A drug used to quell nausea caused by chemotherapy has a strong anti-HIV effect in the test-tube, and this effect is intensified if the HIV protease inhibitors saquinavir or ritonavir are also present.
The drug, aprepitant (Emend, manufactured by Merck & Co), also returns the favour by intensifying the antiretroviral effect of ritonavir and saquinavir, and blood levels of aprepitant are boosted by ritonavir.
The findings, reported in an advance online publication of the journal AIDS, have resulted in a clinical trial that is now testing the safety and pharmacokinetics of aprepitant in HIV-positive people.
Aprepitant is one of a class of neurokinin-1 receptor antagonists that block the neuropeptide substance P, which is involved in interactions between the nervous system and the immune system.
The interaction between substance P and the neurokinin-1 receptor is critical for viral infection of a cell, and HIV is no exception.
Previous experiments have shown that a substance P antagonist – a chemical that can block its normal receptor on human cells – reduces HIV infection of macrophages by reducing the display of CCR5 receptors on these cells. Most types of HIV require the CCR5 receptor in order to gain access to CD4 cells and other immune system cells.
Aprepitant is licensed for the prevention and treatment of nausea due to cancer chemotherapy. It was selected for this experiment after the discovery that it could prevent HIV infection of macrophages.
Further tests showed that it had the strongest anti-HIV effect of any neurokinin-1 receptor antagonist.
In this study the drug was incubated alone and in combination with a number of antiretroviral drugs from different classes: ritonavir and saquinavir (protease inhibitors); nevirapine (non-nucleoside reverse transcriptase inhibitor) T-20 (entry inhibitor) and AZT, ddI and 3TC (nucleoside analogues).
The researchers looked at the synergistic effect of the drugs in peripheral blood mononuclear cells infected with a wide range of HIV isolates representing all global sub-types and major recombinant forms, and viruses adapted to use the CCR5 and CXCR4 receptors.
The researchers found that the antiviral effect of aprepitant used together with the two protease inhibitors was greater than would be expected from adding up the antiviral effect of each drug alone: in other words, synergistic. Use of aprepitant with a protease inhibitor resulted in double the expected antiviral effect. A smaller synergistic effect was observed with 3TC and AZT. No synergy was observed with other drugs.
The researchers found no difference in activity according to viral subtype or receptor usage.
References
Manak MM et al. Anti-HIV-1 activity of the neurokinin-1 receptor antagonist aprepitant and synergistic interactions with other antiretrovirals. AIDS, advance online publication, October 21, 2010.