How HIV Therapy Synergizes

Second-line HIV drugs have the potential to work better when used together, but not for all patients. Now researchers have discovered how that synergy might work, suggesting to develop better HIV drugs.

Current HIV treatment strategies offer a first line of drug combinations or cocktails followed by a second line of defense, when the first one can no longer keep the virus at bay. Two classes of drugs commonly used as second-line therapy, so-called coreceptor antagonists (CoRAs) and fusion inhibitors, have characteristics that should allow them to act synergistically, increasing each-other’s effect and reducing the dose needed to see results, which helps reduce side effects and toxicity. But that synergy only occurs sometimes, puzzling doctors and researchers and limiting the drugs’ potential.

Now, Michael Root and Koree Ahn, in the Department of Biochemistry and Molecular Biology at Jefferson published research in the Journal of Biological Chemistry explaining when and how that synergy fails.

The researchers examined the biochemical dynamics of these two classes of HIV drugs and found that synergy only happened when cells infected with HIV virus had certain characteristics. The cells had to display a large amount of the receptors targeted by CoRA – the chemokine receptor CCR5. Below a certain threshold number of receptors, synergy would not occur. The researchers also showed that the magnitude of the synergy depended on how strongly the fusion inhibitors were able to bind to their targets, the viral envelope protein, which differs between strains of HIV virus.

“We think that natural human genetic variability combined with the genomic variability of HIV viruses conspires to make these drugs less effective for some patients,” says Dr. Root.  The next steps, if this study’s results are confirmed by human clinical trials, might be to develop ways to screen for patients with high levels of chemokine receptors in order to provide more effective doses of the medication. The data could also be used in helping design the next versions of CoRAs and fusion inhibitors for HIV therapy.

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