During HIV infection, antibody can block B cells from fighting pathogens

For the first time, scientists have shown that in certain people living with HIV, a type of antibody called immunoglobulin G3 (IgG3) stops the immune system's B cells from doing their normal job of fighting pathogens. This phenomenon appears to be one way the body tries to reduce the potentially damaging effects of immune-system hyperactivity caused by the presence of HIV, according to the investigators, but in so doing, it also impairs normal immune function.

The research was led by scientists in the Laboratory of Immunoregulation and the Laboratory of Immunogenetics at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The investigators made their discovery by analyzing blood samples from 83 HIV-uninfected, anonymous donors and 108 people who were living with HIV at various stages of infection. The people living with HIV came from a variety of racial and ethnic backgrounds. Some of these people were being treated for their infection, while others had not yet begun therapy.

The scientists observed that IgG3 appeared on the surface of B cells only under certain conditions. It appeared in people living with HIV, but not in HIV-uninfected people. Also, IgG3 predominantly appeared on B cells of people of African American or black African decent during the chronic phase of untreated HIV infection when the virus was not adequately controlled.

A site on B cells called the B-cell receptor normally binds to foreign entities such as pathogens. This binding stimulates the B cell to produce many copies of the antibody form of the receptor, which can trap a pathogen and mark it for destruction. The scientists found that IgG3 short-circuits this process in certain people living with HIV by docking on the B-cell receptor, blocking it from adequately responding to the pathogen or other intended target. The researchers also demonstrated how other components of the immune system contribute to IgG3 interference with normal B-cell function during HIV infection. Finally, they showed that IgG3 stops binding to B-cell receptors when a chronically infected person starts treatment that controls the virus, illustrating that the IgG3 activity is directly linked to the presence of HIV during chronic infection.

Source: https://www.sciencedaily.com/releases/2018/08/180813125236.htm

Proof-of-concept HIV Immunotherapy study passes Phase 1 safety trial

Preliminary results from a phase I clinical trial have demonstrated the safety and tolerability of a cell therapy involving the ex vivo expansion of T cells and their subsequent infusion into HIV-infected individuals previously treated with antiretroviral therapy (ART). The study appears September 21st in the journal Molecular Therapy.

"This study is focused on finding a way to re-educate the body's immune system to better fight HIV infection," says co-senior study author David Margolis of the University of North Carolina (UNC) at Chapel Hill. "We found that this approach of re-educating the immune cells and reinfusing them was safe, which was the primary goal of the study. The data from this trial will continue to help us design improved immunotherapies against HIV."

A game changer for patients living with HIV, ART has turned what was once a death sentence into a chronically managed disease. But it is not a cure, and the virus continues to persist within a latent reservoir that remains hidden from the immune system. Approaches using pharmacological HIV-latency-reversal agents to induce latent virus to express viral protein could make this reservoir vulnerable to T cells. However, the existing HIV-specific immune response in ART-treated individuals is insufficient to clear persistent infection, even in the presence of latency-reversal agents that induce HIV expression.

One safe avenue for harnessing T cell responses to fight HIV is adoptive cellular therapy. This procedure involves collecting T cells from a patient, growing them in the laboratory to increase their numbers, and then giving them back to the patient to help the immune system fight disease. Earlier adoptive-T-cell-therapy approaches for HIV had limited efficacy as a result of multiple factors. Since these earlier attempts, the adoptive-T-cell-therapy field has made significant advances, largely in the oncology field, that could help to overcome some of the pitfalls encountered with earlier T-cell-therapy approaches for HIV. T cells generated by these sophisticated methods of expansion have been safe and well tolerated, as well as highly effective.

"Before we can combine this approach with treatments meant to bring HIV out from hiding so the improved immune response can clear it from the body, we need to first establish that this immunotherapy approach is safe on its own," says co-senior study author Catherine Bollard of the Children's National Health System. "We have long-standing experience treating patients with virus-specific T cells targeting latent viruses such as Epstein-Barr virus and cytomegalovirus. Therefore, we were extremely excited to work with the UNC team to adapt this virus-specific T-cell-therapy approach to the HIV setting."

In the small proof-of-concept study, Margolis, Bollard, and their collaborators produced ex vivo expanded HIV-specific T cells (HXTCs); their long-term goal was to use HXTCs as part of a strategy to clear persistent HIV infection. The researchers administered two infusions of HXTCs over a 2 week period to six HIV-infected participants whose viral load had been reduced to an undetectable level by ART.

This treatment was well tolerated and had few adverse events. Moreover, two patients exhibited a detectable increase in T-cell-mediated antiviral activity after the two infusions, although the clinical significance of this mild-to-modest impact is unknown. When evaluating participants in aggregate, the research team found no overall enhancement of the magnitude of the HIV-specific immune response. This could be due to the low dose of the two infusions and the lack of strategies to promote the expansion of the T cells once they are in the body.

There was also no decrease in the size of the latent reservoir, most likely because of the absence of therapies such as latency-reversal agents, which are designed to perturb the reservoir and induce recognizable expression of HIV proteins that trigger immune responses. In the future, a critical question will be whether HXTC therapy in combination with latency-reversal agents can deplete the HIV reservoir to an extent that is measurable by current gold-standard assays of HIV latency. A study of HXTC in combination with the latency-reversal agent vorinostat is currently undergoing evaluation in an ongoing clinical trial.

"This is a promising advancement for the field," says first author Julia Sung of UNC, although she also cautions people against over-interpreting the results. "The study did not cure HIV and should not be interpreted as doing so, but we also are very encouraged by the safety data, so it should not be considered discouraging either. This paves the way for the next step, which is to combine this immunotherapy approach with latency-reversal therapy in order to wake up the HIV out of its latent state, where it is invisible to the immune system, then clear it out with the immunotherapy."

A New Method for Removing Cells Infected with the AIDS Virus

With the successful suppression of the AIDS virus (HIV) through medication, the focus turns toward its eradication. Researchers from Kumamoto University in Japan have developed a new compound that is key to the destruction of HIV. When the compound is introduced into infected cells, viral budding (release) is suppressed thereby confining it within the host cells. The cells then die naturally through apoptosis (cell death). This treatment is believed to lead to the complete recovery from AIDS in the near future.

In recent years, multi-drug therapy has made it possible to suppress HIV multiplication in the body when taken properly. This method, however, cannot remove the virus particles of the latent HIV reservoir—non-replicating virus particles that remain dormant in the cells of the body. As soon as drug administration is stopped, the viral load will again increase in the body. Removal of the viral reservoir is currently the top goal in AIDS research.

The "kick and kill" approach, which was developed several years ago, is a strategy for killing reservoir cells. This technique uses a drug that targets the reservoir cells and activates the virus which then allows the immune system to find these cells using the activated virus as a landmark. Although this approach was clinically tested, there is still the problem of not being able to efficiently deactivate the virus after successful activation.

Researchers at Kumamoto University developed a new approach that they call "Lock-in and apoptosis." First, they synthesized the compound L-HIPPO, which binds strongly to the HIV protein Pr55Gag and suppresses viral budding. When L-HIPPO was added to virus-infected cells via a carrier called α-CDE, the virus became confined within the cell and the cell would die through natural apoptosis.

"Unfortunately, this approach is not immediately available for people infected with HIV," said Associate Professor Mikako Fujita of Kumamoto University, one of the leaders of the study. "First, we have to improve upon the drugs that activate the virus and combine them with L-HIPPO to efficiently target the viral reservoir. This would be a big step towards a complete recovery from HIV. We believe that our research will help to completely eradicate AIDS."

Source: https://medicalxpress.com/news/2017-10-method-cells-infected-aids-virus.html

Antiviral Compound "Viperin" Found in the Human Body

The human body can make a compound with a special power to fight viruses; viperin is an enzyme made naturally in many mammals. Scientists have found that it has an antiviral effect on a variety of pathogens including hepatitis C, rabies and West Nile viruses. The enzyme aids the chemical reaction that generates ddhCTP, a molecule that can prevent viruses from replicating their genetic material, halting the expansion of the viral population. This work, which was reported in Nature, could have important implications in antiviral drug development.

"We knew viperin had broad antiviral effects through some sort of enzymatic activity, but other antivirals use a different method to stop viruses," explained study author Craig Cameron, a professor and the Eberly Chair in Biochemistry and Molecular Biology at Penn State. "Our collaborators at the Albert Einstein College of Medicine, led by senior authors Tyler Grove and Steven Almo, revealed that viperin catalyzes an important reaction that results in the creation of a molecule called ddhCTP. 

“Our team at Penn State then showed the effects of ddhCTP on a virus's ability to replicate its genetic material. Surprisingly, the molecule acts in a similar manner to drugs that were developed to treat viruses like HIV and hepatitis C. With a better understanding of how viperin prevents viruses from replicating, we hope to be able to design better antivirals."

Viruses usually have small genomes and lack critical cell components found in normal cells, so they hijack the cellular machinery they lack, using nucleotide bases from their host to build new genetic material - viral RNA. The ddhCTP chemical can mimic nucleotides, the foundations of DNA and RNA, and these 'nucleotide analogs' get incorporated into the new viral RNA that is made. Then they can interfere with the extension of the genetic strand, which stops the virus from making new copies of itself.

"Long ago, the paradigm was that in order to kill a virus, you had to kill the infected cell," said Cameron. "Such a paradigm is of no use when the virus infects an essential cell type with limited capacity for replenishment. The development of nucleotide analogs that function without actually killing the infected cell changed everything."

Usually, nucleotide analogs are synthetic and come with risks. Nucleotides are important in many ways, so they can have dangerous side effects.

"The major obstacle to developing therapeutically useful antiviral nucleotides is unintended targets," noted study author Jamie Arnold, associate research professor of biochemistry and molecular biology at Penn State. "For example, a few years ago we discovered that a nucleotide analog under development for [the] treatment of hepatitis C could interfere with the production of RNA in mitochondria, subcellular organelles important for energy production in the patient's own cells. That meant people with mitochondrial dysfunction are predisposed to any negative effects of this unintended interference."

However, ddhCTP appears to be safe so far; it does not seem to have unintended targets.

"Unlike many of our current drugs, ddhCTP is encoded by the cells of humans and other mammals," said Cameron. "We have been synthesizing nucleotide analogs for years, but here we see that nature beat us to the punch and created a nucleotide analog that can deal with a virus in living cells and does not exhibit any toxicity to date. If there's something out there that's going to work, nature has probably thought of it first. We just have to find it."

The researchers tested ddhCTP against West Nile, Zika and dengue viruses, and found that the ddhCTP could stop the replication of Zika in live cells.

"The molecule directly inhibited replication of three different strains of Zika virus," said study author Joyce Jose, assistant professor of biochemistry and molecular biology at Penn State. "It was equally effective against the original strain from 1947 as it was against two strains from the recent 2016 outbreak. This is particularly exciting because there are no known treatments for Zika. This study highlights a new avenue of research into natural compounds like ddhCTP that could be used in future treatments."

The researchers have shown that ddhCTP has a lot of potential as a therapeutic, although it was not effective against a class of viruses called picornaviruses; that group includes polio and rhinovirus. The researchers would like to find out why and determine if a vulnerable virus might gain resistance against ddhCTP.

"Development of resistance to an antiviral agent is always an issue," said Cameron, "Having some idea of how resistance happens, or being able to prevent it from happening, will be critical if this is to be used as a broad-spectrum therapy."

Source: https://www.labroots.com/trending/microbiology/11860/antiviral-compound-found-human-body

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