Novel Entry Inhibitor VIR-576 Shows Promise in Early Study

		SUMMARY: A novel type of HIV entry inhibitor dubbed VIR-576, which blocks HIV's ability to insert its gp41 fusion peptide into the outer membrane of a host cell, demonstrated promising safety and efficacy in a small clinical study published in the December 20, 2010 issue of Science Translational Medicine. VIR-576 did not show cross-resistance with other antiretroviral drugs -- including other entry inhibitors -- and is unlikely to promote resistance itself, according to study investigators.

By Liz Highleyman

In order to infect host cells, HIV must grab onto and fuse with the cell's membrane, allowing virus components access the cell's interior. A new therapy based on a natural substance produced by the body may block this interaction.

As described in a media advisory from the American Association for the Advancement of Science (publisher of Science Translational Medicine), Wolf-Georg Forssmann from Hannover Medical School in Germany and an international team of colleagues conducted a Phase I/II clinical trial to test whether VIR-576 can suppress HIV replication.

VIR-576 is a variant form of a fragment of alpha-1-antitrypsin designated as virus-inhibitory peptide, or VIRIP. It binds to HIV's hydrophobic fusion peptide gp41 -- described as the "sticky" end of its outer envelope -- preventing the virus from inserting itself into a host cell's membrane to initiate infection. The novel compound works differently than the 2 approved entry inhibitors, enfuvirtide (Fuzeon or T-20) and maraviroc (Selzentry).

The study included 18 treatment-naive participants with HIV viral loads of at least 10,000 copies/mL and CD4 T-cell counts of at least 350 cells/mm3. They received injections of one of 3 doses of VIR-576 (0.5, 1.5, or 5.0 grams/day) as monotherapy for 10 days, before commencing combination antiretroviral therapy (ART).

Results

	At the end of treatment, VIR-576 reduced mean plasma HIV RNA by 0.06 log copies/mL in the 0.5 g/day arm, 0.30 log in the 1.5 g/day group, and 1.23 log in the 5.0 g/day group.
	At the highest dose, VIR-576 reduced average viral load by about 95%.
	Efficacy was variable among individuals, however, ranging from 0.30 to 1.90 log in the high-dose group.
	There was a significant correlation between viral load reduction and plasma concentrations of VIR-576.
	No changes in CD4 cell counts were seen during this short treatment period.
	VIR-576 was generally well-tolerated.
	No major adverse effects were reported.
	The most frequent adverse events were mild-to-moderate constipation, headache, and fever, which were not dose-related.
	2 study participants experienced moderate allergic reactions, which resolved after stopping the drug.

Based on these findings, the investigators wrote, "Our results are proof of concept that fusion peptide inhibitors suppress viral replication in human patients, and offer prospects for the development of a new class of drugs that prevent virus particles from anchoring to and infecting host cells."

VIRIP-related compounds do not show cross-resistance with other antiretroviral drugs, including enfuvirtide, they elaborated in their discussion. Furthermore, because the gp41 fusion peptide is "highly conserved," or unable to tolerate much genetic mutation, it is likely to have a high barrier to resistance itself. Unlike the CCR5 co-receptor targeted by maraviroc, all strains of HIV-1 rely on gp41 to enter cells.

But the large VIR-576 peptide must be injected, which limits its convenience and attractiveness to HIV patients with other treatment options. Investigators are now exploring small-molecule oral agents that work by a similar mechanism.

"Further clinical development of fusion peptide inhibitors seems warranted and may provide a useful addition to the current armamentarium of antiretroviral drugs, particularly for salvage therapy of individuals infected with multiresistant HIV-1 strains and for the risk reduction of transmission between an HIV-infected mother and her fetus during birth," the study authors concluded.

This type of approach may also be effective against other enveloped viruses that use fusion peptides, such as influenza virus, Ebola, and hepatitis B and C.

Investigator affiliations: Department of Immunology and Rheumatology, Hannover Medical University, Hannover, Germany; VIRO Pharmaceuticals GmbH & Co, Hannover, Germany; Mediconomics GmbH, Hannover, Germany, Department of Chemistry,University of Patras, Rion-Patras, Greece; CBL-Patras, Patras, Greece; Departamento de Biología Físico-Química, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain; Institute of Molecular Virology, University Hospital of Ulm, Ulm, Germany; Departamento de Química, Facultad de Farmacia, Universidad San Pablo CEU, Madrid, Spain.

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Reference
W-G Forssmann, Y-H The, M Stoll, and others. Short-Term Monotherapy in HIV-infected Patients with a Virus Entry Inhibitor against the gp41 Fusion Peptide. Science Translational Medicine 2(63): 63re3 (Abstract). December 20, 2010.

Other Source
AAAS. Advance Information for the 22 December 2010 Issue of Science Translational Medicine. Media advisory. December 20, 2010.