HIV Goes After B Cells

Researchers from the National Institute of Allergy and Infectious Diseases have shown that HIV attacks B cells as well as the T cells that are its main host, giving it another weapon in its conquest of the immune system. Previous studies had identified multiple abnormalities of B cells (as well as most other blood cell types) in HIV-infected individuals, but those had been ascribed to the effects of chronic infection. In their studies, the authors showed that at least some of those abnormalities resulted from HIV’s binding to B cells via its gp120 receptor, which directly had a “profoundly negative effect” on B-cell function. Such B cells were less likely to become activated, and less likely to proliferate. The team said those results “explain at least in part the perplexing inadequacy of the initial humoral immune response to infection with HIV-1.” They appeared in the Oct. 27, 2013, online issue of Nature Immunology.

Chimeric Peptide Improves Metabolism . . .

Researchers from Indiana University and the German Helmholtz Zentrum Muenchen have reported that by using a synthetic peptide whose sequence was a mix of two naturally occurring peptides, they were able to “maximize metabolic benefits in rodents, monkeys and humans.” The peptide contained mixed sequences of two hormones that are both incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and was an agonist of both receptors. When it was administered to animals, the peptide led to more weight loss and better blood sugar control than GLP-1 agonists, and did not have the gastrointestinal side effects that are often dose-limiting for GLP-1 agonists. The authors concluded that “these results highlight the strengths of this single-molecule combination therapy and broaden our perspective on how to achieve more effective treatments for chronic diseases.” Their work appeared in the Oct. 31, 2013, issue of Science Translational Medicine.

. . . As Does Adiponectin Receptor Agonist

Scientists from the Japanese University of Tokyo have developed a molecule that improved both the metabolic profile and lengthened the life span of rodents treated with it. The molecule activated two receptors that are normally stimulated by the hormone adiponectin, AdipoR1 and AdipoR2. Adiponectin is a hormone secreted by fat cells that is involved in controlling many metabolic functions through its effects on both liver and muscle cells. In particular, mice fed high-fat diets but treated with the adiponectin receptor agonist remained very similar to mice that were fed standard, lower-fat diets, suggesting it could prevent the consequences of a sedentary lifestyle. “Orally active AdipoR agonists,” the authors concluded, “are a promising novel therapeutic approach for treating obesity-related disorders such as type 2 diabetes.” Their findings were published in the Oct. 31, 2013, issue of Nature.

Beating Back HIV

Two separate research teams, one from Beth Israel Deaconess Medical Center and one from the National Institute of Allergy and Infectious Diseases, have reported successfully treating monkeys that were chronically infected with simian immunodeficiency virus (SIV), the monkey equivalent of HIV. Both groups used cocktails of broadly neutralizing antibodies that led to rapidly falling viral levels in the animals. Viral levels remained low for weeks or months after the treatment. Highly active antiretroviral therapy (HAART) is also very effective at reducing viral levels, but its complex treatment schedule makes it challenging to adhere to, and partial adherence can backfire, as it creates conditions under which HIV can evolve resistance. The researchers noted in their paper that viral levels increased when antibody levels decreased, but they did not see resistant strains emerge. The findings, which suggested that broadly neutralizing antibodies might find a role in HIV treatment, appeared back to back in the Oct. 31, 2013, advance online edition of Nature.

Different Mutations, Different Tumors

When a gene is implicated in several different types of tumors, the underlying mutation is usually the same one. But that is not true for one protein, the histone protein H3.3. Scientists from the British University College London have discovered that with H3.3 “a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions.” In their work, the authors looked at two different types of bone cancers, chondroblastomas and giant cell tumors of bone. H3.3 is encoded by two separate genes whose DNA sequences differ but converge on the same amino acid sequence. The authors found that chondroblastoma patients almost always had mutations in one of the two genes, H3F3B, while giant cell tumors of bone were due to mutations in H3F3A. Both mutations were different from others that have been implicated in childhood brain tumors, a finding that further confirmed that different mutations in H3.3 have very different consequences. The study was published in the Oct. 27, 2013, online issue of Nature Genetics.

Fight Left Yet in Serotonin Receptor

A team from the University of Chicago has reported that by targeting a specific subtype of serotonin receptor, they were able to induce antidepressant effects in mice more rapidly than the current serotonin-targeting drugs. Current serotonin-targeting antidepressants, the selective serotonin reuptake inhibitors, or SSRIs, typically take weeks to start working, while experimental faster-acting antidepressants target another neurotransmitter, glutamate. In their experiments, the researchers focused on one particular subtype of serotonin receptors, the 5-HT2C receptor. They found that selectively blocking that receptor led to antidepressant effects in mice within five days, while SSRIs took almost three times as long, 14 days, to show a behavioral effect. The team found that blocking the receptors ultimately increased dopamine signaling from the midbrain to the cortex, which appeared to be the basis of the rapid antidepressant effects. The results appeared in the Oct. 29, 2013, issue of Molecular Psychiatry.

New Gene Rearrangement in Lung Cancer

Scientists from the University of Colorado at Denver have identified two gene rearrangements that are oncogenic, drug-sensitive and present in slightly more than 3 percent of lung cancer patients. Lung cancer continues to be one of the most challenging cancers to get a genetic handle on, due to its enormous complexity, and the majority of patients have no mutations that make obvious drug targets. In their work, the authors used next-generation sequencing (NGS) to look at the lung tumors of about 90 patients, and they identified three with gene fusions involving the receptor tyrosine kinase TRKA, a receptor for nerve growth factor. The authors concluded that “our study further highlights the utility of targeted NGS to discover drug-sensitive genetic alterations in patients with lung cancer,” as well as that “based on our data, clinical studies of selective TRKA inhibitors in NTRK1-rearranged non-small-cell lung cancer are warranted.” The findings appeared in the Oct. 27, 2013, issue of Nature Medicine.

Applying Genomics to Lung Cancer

Another group, this one led by researchers from the German University of Koeln, reported findings that suggested the majority of lung cancer patients could have actionable mutations that can be identified, if genomic technologies are used. In their work, the authors searched for genomic alterations in more than 1,200 malignant lung tumors, and found that more than half of them “harbored at least one genetic alteration with features of a possibly tractable target.” A follow-up prospective study identified such actionable mutations in 75 percent of patients. Overall survival of patients in the second cohort improved due to the genotyping and subsequent personalized therapy. The authors noted that “these epidemiological results emphasize the need for broad availability of systematic and comprehensive genomic lung cancer diagnoses.” They published their work in the Oct. 31, 2013, issue of Science Translational Medicine.

Synuclein Culprit Found

Researchers from the Translational Genomics Research Institute have used siRNA knockdown screening to identify a protein that regulates alpha-synuclein, which plays a role in several different neurodegenerative disorders when it aggregates. Alpha-synuclein tends to aggregate when it is phosphorylated at a particular amino acid, and so the authors looked at the consequences of knocking down different kinases, enzymes which add phosphorylation tags to proteins, and phosphatases, which remove them. Screening more than 900 such enzymes, the authors found that knocking down the kinase SMG1 increased the levels of phosphorylated alpha-synuclein in cell culture. In brain samples from patients with two separate alpha-synuclein-related diseases, Parkinson’s disease and dementia with Lewy bodies, levels of SMG1 were low. The authors concluded that “SMG1 may play an important role in increased alpha-synuclein pathology during the course of [Parkinson’s disease dementia, dementia with Lewy bodies] and possibly other synucleinopathies.” Their findings appeared in the Oct. 30, 2013, online issue of PLoS ONE.

Rationally Designed RSV Vaccine

Researchers from the National Institutes of Health have designed an antigen for a vaccine to respiratory syncytial virus (RSV). RSV has long been recognized as a leading cause of death and disease in infants – in children younger than 1 year, it is second only to malaria in the number of deaths it causes. Recent studies also have shown that in adults, it may be responsible for many infections ascribed to the flu, and may in fact lead to higher rates of complication than the flu. In their studies, the authors used previous insights from structure-based drug design to design an antigen that elicited antibodies to a highly conserved part of the virus. Mice and monkeys vaccinated with that antigen produced antibodies at levels much higher than the protective threshold. Beyond the specific RSV antigen it reports, the paper showed that “atomic-level control of antigenicity increasingly appears to be within the reach of structure-based design.” It appeared in the Nov 1, 2013, issue of Science.