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

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.   

Join the STD 2018 conference taking place at Toronto Canada this December, meet top speakers and network with your peers in the field. To register, please visit: https://std-hiv-aids.cmesociety.com/registration

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

Collaborators of STD 2018

STD 2018 proudly presents the collaborators of the event: https://std-hiv-aids.cmesociety.com/collaborators

To become a collaborator, mail us at std@pulsusevents.org