As millions cling to antiretrovirals for life, scientists say they now understand how the human immunodeficiency virus (HIV) is adapting to resist efavirenz and other non-nucleoside reverse transcriptase inhibitors (NNRTIs).
Combined with other antiretrovirals, efavirenz and similar drugs slow the viral infection to allow 34 million people around the globe, including one million Americans, to live longer, healthier lives. Yet some studies show the effects of NNRTIs increasingly ephemeral as the virus’ genetic code mutates in a way similar to the development of drug-resistant bacteria. Such single “point” mutations in the viral RNA may lead to drug-resistant infections, scientists say.
By using imaging and computer modelling, cell biologist Sanford Leuba and his colleagues at the University of Pittsburgh say they now understand the biology of drug-resistant infection. Usually, drugs such as efavirenz block the effects of the reverse transcriptase enzyme, which the virus uses to convert its RNA genetic material into the single-stranded copies of DNA it then inserts into the genome of its cellular host. Once ensconced in our human genome, the viral DNA instructs its host to propagate the virus, gradually overwhelming the immune system — and sometimes leading to full-blown AIDS.
The drugs work by binding to the enzyme to form a molecular-sized “salt bridge” holding the reverse transcriptase in an “open state,” Leuba said in a statement. “The reverse transcriptase can still bind to the template, but it continually slides, preventing the enzyme from polymerizing nucleotides. The virus cannot replicate itself.”
The findings were presented at the Biophysical Society's annual meeting, which took place in San Fransisco.
With point mutations, however, the virus prevents the formation of the molecular salt bridge, thereby allowing the reverse transcriptase to function, while still allowing the drug to bind to the enzyme. "This type of inhibition, which does not involve drug-binding affinity, has not been described previously,” Leba said.
The investigators say they now have some ideas toward designing the next generation of NNRTIs.