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

Herpes linked to Alzheimer's: Antivirals may help

A new commentary by scientists at the Universities of Manchester and Edinburgh on a study by Taiwanese epidemiologists supports the viability of a potential way to reduce the risk of Alzheimer's disease.

When the Taiwanese authors looked at subjects who suffered severe herpes infection and who were treated aggressively with antiviral drugs, the relative risk of dementia was reduced by a factor of 10.

Manchester's Professor Ruth Itzhaki and Edinburgh's Professor Richard Lathe say the paper, by Tzeng et al. and published in Neurotherapeutics in February 2018, also shows that herpes simplex virus type 1 (HSV1) leads to an increased risk of developing the disease.

"This article and two others by different research groups in Taiwan provide the first population evidence for a causal link between herpes virus infection and Alzheimer's disease, a hugely important finding," said Professor Itzhaki.

They publish a commentary in the Journal of Alzheimer's Disease on the three articles, arguing that they provide the strongest evidence yet for a causal link between herpes infection and Alzheimer's disease, backing 30 years of research by Professor Itzhaki.

Professor Itzhaki said: "I believe we are the first to realise the implications of these striking data on this devastating condition which principally affects the elderly. No effective treatments are yet available.

"Almost 30 million people worldwide suffer from it and sadly, this figure will rise as longevity increases.

"But we believe that these safe and easily available antivirals may have a strong part to play in combating the disease in these patients.

"It also raises the future possibility of preventing the disease by vaccination against the virus in infancy.

"Successful treatment by a specific drug, or successful vaccination against the putative microbe, are the only ways to prove that a microbe is the cause of a non- infectious human disease."

Most Alzheimer's disease researchers investigate its main characteristics -- amyloid plaques and neurofibrillary tangles; however, despite the vast amount of research, the causes of their formation are unknown.

HSV1 infects most humans in youth or later and remains lifelong in the body in dormant form within the peripheral nervous system.

From time to time the virus becomes activated and, in some people, it then causes visible damage in the form of cold sores.

The Taiwanese study identified 8,362 subjects aged 50 or more during the period January to December 2000 who were newly diagnosed with severe HSV infection.

The study group was compared to a control group of 25,086 people with no evidence of HSV infection.

The authors then monitored the development of dementia in these individuals over a follow-up period of 10 years between 2001 and 2010.

The risk of developing dementia in the HSV group was increased by a factor of 2.542. But, when the authors compared those among the HSV cohort who were treated with antiviral therapy versus those who did not receive it, there was a dramatic tenfold reduction in the later incidence of dementia over 10 years.

Professor Richard Lathe added: "Not only is the magnitude of the antiviral effect remarkable, but also the fact that -- despite the relatively brief duration and the timing of treatment -- in most patients severely affected by HSV1 it appeared to prevent the long-term damage in brain that results in Alzheimer's.

Professor Itzhaki said: "It was as long ago as 1991 when we discovered that, in many elderly people infected with HSV1, the virus is present also in the brain, and then in 1997 that it confers a strong risk of Alzheimer's disease in the brain of people who have a specific genetic factor.

"In 2009, we went on to show that HSV DNA is inside amyloid plaques in Alzheimer's patients' brains.

"We suggested that the virus in brain is reactivated by certain events such as stress, immunosuppression, and infection/inflammation elsewhere.

"So we believe the cycle of HSV1 reactivation in the brain eventually causes Alzheimer's in at least some patients."

Source: https://www.sciencedaily.com/releases/2018/07/180712100515.htm

Amyloid beta protein protects brain from herpes infection by entrapping viral particles

A Massachusetts General Hospital (MGH) study has found the mechanism by which amyloid beta (A-beta) -- the protein deposited into plaques in the brains of patients with Alzheimer's disease -- protects from the effects of herpes viruses commonly found in the brain. Along with another study appearing in the same July 11 issue of Neuron, which found elevated levels of three types of herpes viruses in the brains of patients with Alzheimer's disease, the MGH team's results support a potential role for viral infection in accelerating A-beta deposition and Alzheimer's progression.

"There have been multiple epidemiological studies suggesting people with herpes infections are at higher risk for Alzheimer's disease, along with the most recent findings from Icahn School of Medicine at Mt. Sinai that are being published with our study," says Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit in the MassGeneral Institute for Neurodegenerative Disease (MIND) and co-corresponding author of the Neuron paper. "Our findings reveal a simple and direct mechanism by which herpes infections trigger the deposition of brain amyloid as a defense response in the brain. In this way, we have merged the infection hypothesis and amyloid hypothesis into one 'Antimicrobial Response Hypothesis' of Alzheimer's disease."

Previous studies led by Tanzi and co-corresponding author Robert Moir, PhD, also of the MIND Genetics and Aging Research Unit, found evidence indicating that A-beta -- long thought to be useless "metabolic garbage" -- was an antimicrobial protein of the body's innate immune system, capable of protecting animal models and cultured human brain cells from dangerous infections. Given that brain infection with herpes simplex -- the virus that causes cold sores -- is known to increase with aging, leading to almost universal presence of that and other herpes strains in the brain by adulthood, the MGH team set out to find whether A-beta could protect against herpes infection and, if so, the mechanism by which such protection takes place.

After first finding that transgenic mice engineered to express human A-beta survive significantly longer after injections of herpes simplex into their brains than do nontransgenic mice, the researchers found that A-beta inhibited infection of cultured human brain cells with herpes simplex and two other herpes strains by binding to proteins on the viral membranes and clumping into fibrils that entrap the virus and prevent it from entering cells. Further experiments with the transgenic mice revealed that introduction of herpes simplex into the brains of 5- to 6-week-old animals induced rapid development of A-beta plaques, which usually appear only when the animals are 10 to 12 weeks old.

"Our findings show that amyloid entrapment of herpes viruses provides immediate, effective protection from infection," says Moir. "But it's possible that chronic infection with pathogens like herpes that remain present throughout life could lead to sustained and damaging activation of the amyloid-based immune response, triggering the brain inflammation that drives a cascade of pathologies leading to the onset of Alzheimer's disease. A key insight is that it's not direct killing of brain cells by herpes that causes Alzheimer's, rather it's the immune response to the virus that leads to brain-damaging neuroinflammation."

He continues, "Our data and the Mt. Sinai findings suggest that an antimicrobial protection model utilizing both anti-herpes and anti-amyloid drugs, could be effective against early Alzheimer's disease. Later on when neuroinflammation has begun, greater benefit may come from targeting inflammatory molecules. However, it remains unclear whether infection is the disease's root cause. After all, Alzheimer's is a highly heterogeneous disease, so multiple factors may be involved in its development.

Tanzi says, "We are currently conducting what we call the 'Brain Microbiome Project,' to characterize the population of microbes normally found in the brain. The brain used to be considered sterile but it turns out to have a resident population of microbes, some of which may be needed for normal brain health. Our preliminary findings suggest that the brain microbiome is severely disturbed in Alzheimer's disease and that bad players -- including herpes viruses -- seem to take advantage of the situation, leading to trouble for the patient. We are exploring whether Alzheimer's pathogenesis parallels the disrupted microbiome models seen in conditions like inflammatory bowel disease, and the data generated to date are both surprising and fascinating."

Source: https://www.sciencedaily.com/releases/2018/07/180705143920.htm

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Screening HPV infection alone more accurate than Pap test in detection of cervical cancer

Screening for human papillomavirus (HPV) infection alone gives more accurate results than Pap (smear) testing for cervical cancer, say the authors of two papers to published today in the journal Gynecologic Oncology. HPV infection causes almost all cervical cancer, and it is estimated that more than half of sexually active people are infected with HPV at some point in their lives. Now new research has shown that in many cases, an HPV test alone can be used for cervical cancer screening instead of a Pap or cotesting with both an HPV and a Pap test, the researchers say.

In the first paper1, Dr Warner Huh, from the Department of Gynecologic Oncology, University of Alabama, Birmingham, USA, sets out the findings of a panel convened to provide guidance on using HPV as the first-line primary screening test. The panel included representatives from all the major US organizations involved in cervical cancer screening, and addressed questions related to the safety and effectiveness of HPV testing for primary screening and whether it could be considered as an alternative to the screening methods currently in use in the US. The panel was convened because of an application to the Food and Drug Administration (FDA) for an existing HPV test to be used for primary HPV cervical cancer screening. The guidance was based on a literature review and also on review of data from the ATHENA study which was conducted to support the primary screening application to the FDA.

"We found that, in patients aged 25 years and upwards, primary HPV testing performed better than a Pap alone, and we recommend that such tests should be carried out no sooner than every three years. This is an important advance in cervical cancer screening because it offers a better reassurance of low cancer risk compared to Pap screening, which is also carried out at three year intervals," Dr Huh said.

Infection with just two HPV genotypes, 16 and 18, is responsible for about 70% of all invasive cervical cancers worldwide. The panel recommends that patients testing positive for either of these two high risk genotypes should have immediate colposcopy - a procedure using a lighted magnifying device that allows doctors to see abnormal areas in the cervix that would be missed by the naked eye. Women with one of the 12 other HPV genotypes can be followed-up in 12 months with repeat testing with both the HPV test and a Pap.

"We believe that there is still considerable confusion over the three current screening options, and the intervals at which they should be performed. We hope that our deliberations will go some way towards reducing this uncertainty. However, I would still like to see more data from the US, and evidence from other countries using primary HPV screening such as Australia and The Netherlands. But in the absence of data to the contrary, we believe that primary HPV testing has potential to further reduce cervical cancer in the US," Dr Huh said.

The second paper2 reveals end-of-study results of the ATHENA trial which evaluated safety and effectiveness of HPV primary screening as an alternative to Pap in women of 25 years and older. 42,209 women in this age group were enrolled into the trial and had both Pap and HPV testing. Those with abnormal Pap test results and those who were HPV positive were referred for colposcopy.

"We found that HPV primary screening was as effective in women aged 25 years and over when compared to Pap alone for women 25 and 29 and cotesting for those aged 30 and over. However, HPV screening alone requires only one test, and this is important for many women who may not be able to afford the cost of two tests," said Dr Thomas Wright, a Professor Emeritus of Pathology and Cell Biology at Columbia University, New York, USA.

To determine the impact of starting HPV screening at different ages, the researchers compared the prevalence of HPV positivity and Pap abnormalities as well as the three year detection rate of high-grade cervical disease by age group. They found that although HPV positivity was almost twice as high in women aged 25-29 as it was in women aged 30-39, HPV testing identified about twice as many high-grade cervical disease cases in women aged 25-29 than did the Pap.

"When Pap screening is used in this age group, the women with missed high-grade cervical disease are told to return in three years for repeat screening and some are likely to develop invasive cervical cancer", said Dr Wright.

"Our results, from the first prospective US study to evaluate the performance of HPV primary screening, have shown clearly that this new screening approach should be considered as an option for women 25 years and older", Dr Wright said. However, he added that the recent FDA approval for HPV primary screening is limited to a single commercially available HPV test and to only one of the two widely utilised liquid-based Pap tests. "In order to facilitate the widespread adoption of this safe and effective method of screening, it would be advantageous to have additional HPV tests and the other liquid-based Pap tests approved. We hope that our research will help reduce morbidity and mortality from cervical cancer worldwide," he said.

Source: https://medicalxpress.com/news/2015-01-screening-hpv-infection-accurate-pap.html