Tag Archives: Blood Test

Microbiology

Simple blood tests for telomeric protein could provide a valuable screen for certain cancers

Leave a comment

Reviewed by Emily Henderson, B.Sc.Feb 21 2023

Once thought incapable of encoding proteins due to their simple monotonous repetitions of DNA, tiny telomeres at the tips of our chromosomes seem to hold a potent biological function that’s potentially relevant to our understanding of cancer and aging.

Reporting in the Proceedings of the National Academy of Science, UNC School of Medicine researchers Taghreed Al-Turki, PhD, and Jack Griffith, PhD, made the stunning discovery that telomeres contain genetic information to produce two small proteins, one of which they found is elevated in some human cancer cells, as well as cells from patients suffering from telomere-related defects.

Based on our research, we think simple blood tests for these proteins could provide a valuable screen for certain cancers and other human diseases. These tests also could provide a measure of ‘telomere health,’ because we know telomeres shorten with age.”

Jack Griffith, PhD, the Kenan Distinguished Professor of Microbiology and Immunology and Member of the UNC Lineberger Comprehensive Cancer Center

Telomeres contain a unique DNA sequence consisting of endless repeats of TTAGGG bases that somehow inhibit chromosomes from sticking to each other. Two decades ago, the Griffith laboratory showed that the end of a telomere’s DNA loops back on itself to form a tiny circle, thus hiding the end and blocking chromosome-to-chromosome fusions. When cells divide, telomeres shorten, eventually becoming so short that the cell can no longer divide properly, leading to cell death.

Scientist first identified telomeres about 80 years ago, and because of their monotonous sequence, the established dogma in the field held that telomeres could not encode for any proteins, let alone ones with potent biological function.

In 2011 a group in Florida working on an inherited form of ALS reported that the culprit was an RNA molecule containing a six-base repeat which by a novel mechanism could generate a series of toxic proteins consisting of two amino acids repeating one after the other. Al-Turki and Griffith note in their paper a striking similarity of this RNA to the RNA generated from human telomeres, and they hypothesized that the same novel mechanism might be in play.

They conducted experiments – as described in the PNAS paper – to show how telomeric DNA can instruct the cell to produce signaling proteins they termed VR (valine-arginine) and GL (glycine-leucine). Signaling proteins are essentially chemicals that trigger a chain reaction of other proteins inside cells that then lead to a biological function important for health or disease.

Al-Turki and Griffith then chemically synthesized VR and GL to examine their properties using powerful electron and confocal microscopes along with state-of-the-art biological methods, revealing that the VR protein is present in elevated amounts in some human cancer cells, as well as cells from patients suffering from diseases resulting from defective telomeres.

“We think it’s possible that as we age, the amount of VR and GL in our blood will steadily rise, potentially providing a new biomarker for biological age as contrasted to chronological age,” said Al-Turki, a postdoctoral researcher in the Griffith lab. “We think inflammation may also trigger the production of these proteins.”

Griffith noted, “When you go against current thinking, you are usually wrong because you are bucking many people who’ve worked so diligently in their fields. But occasionally scientists have failed to put observations from two very distant fields together and that’s what we did. Discovering that telomeres encode two novel signaling proteins will change our understanding of cancer, aging, and how cells communicate with other cells.

“Many questions remain to be answered, but our biggest priority now is developing a simple blood test for these proteins. This could inform us of our biological age and also provide warnings of issues, such as cancer or inflammation.”

Source:

University of North Carolina Health Care

Journal reference:

Al-Turki, T., et al. (2023) Mammalian Telomeric RNA (TERRA) can be translated to produce valine-arginine and glycine-leucine dipeptide repeat proteins. PNAS. doi.org/10.1073/pnas.2221529120.

Microbiology

Analysis of rebound virus suggests two separate reservoirs of latent HIV in patients

Leave a comment

Reviewed by Emily Henderson, B.Sc.Feb 1 2023

When people living with HIV take antiviral therapy (ART), their viral loads are driven so low that a standard blood test cannot detect the virus. However, once ART is stopped, detectable HIV re-emerges with new cells getting infected. This is called “rebound” virus, and the cells that release the virus to re-ignite the infection come from a small population of HIV-infected CD4+ T cells that had remained dormant in blood and lymph tissue while individuals were on ART.

It’s a problem called latency, and overcoming it remains a major goal for researchers trying to create curative therapies for HIV-;the special focus of the UNC HIV Cure Center.

Now, scientists led by virologist Ron Swanstrom, PhD, Director of the UNC Center for AIDS Research and the Charles P. Postelle, Jr. Distinguished Professor of Biochemistry & Biophysics at the UNC School of Medicine, describe another layer to the challenge of HIV latency and published their work in Nature Microbiology.

Swanstrom and colleagues, with collaborators at UCSF, Yale, the University of Gothenburg in Sweden, and others, provide indirect evidence for the existence of a distinct latent reservoir of CD4+ T cells in the central nervous system (CNS). They accomplished this by analyzing rebound virus in the cerebral spinal fluid (CSF) during the period when people had just stopped taking ART.

Our analysis of rebound virus suggests latently infected T cells in the CNS are separate from the latent reservoir in the blood. Our analysis allows us to infer the presence of a distinct pool of latently infected cells in the CNS waiting to reinitiate infection once ART is interrupted.”

Dr. Ron Swanstrom, senior author of the study

The researchers compared the genetic sequences of rebound virus particles when ART was discontinued in 11 human participants. This approach allowed the scientists to assess the similarities between viral populations in the blood and CSF to determine whether they were part of a common latent reservoir. In many cases, the viral populations were not the same, which suggested they can represent different populations of latently infected cells.

The researchers also studied details of viral replication to determine if rebound virus had been selected for replication in CD4+ T cells – the primary home of the virus – or had evolved to replicate in central nervous system myeloid cells, such as macrophages and microglia. All rebound viruses tested were adapted to growth in T cells. For several participants, the researchers also compared viral populations in blood and CSF before ART initiation and after ART was stopped.

These experiments provide further evidence that HIV-infected CD4+ T cells can cross over from blood into the CNS, but also that some latently infected cells may be resident in the CNS during therapy. Any curative therapy would need to activate this dormant reservoir, as well as the latent reservoir in the blood and lymph tissue.

Source:

University of North Carolina Health Care

Journal reference:

Swanstrom, R., et al. (2022) Rebound virus in the cerebrospinal fluid reveals a possible HIV-1 reservoir. Nature Microbiology. doi.org/10.1038/s41564-022-01309-3.