as the drug of choice for patients who are getting their first protease inhibitor.

Should resistance then emerge to lopinavir, the analysis indicates that patients should try one of the four other protease inhibitors that are prone to cross-resistance, while saving the two that are least affected by cross- as agents of last-resort.

Clinical implementation of these recommendations will be needed to test the predictions of the computational modeling. But as Gan notes, the insights gleaned from his group's structural analysis would be hard to come by any other way. "This paper," he says, "represents a landmark analysis using bioinformatics to go where experimental labs and clinical trials cannot easily investigate."

Explore further: Protease inhibitor resistance involves multiple stages of the HIV-1 life cycle

More information: Chinh Tran-To Su et al. Structural analyses of 2015-updated drug-resistant mutations in HIV-1 protease: an implication of protease inhibitor cross-resistance, BMC Bioinformatics (2016). DOI: 10.1186/s12859-016-1372-3

Related Stories

Protease inhibitor resistance involves multiple stages of the HIV-1 life cycle

August 27, 2013
HIV-1 protease inhibitors are very effective antiviral drugs. These drugs target HIV-1 proteases, which are required for viral replication. Despite the success of protease inhibitors for suppressing HIV-1, some patients do ...

Drug designer: New tool reveals mutations that cause HIV-drug resistance

July 8, 2011
Protease inhibitor drugs are one of the major weapons in the fight against HIV, the virus that causes AIDS, but their effectiveness is limited as the virus mutates and develops resistance to the drugs over time. Now a new ...

Protease inhibitor and NRTIs safe, effective in HIV treatment

July 19, 2014
(HealthDay)—An HIV treatment regimen of a boosted protease inhibitor (lopinavir) combined with nucleoside reverse-transcriptase inhibitors (NRTIs) is safe and effective in low-resource settings, according to a study published ...

HIV treatment reduces risk of malaria recurrence in children, study shows

November 28, 2012
A combination of anti-HIV drugs has been found to also reduce the risk of recurrent malaria by nearly half among HIV-positive children, according to researchers supported by the National Institutes of Health.

Discovery of new prostate cancer biomarkers could improve precision therapy

August 14, 2017
Mayo Clinic researchers have identified a new cause of treatment resistance in prostate cancer. Their discovery also suggests ways to improve prostate cancer therapy. The findings appear in Nature Medicine. In the publication, ...

Structural analysis of relevant drug targets for Alzheimer's disease

June 12, 2017
Alzheimer's Disease (AD) is classified as a neurodegenerative non-curable disease that affects millions worldwide. Current drugs have side effects that are significant. In AD, the beta-amyloid precursor protein (β-APP) that ...

Recommended for you

Unlocking the secrets of HIV's persistence

May 22, 2018
Thanks to advances in the development of anti-retroviral therapy (ART), patients with HIV are living longer than ever before. And yet, even in patients on very effective, long-term ART, HIV persists, requiring patients to ...

Discovery of how HIV hedges its bets opens the door to new therapies

May 10, 2018
A stem cell is one with infinite possibilities. So, for decades, scientists have puzzled over how the cell chooses to keep being a stem cell and continue dividing, or specialize into a specific cell type, like a heart or ...

Researchers find link between crystal methamphetamine and immune changes in HIV

May 4, 2018
A researcher at the University of Miami Miller School of Medicine has found that the use of stimulants, such as methamphetamine, can negatively affect the health of HIV-positive persons even when they are adhering to medical ...

Study challenges 'shock and kill' approach to eliminating HIV

May 1, 2018
Researchers have provided new insight into the cellular processes behind the 'shock and kill' approach to curing HIV, which they say challenges the effectiveness of the treatment.

State-of-the-art HIV drug could curb HIV transmission, improve survival in India

April 30, 2018
An HIV treatment regimen already widely used in North America and Europe would likely increase the life expectancy of people living with HIV in India by nearly three years and reduce the number of new HIV infections by 23 ...

Risks to babies of mothers with HIV from three antiretroviral regimens appear to be low

April 25, 2018
The risk for preterm birth and early infant death is similar for three antiretroviral drug regimens taken by pregnant women with HIV according to a new study from Harvard T.H. Chan School of Public Health.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.