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Sep 12, 2013

Receptor Structure Sheds Light on How HIV Infects Cells

  • The crystallographic determination of the CCR5 receptor has been achieved, providing insights into its allosteric inhibition by Maraviroc, an HIV drug. The CCR5 receptor, which is known to act as a co-receptor for HIV-1 viral entry, appears to be locked into an HIV-insensitive conformation by Maraviroc.

    As indicated in a study published today in Science, Maraviroc binds to a CCR5 site distinct from the proposed recognition sites for chemokines and the viral glycoprotein gp120. Accordingly, the drug appears to work against HIV indirectly, not by physically blocking the virus, but by locking the receptor structure into an inactive form.

    The study’s senior investigator, Beili Wu, Ph.D., professor at the Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, said, “These structural details should help us understand more precisely how HIV infects cells, and how we can do better at blocking that process with next-generation drugs.”

    The CCR5 receptor is one of the most sought-after targets for new anti-HIV drugs. Although the AIDS-causing virus was initially discovered to infect cells via another receptor, CD4, researchers found in 1996 that HIV infection also requires a co-receptor—usually CCR5, which sits alongside CD4 on a variety of immune cells.

    CCR5’s importance to HIV infection is underscored by the fact that certain genetic variants of it can dramatically raise or lower HIV infection risk, as well as the speed of the disease process after infection. One shortened CCR5 variant, found in about 10% of Europeans, is not expressed at all on immune cell surfaces. People who produce only this variant are almost invulnerable to HIV infection.

    Scientists therefore have sought to develop anti-HIV drugs that block the virus from binding to CCR5 or otherwise render the receptor inactive. Yet only a handful of CCR5-inhibiting compounds have been developed so far, and no one knows exactly how they work. “One thing that we’ve lacked is a high-resolution molecular ‘picture’ of the CCR5 receptor structure that we can use for precise drug design,” Wu said.

    Study co-author Raymond C. Stevens, Ph.D., a professor at The Scripps Research Institute, added, “Now that we have both human CXCR4 and CCR5 HIV co-receptor 3D structures, it is likely we will see the next generation of HIV therapeutics.”

    In that statement, Dr. Stevens was referring to research conducted earlier by a Scripps-based team that included Dr. Wu. The team found that CXCR4, an alternative co-receptor for HIV, posed fewer technical challenges, and so CXCR4’s structure was revealed first, in a 2010 article published in Science.

    The CXCR4 experience proved valuable in the CCR5 investigation. Both CCR5 and CXCR4 belong to a large family of cell receptors known as G protein-coupled receptors (GPCRs). GPCRs are notoriously hard to produce in useful amounts for structural analysis, a point emphasized in another paper in which Dr. Stevens was a co-author: “GPCRs are inherently dynamic proteins, sampling a range of conformations between active and inactive signaling states. This flexibility, along with the scarcity of hydrophilic regions available to form potential crystal contacts, are major impediments to obtaining diffraction quality GPCR crystals.” This paper, published in 2012 in Structure, described the importance of using fusion partners, proteins that facilitate GPCR crystallization.

    In the CCR5 study, Dr. Wu and her team used a novel fusion partner to help hold CCR5 proteins together so that usable crystals could be formed. As in most receptor-structure projects, Wu and her colleagues further stabilized CCR5 with a compound that is known to bind to it, in this case the drug Maraviroc.

    Comparison of the CCR5 structure with the previously determined CXCR4 structure provided hints about an important aspect of HIV evolution during infections. Most HIV infections start by using only CCR5 as a co-receptor for cell entry, but in time the virus often switches its co-receptor usage from CCR5 to CXCR4. That opens up more cell types to HIV infection, and the further spread of the virus inside the body is liable to speed up the disease progression towards full-blown AIDS and death.

    The new data suggest that the distinction between CCR5 and CXCR4 as co-receptors for HIV infection boils down to relatively subtle differences in structural shapes and electric charge distributions in the HIV binding region—differences that will be of interest to HIV drug developers.

    “Knowing the CXCR4 structure and now the CCR5 structure at this level of detail should accelerate the development of drugs that can block HIV by using both of these co-receptors,” said Dr. Wu.

    Dr. Wu and her colleagues now plan to follow up with structural studies of CCR5 and CXCR4 in complex with the HIV envelope protein gp120 and CD4 to obtain even more informative pictures of the process of viral infection.



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