New possibilities against the HIV epidemic

Research identifies new antibodies with potent activity against virus and infected cells

The Human Immunodeficiency Virus type-1 (HIV-1) currently infects 37 million people worldwide, with an additional 2 million new infections each year. Following infection, the virus has a long period of latency, during which it multiplies without causing symptoms. HIV attacks the cells of the immune system, especially the cells called CD4+ T-lymphocytes, which are responsible for triggering the body’s response chain against infections. Thus, by suppressing the action of the immune system, the virus destroys the body’s ability to defend itself against other diseases, leading to the so-called Acquired Immunodeficiency Syndrome, or AIDS.
Even with the development of antiretroviral therapies that have improved quality of life and increased the life expectancy of patients with HIV/AIDS, it is widely accepted that the only way to effectively curb this devastating epidemic is through the development of an HIV-1 vaccine.

>Read more on the Brazilian Synchrotron Light Laboratory website

Image: Part of the structure of the CAP228-16H protein with the region of the V2 loop highlighted in yellow. (Full image here)

A new molecule could help put the STING on cancer

The protein STING (stimulator of interferon genes) is a component of the innate immune system. It plays a major role in the immune response to cancer, and abnormal STING signaling has been shown to be associated with certain cancers. Immunomodulatory approaches using agonists to target STING signaling are therefore being investigated as anticancer treatments. However, the compounds in clinical trials typically are injected intratumorally in patients with solid cancers. In this study, researchers discovered a novel STING agonist, known as an amidobenzimidazole (ABZI), which can be given by intravenous injection and could therefore potentially open up its evaluation as a treatment for hard-to-reach cancers. Using x-ray diffraction data collected at the U.S. Department of Energy’s Advanced Photon Source (APS), researchers from GlaxoSmithKline (GSK) investigated ABZI compounds and STING. Their results, published in the journal Nature, may have important implications for anticancer immunotherapy.

STING is a protein that mediates innate immunity, and one function of the STING signaling pathway is in mobilizing an immune response against tumors. STING proteins can be activated by cyclic dinucleotides, small molecules that are made by the cytosolic DNA sensor, cGAS, upon sensing of DNA leaking out of the nucleus as a result of DNA damage, including that which might be associated with cancer development.

>Read more on the Advanced Photon Source at Argonne National Lab.

Figure: X-ray crystal structure of the STING protein bound to one of the new molecules.

Targeting bacteria that cause meningitis and sepsis

The work provides molecular-level information about how the antibody confers broad immunity against a variable target and suggests strategies for further improvement of available vaccines.

Our central nervous systems (brain and spinal cord) are surrounded by three membranes called “meninges.” Meningitis is caused by the swelling of these membranes, resulting in headache, fever, and neck stiffness. Most cases of meningitis in the United States are the result of viral infections and are relatively mild. However, meningitis caused by bacterial infection, if left untreated, can be deadly or lead to serious complications, including hearing loss and neurologic damage.

The bacterium responsible for meningitis (Neisseria meningitidis) can also infect the bloodstream, causing another life-threatening condition known as sepsis. N. meningitidis is spread through close contact (coughing or kissing) or lengthy contact (e.g. in dorm rooms or military barracks). In this work, researchers were interested in understanding how humans develop immunity to bacterial meningitis and sepsis, collectively known as meningococcal disease, by vaccination with a new protein-based vaccine.

>Read more on the Advanced Light Source website

Image: The work provides molecular-level information about how the antibody confers broad immunity against a variable target and suggests strategies for further improvement of available vaccines.

Insights into the development of more effective anti-tumour drug

Natural killer cells are powerful weapons our body’s immune systems count on to fight infection and combat diseases like cancer, multiple sclerosis, and lupus. Finding ways to spark these potent cells into action could lead to more effective cancer treatments and vaccines.

While several chemical compounds have shown promise stimulating a type of natural killer cells, invariant natural killer T cells (iNKT) cells in animal models, their ability to activate human iNKT cells has been limited.

Now, an international team of top immunologists, structural biologists, and chemists published in Cell Chemical Biology the creation of a new compound that appears to have the properties researchers have been looking for. The research was co-led by Monash Biomedicine Discovery Institute’s (BDI) Dr Jérôme Le Nours, University of Connecticut’s Professor Amy Howell and Albert Einstein College of Medicine’s Dr Steve Porcelli. Dr Le Nours used the Micro Crystallography beamline (MX2) at the Australian Synchrotron as part of the study.

The compound – a modified version of an earlier synthesized ligand – is highly effective in activating human iNKT cells. It is also selective – encouraging iNKT cells to release a specific set of proteins known as Th1 cytokines, which stimulate anti-tumour immunity.

>Read more on the Australian Synchrotron website

Image: 3D structure of proteins behind interaction of new drug that stimulates immune response to cancer cells. (Entire image here)

Scientists map important immune system enzyme for the first time

Biochemists from McGill University are getting a good look at just how a specific enzyme that is part of the human immune system interacts with a certain group of bacteria that are described as gram-negative.

Researchers around the world “have been studying the enzyme, known as AOAH, for more than 30 years. This is the first time anyone has been able to see exactly what it looks like,” according to Bhushan Nagar, an associate professor of biochemistry at McGill University in Montreal.

More than that, the 3D images captured a moment in time which shows just how AOAH inactivates a toxic molecule that is commonly part of various gram-negative bacteria. The research was conducted at the Canadian Light Source.

Numerous types of gram-negative bacteria exist throughout the environment. While some are harmless, many cause a variety of human illnesses, says Nagar. For example, several species such as E. coli and Salmonella, cause food borne illness. Others cause infections such as pneumonia, meningitis, bloodstream infections or gonorrhea.

>Read more on the Canadian Light Source

Image: Bhushan Nagar (principal investigator), Alexei Gorelik (first author of paper) and Katalin Illes (research assistant at Nagar lab) at their McGill University lab.
Credit: Bhushan Nagar.