How viruses affect the immune system

Fighting infections depends on bodies' capacity to quickly recognize infected cells and destroy them, a job done by a class of immune cells known as CD8+ T cells. These soldiers get some of their orders from chemical mediators known as cytokines that make them more or less responsive to outside threats. In most cases, CD8+ T cells quickly recognize and destroy infected cells to prevent the infection from spreading.

When it comes to viruses that lead to chronic infection, immune cells receive the wrong set of marching orders, which makes them less responsive," says Martin Richer, an assistant professor at McGill's Department of Microbiology & Immunology and senior author of the study. The research, conducted in Richer's lab by graduate student Logan Smith, revealed that certain viruses persist by driving the production of a cytokine that leads to modification of glycoproteins on the surface of the CD8+ T cells, making the cells less functional.

That maneuver creates time for the pathogen to outpace the immune response and establish a chronic infection. Importantly, this pathway can be targeted to restore some functionality to the T cells and enhance the capacity to control infection. The discovery of this regulatory pathway could help identify new therapeutic targets for a variety of diseases.
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Latent HIV reservoirs show resistance to white blood cells

A recent study by researchers at the George Washington University (GW) found that latent HIV reservoirs show resistance to CD8+ T-cells, a type of white blood cell whose primary function is to kill infected cells.

According to Brad Jones, PhD, primary author of the study and assistant professor of microbiology, immunology, and tropical medicine at the GW School of Medicine and Health Sciences, researchers have identified a barrier.

It is difficult to understand the nature of that barrier, they used the most powerful combinations against these cells, and when the dust settled they found that the virus was present at just as high levels as what was started with.

HIV/AIDS treatment currently includes lifelong, antiretroviral therapy while the search for a cure continues. Persistent, latent reservoirs of the virus make efforts to cure infection difficult. In order to eradicate those HIV reservoirs, researchers must find a way to eliminate persistent populations of cells with integrated HIV proviruses.

The paradigm is aimed at combining latency reversing agents (LRA) with immune effectors, such as T-cells, to wake up the virus and kill the reactivated cells.The study found that latent HIV reservoirs exhibit inherent resistance to CD8+ T-cells.

The team conducted their research using the CD8+ T-cells of people living with HIV, in the combination with LRAs to attack and kill the infected cells. The results suggest that cells infected by replication-competent HIV possess inherent resistance to the T-cells, which present an obstacle on the road to curing HIV.
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Gene therapy may kill HIV

Gene therapy may have the potential to eradicate HIV in people infected with the virus, new animal research suggests. The science centers around the use of "chimeric antigen receptor" (CAR) genes. In laboratory work with monkeys, these engineered cells have destroyed HIV-infected cells for more than two years, scientists reported.

T-cells are the cells that are largely responsible for human ability to fight off pathogens and get rid of infections in the body. Every T-cell has a unique receptor, or molecule, on it. That receptor allows the cell to recognize a specific target-a bacteria, or fungus or virus. And when it recognizes that target, it's called into duty to clear it from the body. Taking artificial receptors- CAR that can go on to these cells and allow them to recognize what we want them to recognize," he noted. "In this case that's HIV."

First, the team genetically engineered CAR to find and bind to simian/human immunodeficiency virus (SHIV), a lab-engineered HIV hybrid composed of human virus and monkey virus. Then the researchers modified the DNA of certain blood-forming stem cells so they would carry SHIV-killing CAR. The resulting cells were introduced into the bloodstream of four male juvenile SHIV-infected macaque monkeys.

The engineered cells successfully took up residence in each monkey's bone marrow. The cells moved widely throughout the body, targeting and killing SHIV-infected cells, without producing any notable adverse side effects. The advantage of the stem cell-based approach is that once these cells are grafted into the body, they continuously produce new T-cells that have this gene in them that can target HIV cells.

Plans are underway for a human trial, this study shows both that these cells will respond to HIV and that it's safe. This strategy is unlikely to fully work on its own, CAR will most likely need to be used with antiretroviral therapy. CAR therapy is already leading to impressive results in cancer and holds promise for HIV eradication.
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Gene therapy can destroy HIV infected cells

Through gene therapy, researchers engineered blood-forming stem cells (hematopoietic stem/progenitor cells, or HSPCs) to carry chimeric antigen receptor (CAR) genes to make cells that can detect and destroy HIV-infected cells. These engineered cells not only destroyed the infected cells, they persisted for more than two years, suggesting the potential to create long-term immunity from the virus that causes AIDS.

Antiviral drugs can suppress the amount of HIV in the body to nearly undetectable levels, but only an effective immune response can eradicate the virus. Researchers have been seeking a way to improve the body's ability to combat the virus by engineering blood-forming stem cells to specifically target and kill HIV-infected cells for the life of the individual.

 Although chimeric antigen receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer -- and show promise in treating HIV-1 infection -- the therapy may not impart long-lasting immunity. Researchers, physicians and patients need T cell-based products that can respond to malignant or infected cells that may reappear months or years after treatment.

Because HIV uses CD4 to infect cells, the researchers used a CAR molecule that hijacks the essential interaction between HIV and the cell surface molecule CD4 to make stem cell-derived T-cells target infected cells. When the CD4 on the CAR molecule binds to HIV, other regions of the CAR molecule signal the cell to become activated and kill the HIV infected cell.

The researchers found that, in test animals, modification of the blood-forming stem cells resulted in more than two years of stable production of CAR-expressing cells without any adverse effects. In addition, these cells were widely distributed throughout the lymphoid tissues and gastrointestinal tract, which are major anatomic sites for HIV replication and persistence in infected people. Most important, engineered CAR T-cells showed efficacy in attacking and killing HIV-infected cells.
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Using viruses to fight viruses

Researchers at The Ottawa Hospital and the University of Ottawa have discovered that the Maraba virus, or MG1, can target and destroy the kind of HIV-infected cells that standard antiretroviral therapies can't reach. Daily medications keep the level of HIV virus in the blood low, there is currently no way to totally eliminate dormant HIV-infected cells from the body. If a person living with HIV stops taking antiretroviral medications, these hidden viruses rapidly rebound.

These latently HIV-infected cells are hard to target because they are not distinguishable from normal cells. Dr. Jonathan Angel and his team tried a new approach of identifying these dormant cells by using the MG1 virus. This virus attacks cancer cells that have defects in their interferon pathway, which makes the cells more vulnerable to viruses. Dr. Angel and his team previously found that latently HIV-infected cells also have defects in this pathway.

Using a number of laboratory models of latently HIV-infected cells, the researchers found that the MG1 virus targeted and eliminated the infected cells, and left healthy cells unharmed.
While most of these cells in patients are in the lymph nodes and other organs, a tiny number are found in the blood. When the researchers added MG1 to relevant blood cells taken from HIV-positive individuals, the levels of HIV DNA in the sample dropped. This indicated that the HIV-infected cells had been eliminated.
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How Zika virus infects developing brain

Zika virus is transmitted from mother to fetus by infected cells that later develop into the brain's first and primary form of defense against invasive pathogens. During embryogenesis- the early stages of prenatal development cells called microglia form in the yolk sac and then disperse throughout the central nervous system CNS of the developing fetus.

In the brain, these microglia will become resident macrophages whose job is to constantly clear away plaques, damaged cells and infectious agents. The Zika virus can infect these early microglia, moving into the brain where they transmit the virus to other brain cells, leading to devastating neurological damage.

The Zika virus is transmitted to people through the bite of infected Aedes species mosquitoes. However, a pregnant woman can also pass the virus to her fetus, the researchers used human induced pluripotent stem cells to create two relevant CNS cell types: microglia and neural progenitor cells (NPCs), which generate the millions of neurons and glial cells required during embryonic development.

Then they established a co-culture system that mimicked the interactions of the two cell types in vitro when exposed to the Zika virus. They discovered that the microglia cells engulfed Zika-infected NPCs, doing their job. But when these microglia carrying the virus were placed in contact with non-infected NPCs, they transmitted the virus to the latter.
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Strong persistence of viral infection

Infections caused by viruses, such as respiratory syncytial virus, measles, parainfluenza and Ebola, are acute. These viruses cause disease quickly and live within a host for a limited time. But in some cases the effects of the infection, and presence of the virus can lead to chronic problems.

Viral infection leads to defective viral genomes, DVG which involved in triggering an immune response, can also kick off a molecular pathway that keeps infected cells alive. The study used a novel technique to examine the presence of DVGs on a cell-by-cell basis to show that DVG-enriched cells had strategies to survive during an immune-system attack.

Partial viral genomes are produced in infected cells when a virus begins to replicate rapidly, leading to defective versions that contain large deletions. DVGs are increasingly believed to be important components of viral infections.

DVGs are critical in stimulating an immune response to respiratory viruses, they are also critical for stimulating an immune response to the human virus RSV, the presence of DVGs in human respiratory samples from infected patients correlates with enhanced antiviral immune responses.

Researchers used a sophisticated technique that allowed them to differentiate full-length genomes from the partial genomes of DVGs at the single-cell level. They studied cells in culture infected with the Sendai virus, or with RSV, a virus that often affects infants and can lead to chronic respiratory problems.

To dig deeper into how the DVGs were influencing the course of infection, the researchers infected cells either with a version of the Sendai virus that lacked DVGs or one enriched in DVGs. The cells infected with the virus high in DVGs survived more than twice as long as those infected with virus lacking DVGs.

 Adding purified DVGs boosted the cells' survival time, indicating a direct role for the DVGs in promoting cell survival.
The results were similar in parallel experiments with RSV, suggesting that the pro-survival role of DVGs held across viral types.

The researchers next were curious to know what molecular pathways might enable the DVG-rich cells to avoid apoptosis. An analysis of highly-expressed genes in DVG-enriched cells compared to the cells with full-length viral genomes revealed that a host of pro-survival genes were activated in the DVG-rich cells.
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How viruses developed immunity

 SIDT2 protein is an important factor for cells to detect viral components in their environment, and create an immune response to reduce or stop the spread of the virus.

During a viral infection, ribonucleic acid RNA a genetic material similar to DNA is released into the environment around the infected cells. SIDT2 allowed viral RNA to be shuttled between compartments within cells, allowing it to reach the proteins that trigger anti-viral immunity.

The RNA is in a 'double-stranded' form, called 'dsRNA', that is not normally found in human body. Human cells have evolved ways to detect double stranded ribonucleic acid dsRNA as a warning sign of an active viral infection and, in this way, dsRNA acts as an important trigger for cells to produce an anti-viral immune response.

Cells constantly protect their environment by swallowing small samples of their environment into compartments known as endosomes. SIDT2 was the crucial missing link needed to transport dsRNA out of endosomes, and enable activation of immune response.

Viruses have many strategies to prevent an infected cell from activating the immune system to their presence.
SIDT2 is critical for uninfected cells to detect viral RNA in their environment, this means uninfected cells can trigger protective immunity before they even encounter the virus.
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