In brief

Even in the absence of antiviral drugs or an immune system, HIV accumulates mutations at specific hotspots—laying the foundation for drug resistance.

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Confessions of a shape-shifting virus

17 Nov 2021

Contrary to popular belief, a new A*STAR study shows that HIV mutations are far from random, emerging at specific locations at specific rates.

You can think of viruses as nature’s shapeshifters. To adapt to environmental pressures and more effectively infect their hosts, viruses gradually accumulate beneficial mutations—a phenomenon we are currently seeing with the rise of Delta and other SARS-CoV-2 variants.

The human immunodeficiency virus (HIV), however, takes shapeshifting to the extreme, rapidly accruing seemingly random mutations due to an error-prone enzyme involved in replication called reverse transcriptase. Some of these mutations allow the virus to become resistant to anti-HIV drugs, rendering them ineffective. Consequently, developing treatments that lower transmission risk or suppress viral levels throughout a patient’s lifetime remains a challenge.

Given the complexity of HIV drug resistance, the relationship between viral genetics and both when and where mutations occur had long eluded scientists. Historically, studies on the occurrence of mutations in HIV relied on reporter genes: segments of foreign DNA sequences that, when expressed by the virus, produce easily measurable signals that allow scientists to predict HIV’s mutational dynamics.

But according to experts, this experimental strategy does not always paint a clear picture of when, where and how mutations that cause HIV drug resistance arises. “Studying native genes is the only way to get this information,” explained Samuel Gan, Senior Principal Investigator at the Antibody and Product Development Lab of A*STAR’s Experimental Drug Development Centre (EDDC) & Bioinformatics Institute (BII).

To bridge the gap, the Gan lab studied a panel of HIV genes encoding the Gag and protease viral proteins. These components are crucial for assembling the virus once it begins to divide inside an infected host cell. They also examined mutations in the p66 sub-unit of HIV reverse transcriptase.

Fascinatingly, the scientists found that HIV mutations were not as random and unrestrained as previously thought. Far from being random, they instead observed that certain genes naturally accumulated mutations at particular hotspots. The mutations generally did not occur in gene regions with a significant impact on function, such as the active site of the HIV protease—a critical molecular pocket within the enzyme responsible for viral maturation.

Notably, Gan’s team observed that these mutations occurred even without selection pressures, like the presence of the immune system or antiviral drugs. These findings suggest that even early in infection, HIV may already be laying down the genetic groundwork for drug resistance. Indeed, native codon usage by the virus appears to control the emergence of such mutations and where they occur.

When it comes to dealing with highly adaptable, rapidly mutating viruses such as HIV, it seems that prevention remains better than a cure. “Fortunately, most viruses are less adaptive,” reassured Gan, “The next key step would be to study why some HIV proteins can tolerate specific mutations and not others.”

The A*STAR-affiliated researchers contributing to this research are from the Experimental Drug Development Centre (EDDC) and Bioinformatics Institute (BII).

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Yeo, J.Y., Koh, D.W.S., Yap, P., Goh, G.R., Gan, S.K.E. Spontaneous mutations in HIV-1 Gag, protease, RT p66 in the first replication cycle and how they appear: Insights from an in vitro assay on mutation rates and types, International Journal of Molecular Sciences 22, 370 (2021) | article

About the Researcher

Samuel Gan was the Senior Principal Investigator at the Antibody and Product Development Lab of A*STAR and is adjunct Associate Professor at James Cook University Singapore (JCUS). Gan’s cross-disciplinary research interests include antibody engineering and virus drug resistance for sagacious drug design. He has been recognised as one of the “World’s Most Promising Researchers” in the Interstellar Initiative by the New York Academy of Sciences and the Japan Agency for Medical Research and Development, as well as one of the 30 world class fusion innovators in the book “Innovation Through Fusion” by SP Jain School of Global Management. He is also the Bronze winner of the inaugural Merck Lab Connectivity Challenge 2020, and the 2021-22 “Science and Sustainability” category of the UK Alumni Awards, Singapore.

This article was made for A*STAR Research by Wildtype Media Group