The New Molecule eCD4-Ig Shows Promising Results in Controlling HIV

Researchers have developed a new molecule that shows promise for controlling HIV devoid of day-to-day antiretroviral medication. The molecule foils a broader range of HIV strains in the lab than any identified broadly neutralizing HIV antibody and is much more highly effective than some of the very potent of these antibodies. In addition, the compound safely shielded monkeys from infection with an HIV-like virus while in a 40-week study time. Together, the data recommend that the compound could, with additional research, be used to subdue HIV in human beings. The authors note that the molecule most likely could be applied as both a precautionary drug and as a treatment. These new finding published in the journal Nature.

This image shows how eCD4-Ig attaches to HIV surface and neutralize it. image credit: MICHAEL FARZAN ET AL., NATURE (2015)

Director of the National Institute of Allergy and Infectious Diseases S. Fauci stated “This innovative research keeps assurance for moving us in the direction of two important goals: obtaining long-term protection from HIV infection, and placing HIV into sustained remission in chronically infected individuals.”

The study was lead by Michael Farzan and was funded primarily by NIAID.

The new molecule is known as eCD4-Ig and performs by tightly binding to two constant sites on the surface area of HIV that the virus utilizes to attach to receptors on cells known as CD4 and CCR5. Generally, when HIV binds to these receptors, it opens a door to the cell and gets inside. However, when eCD4-Ig attaches to HIV, it efficiently takes away the virus’s key, securing it out of the cell and avoiding it from multiplying.

To make eCD4-Ig, the researchers took an antibody-like molecule that latches onto the CD4 holding site but doesn’t neutralize HIV on its own, and fused it with a small protein fragment that attaches firmly to the CCR5 binding site. Jointly, these two arms of the molecule are much more efficient at preventing HIV than either one is alone.

To examine whether eCD4-Ig would secure monkeys from an HIV-like virus (simian immunodeficiency virus, or SIV), the scientists synthesized genetic instructions for developing the molecule and positioned them inside a harmless carrier virus known as adeno-associated virus, or AAV. This gene therapy tool was developed to ensure that once the AAV-modified virus attacked a cell, it would trigger the cell to develop eCD4-Ig consistently. The scientists injected the genetically modified AAV into 4 monkeys. Then they exposed both the treated monkeys and four un-treated monkeys to SIV six times at significantly higher doses over a 34-week interval. None of the treated monkeys became attacked with SIV, while all of the un-treated monkeys did.  The eCD4-Ig molecule made in the monkey’s cells persisted in the animals’ blood in a fully efficient form and at protective levels for the complete 40-week study interval.

In add-on, the researchers identified that while monkeys’ immune systems view both eCD4-Ig and broadly neutralizing antibodies to HIV-like viruses as foreign substances to some level, the unwanted immune reaction produced by eCD4-Ig is milder than that produced by infusions of broadly neutralizing HIV antibodies. Researchers have been examining these antibodies as one more promising approach to long-acting therapy for HIV.

Lead author Dr. Farzan stated “Our molecule seems to be the very effective and broadest inhibitor of HIV access so far explained in a preclinical study, If one could inject either eCD4-Ig or our gene therapy tool into individuals with HIV infection, it might manage HIV for prolonged periods in the absence of antiretroviral medicines. Additional study will help illuminate the promise of these methods.”

To build on their results, the researchers are studying both the therapeutic potential of eCD4-Ig in monkeys attacked with HIV-like viruses and the capability of eCD4-Ig to prevent infection towards a broader range of HIV and HIV-like strains.

NIAID has financed the newly presented and on-going study via an initiative known as Beyond HAART: Modern Treatments to Control HIV-1, which supports the progression of methods for controlling HIV in the shortage of antiretroviral medicines.