The building blocks of the viral protein capsid are rearranged as HI viruses mature into infectious AIDS-causing agents. Researchers from Heidelberg have made these structural changes visible on the molecular level. The findings could potentially be used for developing much-needed new AIDS therapeutics.
Over thirty years of AIDS research since the immunodeficiency syndrome resulting from HIV infection became a recognised disease, have produced ambiguous results. The HI virus has been successfully identified and characterised and infection pathways elucidated, more quickly than was the case for any other virus. This has led to the development of around 25 drugs for the treatment of AIDS. Anti-HIV drugs have enabled many HIV-positive people to live a long and healthier life, at least in highly developed countries such as Germany where the expensive antiretroviral drugs are available and their life-long use can be closely monitored.
On the other hand, with around 35 million infected people, AIDS is a pandemic on the scale of the largest epidemics in human history. With an estimated 1.5 million people who died from HIV in 2013, the World Health Organization (WHO) classifies AIDS as the sixth leading cause of death in the world. Despite occasional sensational media reports, AIDS still has no cure, there is no effective vaccine against the disease, and resistance to existing drugs is rapidly increasing.
The detailed analysis of HIV architecture and its dynamic changes during virus development and maturation might explain the mechanisms that cause the virus to resist existing therapeutics. In addition, scientists are hoping that structural data will provide them with the information needed to develop customised new drugs that prevent the viral components from assembling into infectious viral particles. With a paper published in the prestigious journal Nature, researchers from the European Molecular Biology Laboratory (EMBL) and the University of Heidelberg have come closer to their objectives.
The immature HIV particle, which is synthesised in an infected human immune system cell, consists of two copies of the viral RNA genome surrounded by a spherical protein capsid composed of two to three thousand Gag molecules. During budding on the cell surface, the virus remains enveloped in a piece of plasma membrane. The Gag polyprotein, which plays a key role in the assembly of the individual building blocks and budding during the maturation of the viruses outside the cell, is cleaved by the viral protease, which leads to the rearrangement of the capsid. The newly formed infectious virus particles now have a conical rather than a spherical capsid.
Drugs that are able to inhibit the viral protease enzyme, and thus prevent the HIV particles from maturing and becoming infective, are among the major pillars of existing anti-HIV therapies. However, their effectiveness is becoming increasingly limited due to HIV’s ability to mutate and become resistant to antiretroviral drugs. Briggs and Kräusslich point out that the assembly of the protein scaffold – both for intracellular, immature particles as well as for extracellular mature viruses – is an excellent target structure for antiviral drugs. The ordered assembly of the protein building blocks of the viral envelope that has now been visualised using cryo-electron tomography, is the result of many weak molecular interactions. Molecules that interrupt the assembly and prevent the proliferation of the virus can target these interactions, making them excellent candidates for novel anti-AIDS drugs.
The study was carried out in the joint Molecular Medicine Partnership Unit (MMPU) and also involved PD Dr. Barbara Müller from the Centre for Infectious Diseases. Briggs and Kräusslich have been working on elucidating the structure and assembly of HIV for many years. The MMPU was established as a joint venture between EMBL and the University of Heidelberg in 2002 with the objective of pooling outstanding basic molecular biology research and clinically relevant medical research.
Original paper:Schur FKM, Hagen WJH, Rumlová M, Ruml T, Müller B, Kräusslich H, Briggs JAG: The structure of the immature HIV-1 capsid in intact virus particles at 8.8 Å resolution. Nature, 2 November 2014. DOI: 10.1038/nature 13838.