Study Reveals Why HIV Mutation Resistant to Some Drugs Becomes Vulnerable to Islatravir
Researchers determined the crystal structure of an HIV reverse transcriptase mutation (F227C) and found it unexpectedly increases susceptibility to islatravir, a newly FDA-approved HIV drug. The mutation, which normally confers resistance to other antiretroviral drugs like doravirine, impairs the virus's ability to remove islatravir from its genetic material. This finding could inform the design of combination HIV treatments that strategically exploit such collateral sensitivities.
Scientists used X-ray crystallography to resolve the atomic structure of HIV-1 reverse transcriptase carrying the F227C mutation in complex with islatravir, revealing how this resistance mutation paradoxically increases the virus's vulnerability to the drug. The F227C mutation, which typically confers resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) including doravirine, causes conformational changes that impair the enzyme's ability to perform ATP-dependent removal of islatravir-terminated primers. Biochemical experiments confirmed that while the mutation does not significantly affect islatravir incorporation into viral DNA, it substantially reduces the virus's capacity to excise the drug, thereby enhancing susceptibility. The findings establish a direct structural and mechanistic link between resistance to one class of antivirals and hypersusceptibility to another, a phenomenon known as collateral sensitivity. This knowledge could enable clinicians to design rational combination regimens that exploit such vulnerabilities to overcome drug resistance.
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- bioRxivCenter
Structural and Mechanistic Basis of F227C-Mediated Hypersusceptibility to Islatravir in HIV-1 Reverse Transcriptase
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