Artificial answers

By | Science & Technology
HIV virion structure. Credit@NIAID

Immunologists at the Scripps Research Institute in Florida have shown that a synthetic molecule binds the human immunodeficiency virus (HIV) more potently than any antibody produced by the body. The study was published in Nature and demonstrates how the lab-made molecule prevented HIV infection in four monkeys, despite receiving large doses of the virus.

HIV affects approximately 35 million people worldwide, with the highest prevalence in Sub-Saharan Africa. Once a patient’s CD4+ T-cell count falls below 200 cells per cubic millilitres, they are diagnosed with acquired immunodeficiency syndrome (AIDS). The average time for HIV to progress to this stage is around 10 years. Its ability to evade the human body’s immune system has driven scientists and public health agencies to work determinedly towards a cure for many years and continue to do so. Efforts, including developments in antiretroviral therapy and a number of antibodies have come close. In this case, a team of researchers has taken to a different strategy, constructing a novel protein based on knowledge of how HIV infects cells.

Entry of the virion into a human cell essentially requires two steps. To begin, HIV’s gp120 surface glycoprotein docks onto a CD4 receptor on the surface of a white blood cell. This binding causes a structural change in the viral membrane, which exposes gp41. This allows it to penetrate the membrane of the target cell by attaching to a second cellular receptor, CCR5, bringing the two cells close enough to fuse and allow the viral capsid to enter the cell.

The artificial protein synthesised by Farzan’s team is effectively a fusion of the CD4 molecule and a mimic of the CCR5 molecule. The construct, called eCD4-Ig, locks onto HIV by binding the envelope proteins gp120 and gp41, mimicking how the virus normally attaches to a cell.

Comparison of the synthetic construct, broadly neutralising antibodies, and the natural CD4 immunoglobulin. Credit@MichaelFarzan

Comparison of the synthetic construct, broadly neutralising antibodies, and the natural CD4 immunoglobulin. Credit@MichaelFarzan

The team demonstrated the greater potency of eCD4-Ig relative to extensively studied broadly neutralising antibodies (bNAbs) by comparing their abilities to bind HIV envelope proteins. Furthermore, the construct is effective on an even broader suite of targets than bNAbs. Subsequently, the team investigated whether the construct might be able to function as a vaccine by delivering eCD4-Ig into four monkeys using a harmless viral vector. eCD4-Ig causes the monkey’s immune cells to mass produce the construct. Despite being inoculated with successively higher doses of HIV over a period of 34 weeks, the monkeys remained free from infection, compared to untreated monkeys who all became infected.

Monkeys treated with eCD4-Ig continued to produce the construct for 40 weeks and this is expected to be able to continue indefinitely. Promisingly, immune response against the construct was undetected; likely due to it close resemblance to typical host proteins.

Part of HIV-1 that attaches to the constructs two receptors, CD4 and CCR5. Credit@MichaelFarzan

Part of HIV-1 that attaches to the constructs two receptors, CD4 and CCR5. Credit@MichaelFarzan

The image above shows the part of HIV (shown in beige) that attaches to the two receptors, CD4 and CCR5. The eCD4-Ig construct includes part of CD4 (shown in red), connected to a mimic of CCR5 (green) connected by a conserved fragment of an antibody (grey).

Professor Michael Farzan, who led the study, explained to The Positive, “Our approach has the potential to be an alternative vaccine, and we have some confidence on its efficacy, however we’ve got a long way to go to establish its safety.  We are uncertain whether the same approach could suppress an ongoing infection (those studies have just started)…At best it might supplement or replace current antiviral regimens.”

This work is still in the early stages of test-tube experiments and animal trials. Nevertheless, scientists like Nobel laureate, David Baltimore, consider it “impressive”. The construct binds HIV tightly and triggers the membrane to change its shape, inhibiting HIV more effectively than any available antibody therapy today. Ultimately, the success of eCD4-Ig as a treatment for HIV may be determined further down the line in human trials.

How might this technique productively influence the development of future medical therapies?

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