5th International Conference on Sexually Transmitted Diseases

The next series of the "2nd International Conference on Sexually transmitted Diseases" , "5th International Conference on Sexually Transmitted Diseases" slated on July 17-18, 2019 at London, UK warmly invites you all to present your respective research paper at our conference.

Abstract submission : https://std-hiv-aids.cmesociety.com/abstract-submission
Registration : https://std-hiv-aids.cmesociety.com/registration
Next series blogger info : std2019.blogger.com

No 'reservoir': Detectable HIV-1 in treated human liver cells found to be inert

Novel study suggests HIV-1 still detectable in human liver macrophages unlikely to stay infectious after long-term antiretroviral therapy. In a proof-of-principle study, researchers at Johns Hopkins report that a certain liver immune cell called a macrophage contains only defective or inert HIV-1 copies and aren't likely to restart infection on their own in HIV-1-infected people on long-term antiretroviral therapy (ART).

The study, the investigators say, strongly suggest that defective or inert HIV-1 can remain in the liver macrophages for up to ten years without functioning as an HIV-1 "reservoir" that can replicate the virus at high levels.

But the finding, they say, also suggests that HIV-1 treatment strategies that only or mostly focus on these macrophages in a search for a cure might need to shift more heavily to other cell types more likely to serve as active reservoirs of the virus.

A report of the findings was published online on Sept. 10 and in the Oct. issue of the Journal of Clinical Investigation.

"Our study was the first, to our knowledge, in which purified liver tissue macrophages from HIV-1 infected people taking ART directly tested the idea that tissue macrophages are a long-lived active HIV-1 reservoir," says Ashwin Balagopal, M.D., an associate professor in the Division of Infectious Diseases at the Johns Hopkins University School of Medicine.

According to the U.S. Centers for Disease Control and Prevention (CDC), 36.7 million people worldwide and 1.1 million people in the U.S. are infected with HIV-1. Commonly, ART is successfully used to suppress the replication of HIV-1 and stop or control the progression of acquired immunodeficiency syndrome (AIDS) in humans. The virus infects the body's immune system cells, commonly forming a persistent, and reservoir in humans in so-called resting memory CD4+ T white blood cells. Macrophages work with T cells normally to envelop and clear tissues of microbes and debris.

The inability to completely wipe out pools of infectious HIV-1 has for decades frustrated efforts to completely cure the infection. And it means that the interruption or discontinuation of ART at any time re-activates HIV-1 replication, spreading the virus to new cells.

As a result, Balagopal says, investigators are increasingly focused more specifically on the location and biology of these HIV-1 reservoirs.

To determine if liver macrophages were a true source of infection-capable HIV-1 reservoir after ART, liver tissue samples were taken from nine HIV-1 infected persons, seven of whom underwent liver transplantation at the Johns Hopkins Hospital and would have otherwise had their livers discarded. Eight of the nine persons were on ART for periods ranging from eight to 140 months.

The sample group included only adults whose demographic information is considered exempt from human subject research because all samples were obtained strictly for scientific reasons or post-mortem and would otherwise have been discarded. The Johns Hopkins School of Medicine institutional review approved this study protocol.

Using lab techniques that both measure HIV-1 containing T cells and separate out the liver macrophages, the researchers found HIV-1 to be present in the macrophages even after exposure to longstanding virus-suppressing ART.

However, Balagopal said that when his team tried to simulate virus "rebound" from the liver macrophages in the laboratory, they found only "fragments of HIV-1 in small quantities, without robust growth of full-length, infectious virus."

The researchers found that HIV-1 was in the liver macrophages of one subject who took ART for 11.7 years. They concluded that while liver macrophages might harbor HIV-1 for a long time, it's unlikely these viruses could continue an infection on their own, unlikely to function as a reservoir, because the viruses were not able to replicate.

Balagopal cautioned that their study results still affirm the need to address liver macrophage infection, because even if inert, these cells may be able to produce portions of viral proteins that can misdirect the immune system.

"These results contribute an important piece in our efforts to understand the role of non-T cells, such as macrophages, as HIV-1 cellular reservoirs in individuals on long-term ART, but also may help the research community focus on additional cure strategies," Abraham Kandathil, Ph.D., a research associate in the Division of Infectious Diseases at Johns Hopkins University School of Medicine who performed all of the key experiments.

In the future, Kandathil says, more research is needed to determine if the inert HIV-1 infected liver macrophages have any functional significance in people taking ART because expression of defective HIV-1 proteins can confuse the immune system and cause tissue inflammation.

"To find a comprehensive HIV-1 cure, it's important to identify all of the relevant HIV-1 reservoirs in the body, since it's possible that the virus hides in the DNA of numerous cell types and each may require different strategies to get a cure," says Balagopal.

Balagopal noted that their study was limited by the small number of liver macrophages and human samples studied, as well as the small number of CD4+ T cells in the liver cell cultures that may have prevented the researchers' ability to detect them.

Source: https://www.sciencedaily.com/releases/2018/10/181001110210.htm

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

HIV RNA expression inhibitors may restore immune function in HIV-infected individuals

Immune activation and inflammation persist in most treated HIV-infected individuals and is associated with excess risk of mortality and morbidity. A new study by Boston University School of Medicine (BUSM) researchers suggests that use of HIV RNA expression inhibitors as adjunct therapy might diminish atypical inflammation and restore immune function in HIV-infected individuals on combination antiretroviral therapy (cART).

HIV-1-infected individuals have excess risk of developing non-AIDS complications such as cardiovascular atherosclerosis, neurocognitive dysfunctions, non-AIDS cancers, osteoporosis, and renal disorders. Systemic chronic immune activation has been postulated to lead to these non-AIDS complications.

Despite long-term viral suppression by cART, it has remained unclear how chronic inflammation is induced in HIV-infected individuals. In this study, BUSM researchers identified a mechanism of HIV-1-induced chronic immune activation and T cell dysfunction. In studies performed with primary human macrophages and T cells, they found that persistent infection of macrophages with HIV-1 and expression of intron-containing HIV-1 RNA alone even in the absence of infectious virus production lead to induction of type I interferon (IFN-I)-dependent pro-inflammatory responses and immune exhaustion of co-cultured T cells. They believe that these findings might provide an explanation for the observed chronic inflammation-associated morbidities in HIV-infected individuals who are on cART.

"We hope our study will broaden knowledge of host-HIV interactions and might help to reduce inflammation-associated disorders caused by chronic viral infections," said Rahm Gummuluru, PhD, corresponding author and associate professor of microbiology.

Source: https://www.sciencedaily.com/releases/2018/08/180827102648.htm

Submit your abstract here: https://std-hiv-aids.cmesociety.com/abstract-submission and join us at STD 2018 event taking place at Toronto, Canada on December 03-04, 2018.   

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."

Novel method for dating 'hibernating' HIV strains

Researchers at the BC Centre for Excellence in HIV/AIDS (BC-CfE) and Simon Fraser University (SFU), in partnership with University of British Columbia (UBC) and Western University, have developed a novel way for dating "hibernating" HIV strains, in an advancement for HIV cure research in the province. Published in the Proceedings of the National Academy of Sciences (PNAS), the BC-CfE's first major scientific contribution to the area of HIV cure research confirms that dormant HIV strains can persist in the body for decades.

"If you can't identify it, you can't cure it. This research provides further essential clues in the pursuit of an HIV cure -- which will ultimately require the complete eradication of dormant or 'latent' HIV strains," said Dr. Zabrina Brumme, Director, Laboratory with BC-CfE and lead author on the study. "Scientists have long known that strains of HIV can remain essentially in hibernation in an individual living with HIV, only to reactivate many years later. Our study confirms that the latent HIV reservoir is genetically diverse and can contain viral strains dating back to transmission."

 

"The BC-CfE has consistently been a national and global leader on research on HIV and on the implementation of its pioneering Treatment as Prevention® strategy. The addition of molecular biologist Dr. Zabrina Brumme as Director of the innovative BC-CfE Laboratory ensures the BC-CfE will play a significant role in HIV cure research," said Dr. Julio Montaner, Director of the BC-CfE. "Curative strategies will need to address this new study's key findings. I want to acknowledge the study participants and thank them for helping to increase our knowledge on the origins of the latent HIV reservoir."

"By creating family trees of viruses using a technique called molecular phylogenetics, we can reconstruct the evolutionary history of HIV within a person," said Brad Jones, a Ph.D. student with UBC at the BC-CfE and the first author on the study. "In essence, we created a highly calibrated 'time machine' that gives us a specific time stamp for when each dormant HIV strain originally appeared in a person."

Dormant HIV strains, which have integrated their DNA into that of the body's cells, can persist for years and are unreachable by antiretroviral treatments and the immune system. They can reactivate at any time, which is why HIV treatment needs to be maintained for life.

Through advances in antiretroviral therapy, an individual living with HIV can now live a longer, healthier life on treatment. Treatment works by stopping HIV from infecting new cells. On sustained treatment, individuals can achieve a level of virus that is undetectable by standard blood tests. An undetectable viral load means improved health and that the virus is not transmittable to others -- the concept behind Treatment as Prevention®.

"Previous research had already revealed that the HIV reservoir was genetically complex. With our method, we can now understand that complexity with greater granularity, pinpointing exactly when each unique HIV strain originally appeared in a person," said Dr. Jeffrey Joy, Research Scientist at the BC-CfE and co-author on the study.

"In order to eradicate HIV from a person's body, you first need to know the characteristics of HIV in the latent reservoir," said Dr. Art Poon, Assistant Professor in Pathology and Laboratory Medicine at Western University, also a co-author on the study. "We are providing a method for better measuring the timeline of virus latency and evolution within an individual living with HIV."

In order to "date" dormant HIV strains within the viral reservoir, researchers needed to compare these strains to those that evolved within an individual living with HIV over the entire history of their infection. The BC-CfE is one of a handful of institutions worldwide capable of such research, thanks to its maintenance of a historical repository of blood specimens from individuals diagnosed with HIV in BC. These specimens date back to 1996 and were originally collected for viral load and drug resistance testing. The BC-CfE Laboratory has provided HIV drug resistance genotyping for virtually all Canadian provinces and territories since 1998, as well as for many countries worldwide.

This research was funded by the Canadian Institutes of Health Research (CIHR) in partnership with the Canadian Foundation for AIDS Research (CANFAR) and the International AIDS Society (IAS) through its support of the Canadian HIV Cure Enterprise (CanCURE), as well as the US National Institutes of Health (NIH) through its support of the Martin Delaney BELIEVE Collaboratory.

To be a speaker at STD 2018 Conference being held at Toronto, Canada, submit your abstracts here: https:/std-hiv-aids.cmesociety.com/abstract-submission 

 

Source: https://www.sciencedaily.com/releases/2018/09/180905142037.htm