Ageing and inflammation in patients with HIV infection


Summary

Nowadays, HIV+ patients have an expected lifespan that is only slightly shorter than healthy individuals. For this reason, along with the fact that infection can be acquired at a relatively advanced age, the effects of ageing on HIV+ people have begun to be evident. Successful anti-viral treatment is, on one hand, responsible for the development of side effects related to drug toxicity; on the other hand, it is not able to inhibit the onset of several complications caused by persistent immune activation and chronic inflammation. Therefore, patients with a relatively advanced age, i.e. aged more than 50 years, can experience pathologies that affect much older citizens. HIV+ individuals with non-AIDS-related complications can thus come to the attention of clinicians because of the presence of neurocognitive disorders, cardiovascular diseases, metabolic syndrome, bone abnormalities and non-HIV-associated cancers. Chronic inflammation and immune activation, observed typically in elderly people and defined as ‘inflammaging’, can be present in HIV+ patients who experience a type of premature ageing, which affects the quality of life significantly. This relatively new condition is extremely complex, and important factors have been identified as well as the traditional behavioural risk factors, e.g. the toxicity of anti-retroviral treatments and the above-mentioned chronic inflammation leading to a functional decline and a vulnerability to injury or pathologies. Here, we discuss the role of inflammation and immune activation on the most important non-AIDS-related complications of chronic HIV infection, and the contribution of aging per se to this scenario

A Newborn with Thrombocytopenia, Cataracts, and Hepatosplenomegaly


How common is the use of the rubella vaccine worldwide?

The acronym TORCH (toxoplasmosis, other [syphilis, varicella, parvovirus B19 infection, HIV infection], rubella, cytomegalovirus infection, and herpes simplex virus infection) is often used to identify possible congenital infections.

Clinical Pearls

Q: What are some of the clinical manifestations of the congenital rubella syndrome?

A: Cataracts, thrombocytopenia, bony abnormalities, and deafness are consistent with the congenital rubella syndrome.

Table 2. (10.1056/NEJMcpc1706110/T2) Manifestations of the Congenital Rubella Syndrome.

Q: How is the congenital rubella syndrome diagnosed?

A: Newborns with the congenital rubella syndrome shed rubella virus in the throat, nasopharynx, and urine. Because growth of the virus in cultured mammalian cell lines is relatively slow and cultivation and identification of the virus are labor-intensive, nucleic acid amplification tests have been developed to directly detect rubella virus RNA in clinical samples.

Morning Report Questions

Q: Can serologic testing also establish the diagnosis of the congenital rubella syndrome?

A: In addition to direct viral detection, evidence of the production of antibodies to rubella virus in an infant can be used to establish a diagnosis of the congenital rubella syndrome. Affected newborns produce IgM antibodies to rubella virus. These antibodies can usually be detected at birth with the use of a capture enzyme-linked immunosorbent assay; the level increases during the first 3 months of life and then declines over time. At birth, tests for IgG antibodies to rubella virus cannot be used to distinguish between transplacentally acquired maternal antibodies and antibodies produced by the neonate. However, another means of establishing a diagnosis of the congenital rubella syndrome is showing that the level of IgG antibodies to rubella virus does not substantially decrease during the first few months of life, as the maternal antibodies decay. Finally, IgG antibodies to rubella virus that are produced by infants with congenital infection are typically of low avidity; therefore, a diagnosis of the congenital rubella syndrome can be established by detecting low-avidity antibodies in the blood after the maternal antibodies have waned.

Q: How common is use of the rubella vaccine worldwide?

A: The estimated number of cases of the congenital rubella syndrome worldwide is still approximately 100,000 per year. Rubella and the congenital rubella syndrome have been eradicated from the Western hemisphere because of good vaccine coverage. Unfortunately, although rubella has been controlled in many countries in Europe, opposition to vaccination in some countries has prevented the elimination of rubella, and there is much work to be done. In contrast, routine vaccination against rubella has just begun in some Asian countries, including India, Thailand, China, Japan, and Indonesia. Coverage in Africa is spotty, but a few countries have introduced the vaccine. In Nigeria, vaccination is limited to private providers, and coverage is less than 10%. There is a campaign to introduce the combined measles–rubella vaccine throughout the world, and all regions have goals to eradicate both diseases.

CRISPR Identifies Potential Gene Targets to Hobble HIV Infection.


The massive editing project only took months to complete .

HIV-infected H9 T cell. 

Whether or not CRISPR/Cas9 genome editing can create superheroes as depicted on a new Netflix show, what it’s indisputably good at is this: editing a lot of genes really, really fast.

In research published Tuesday in Cell Reports, scientists announced that they had used CRISPR/Cas9 to test gene after gene after gene in human immune system cells—45 genes in all, sometimes simultaneously and sometimes individually—to identify those that have anything to do with infection by theHIV virus, which causes AIDS when it infiltrates those T cells.

For years, scientists have known that mutations in some genes can keep HIV from getting inside T cells (editing genes to create that protective mutation is being tested in a clinical trial). But it never hurts to find more ways to block HIV infection, scientists at the University of California, San Francisco, and its Gladstone Institutes figured.

Enter CRISPR/Cas9, which is so easy to use that even small labs are jumping into the CRISPR pool in a way they couldn’t with the previous generation of genome-editing tools.

When scientists want to edit scores of genes to see which changes protect T cells against HIV, they need to build a separate CRISPR/Cas9 assemblage of multiple molecules each time. Because that’s so easy, the UCSF scientists marched through the genome in human T cells like ants marching across a picnic spread: a project that would take years with the previous generation of genome editing tools instead took months.

Using a clever way that some of the same researchers invented last year to get CRISPR/Cas9 into cells—a jolt of electricity makes cells open their entry gates—they sent one CRISPR complex after another—149 in all—into hundreds of thousands of T cells isolated from the blood of healthy volunteers.

After each edit, the scientists, co-led by UCSF/Gladstone medical geneticist Nevan Krogan and immunologist Dr. Alexander Marson, tested the now-mutated T cells to see if they kept HIV out entirely, kept it from insinuating itself into the T cell’s genes (which is how the virus replicates), or otherwise hobbled infection. They wound up with half a dozen genes (with names like CXCR4, CCR5, LEDGF, and NUP153) whose excision thwarted HIV wholly or partly.

The hope is that using genome editing to change one or more such genes in T cells will prevent or vanquish AIDS. Current therapies keep infections at bay but do not eliminate the virus from a patient’s immune system. Patients must therefore take antiretroviral drugs for the rest of their lives. In its clinical trials of editing the CCR5 gene, Sangamo Biosciences has found that patients’ viral load fell and, in some cases, stayed low even without HIV/AIDS drugs; updated results are expected in 2017, said company spokesperson Elizabeth Wolffe.

Whether editing genes other than CCR5 might help patients is unknown, said Michael Holmes, Sangamo’s vice president of research. The UCSF study did “a good job” of using CRISPR to identify additional potential HIV targets, he said, but “CCR5 and CXCR [another gene] still seem to be the best targets, which is not to say that additional ones might not be useful.”

Editing the genomes of T cells to prevent, let alone cure, HIV/AIDS faces stiff headwinds. Half a dozen papers since 2013 have reported varying degrees of success using CRISPR to block HIV infection in animals or in cells growing in lab dishes, but in some cases HIV overcomes CRISPR’s edits. Multiple genome edits, simultaneously or sequentially, might be necessary.

Whether anyone without first-world medical insurance will be able to afford that remains very much in question. But the UCSF scientists are hopeful that drugs could mimic the genome editing they did, and become at least as affordable as today’s HIV/AIDS drugs.

HIV particles do not cause AIDS, our own immune cells do


Researchers from the Gladstone Institutes have revealed that HIV does not cause AIDS by the virus’s direct effect on the host’s immune cells, but rather through the cells’ lethal influence on one another.

HIV can either be spread through free-floating virus that directly infect the host immune cells or an infected cell can pass the virus to an uninfected cell. The second method, cell to cell transmission, is 100 to 1000 times more efficient, and the new study shows that it is only this method that sets off a cellular chain reaction that ends in the newly infected cells committing suicide.

“The fundamental ‘killing units’ of CD4 T cells in lymphoid tissues are other infected cells, not the free virus,” says co-first author Gilad Doitsh, PhD, a staff research investigator at the Gladstone Institute of Virology and Immunology. “And cell-to-cell transmission of HIV is required for activation of the main HIV death pathway.”

In a previous investigation, the scientists discovered that 95% of cell death from HIV is caused by immune cells committing suicide in self-defense after an unsuccessful infection. When the virus tries to invade a cell that is “at rest,” the infection is aborted. However, fragments of viral DNA remain and are detected by the resting host cell. This triggers a domino effect in the cell’s defense system, resulting in the activation of the enzyme caspase-1, which ultimately causes the induction of pyroptosis, a fiery form of cell suicide.

In the new study, published in Cell Reports, it was revealed that this death pathway is only activated through cell-to-cell transmission of HIV, not from infection by free-floating viral particles. Using lymphoid tissue infected with HIV, the scientists compared cell death rates between cell-to-cell and cell-free virus transfer. They discovered that while overall rates of infection remained the same, there was significantly more CD4 T cell death if HIV was spread by infection from other cells than by free-floating virus.

“Although free-floating viruses establish the initial infection, it is the subsequent cell-to-cell spread of HIV that causes massive CD4 T cell death,” says co-first author Nicole Galloway, PhD, a post-doctoral fellow at the Gladstone Institute of Virology and Immunology. “Cell-to-cell transmission of HIV is absolutely required for activation of the pathogenic HIV cell-death pathway.”

To confirm this finding, the researchers perturbed viral transfer through a number of means: genetically modifying the virus, applying chemical HIV inhibitors, blocking inter-cellular synapses, and increasing the physical distance between the cells so they could not come into contact with one another. Notably, disruption of cell-to-cell contact effectively stopped the death of CD4 T cells. What’s more, only during cell-to-cell transmission was caspase-1 activated within the target cells, thereby initiating pyroptosis, the pro-inflammatory cell-suicide response.

The scientists speculate that the difference in cell death rates between the two methods of infection is due to the increased efficiency of cell-to-cell transmission. Aborted viral DNA fragments are quickly removed during infection by cell-free HIV particles, so they are not detected by the cell’s defensive system. However, in cell-to-cell transmission, the viral DNA fragments overwhelm cell maintenance, building up until they surpass a threshold and are detected. This then triggers caspase-1 activation and pyroptosis.

“This study fundamentally changes our mindset about how HIV causes massive cell death, and puts the spotlight squarely on the infected cells in lymphoid tissues rather than the free virus,” says senior author Warner C. Greene, MD, PhD, director of the Gladstone Institute of Virology and Immunology. “By preventing cell-to-cell transmission, we may able to block the death pathway and stop the progression from HIV infection to AIDS.”

Other investigators on the study include Kathryn Monroe, Zhiyuan Yang, and Isa Muñoz-Arias from the Gladstone Institutes, and David Levy from New York University College of Dentistry. Funding was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases, the UCSF/Robert John Sabo Trust Award, and the Giannini Foundation Postdoctoral Research Fellowship.


Story Source:

The above post is reprinted from materials provided by Gladstone Institutes. Note: Materials may be edited for content and length.


Journal Reference:

  1. Nicole L. Galloway, Gilad Doitsh, Kathryn M. Monroe, Zhiyuan Yang, Isa Muñoz-Arias, David N. Levy, Warner C. Greene. Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue-Derived CD4 T Cells. Cell Reports, 2015 DOI:10.1016/j.celrep.2015.08.011

 

Depo-Provera May Hike HIV Risk in Women


Meta-analysis shows increased risk versus nonhormonal or no contraception.

Increased rates of HIV infection were seen among women using depot medroxyprogesterone acetate (Depo-Provera or DMPA), whereas other methods of contraception including oral contraceptive pills or norethisterone enanthate (Net-En, an injectable progestin steroid) did not, according to a new meta-analysis.

Pooled data from 10 studies conducted in sub-Saharan Africa showed DMPA use was associated with a 40% higher HIV risk (hazard ratio 1.40, 95% CI 1.10-1.57) versus nonhormonal or no contraception, whereas 10 studies examining oral contraceptive pills (pooled HR 1.00, 95% CI 0.86-1.16) and five studies examining norethisterone enanthate (pooled HR 1.10, 95% CI 0.88-1.37) were not associated with increased HIV risk, according to Lauren Ralph, MPH, division of epidemiology of the School of Public Health at the University of California at Berkeley, and colleagues.

After over 2 decades of research, possible links between DMPA and increased incidence of HIV has been a hotly debated issue, the authors explained in The Lancet Infectious Diseases. But despite their findings, they stopped short of calling for a ban on this form of contraception.

Ralph and colleagues wrote that controversy over DMPA has already caused some sub-Saharan African countries to consider withdrawing this form of birth control from family planning programs, which would leave women in these countries with fewer contraceptive options.

“The moderate elevation in risk for DMPA is not enough to justify a complete withdrawal of DMPA from women’s contraceptive options in most settings,” said lead study author Ralph in a press release. “This is likely to lead to more unintended pregnancies and their associated maternal and infant morbidity and mortality.”

For the meta-analysis, the authors reviewed 26 studies, searching PubMed for the terms “hormonal contraception,” “HIV/acquisition,” injectables,” “progestin” and “oral contraceptive pills.” The review included articles published in English after Dec. 1, 2011, as well as relevant abstracts from International AIDS Society meetings and the Conference on Retroviruses and Opportunistic Infections from 2011 to 2014.

Of these, 12 studies were designed to examine the link between hormonal contraception and HIV. The remaining studies sampled women from the general population at health centers and family planning clinics. The median age of participants in the studies ranged from 25 to 40 years.

The link between DMPA and HIV risk was also seen in these general population studies (pooled HR 1.31, 95% CI 1.10-1.57). But because the 10 studies from the primary analysis were associated with a greater level of heterogeneity (I2=42.5%, CI 0%-72%) than the general population studies (I2=27.3%, CI 0%-67%), most results of the primary studies were considered not applicable to the general population.

Two of 12 studies in the primary analysis examined high-risk populations, such asserodiscordant partners and commercial sex workers. Those two high-risk groups were associated with the greatest increases in HIV risk (HR 3.93, 1.37-11.2, and HR 1.73, 1.10-1.57, respectively). However, the high heterogeneity (I2=54.0%, CI 0%-88.7%) between these two studies meant their data couldn’t be pooled, the authors wrote.

Ralph told MedPage Today that there were only “a limited number” of studies that met the criteria for analyzing populations of high-risk women. “Thus, there remains uncertainty for this important subgroup of women,” she said.

While some of these findings may not be statistically significant, they may have clinical significance, including in developed countries. Diane Harper, MD, MPH, MS , professor, department chair for family and geriatric medicine at the University of Louisville School of Medicine in Kentucky, who was not involved with the analysis, suggested that it could help primary care and ob/gyn physicians who treat high-risk patients in the U.S., including serodiscordant couples, commercial sex workers, and drug addicts.

“I think there are valid populations in the U.S. for which we do need to pay attention and I think that the study very clearly says to me that there are so many other options of birth control that do not have this increased risk of HIV,” said Harper. “In these populations we should not be using Depo-Provera, that it just really is not a wise clinical choice.”

 One limitation the authors addressed was that the primary analysis was mainly on observational studies as opposed to a randomized, controlled trial.

In an accompanying editorial, Christopher J. Colvin and Abigail Harrison, division of social and behavioral sciences of the School of Public Health and Family Medicine at the University of Cape Town in South Africa, called the environment surrounding any proposed trial about DMPA and HIV “polarizing” and arguments on both sides “rhetorical” and “generic.”

Colvin and Harrison wrote that studies such as this “synthesize and evaluate the existing observational data and identify many ways in which further modeling, epidemiological studies, behavioral and clinical research, and basic biological silence could work synergistically to increase our knowledge.”

Harper saw this limitation as one of the strengths of the study.

“What makes the paper so strong is that it has been able [to get these results] without increasing costs and doing another trial and putting more women at risk for HIV and repeating this in another population,” she said.

Another limitation cited by the authors was potential “confounding effects of misreported condom use,” especially since “many study populations were drawn from HIV prevention trials in which condom use is strongly encouraged and women may feel pressure to report socially acceptable behaviors,” they wrote. But they added that over-reporting of condom use was likely the same in all groups studied, including the reference samples.

THE BERLIN PATIENT, FIRST AND ONLY PERSON ‘CURED’ OF HIV, SPEAKS OUT


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Timothy Ray Brown, long known only as the “Berlin Patient” had HIV for 12 years before he became the first person in the world to be cured of the infection following a stem cell transplant in 2007. He recalls his many years of illness, a series of difficult decisions, and his long road to recovery in the first-person account, “I Am the Berlin Patient: A Personal Reflection,” published in AIDS Research and Human Retroviruses, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is part of a special issue on HIV Cure Research and is available free on the AIDS Research and Human Retroviruses website.

Brown’s Commentary describes the bold experiment of using a stem cell donor who was naturally resistant to HIV infection to treat the acute myeloid leukemia (AML) diagnosed 10 years after he became HIV-positive. The stem cell donor had a specific genetic mutation called CCR5 Delta 32 that can protect a person against HIV infection. The virus is not able to enter its target, the CD4 cells. After the stem cell transplant, Brown was able to stop all antiretroviral treatment and the HIV has not returned.

“This is the first time that we get to read this important story written by the man who lived it,” says Thomas Hope, PhD, Editor-in-Chief of AIDS Research and Human Retroviruses and Professor of Cell and Molecular Biology at Northwestern University, Feinberg School of Medicine, Chicago, IL. “It is a unique opportunity to share in the human side of this transformative experience.”

The Challenge Of Creating An HIV Vaccine: Virus Infects Very Cells Induced By Drug


The reason there’s no vaccine for HIV/AIDS, the National Institutes of Health explains, is because HIV has “unique ways of evading the immune system, and the human body seems incapable of mounting an effective immune response against it.” A recently published animal study further clarifies the problem by showing how vaccines designed to protect against HIV backfire, leading to an increase, not decrease, in new infections. Specifically, it is the higher number of activated CD4+ T cells which may be a possible cause for spiking rates of new infection among those already vaccinated.

HIV infected T cell

“The virus infects the very cells of the immune system that any vaccine is supposed to [activate],” Dr. Guido Silvestri, senior author and chief of microbiology and immunology at Yerkes National Primate Research Center, stated in a press release. The vaccines meant to prevent disease seem to make the target larger and therefore easier to hit.

Killer Cells and Their Helpers

T cells are a type of white blood cells that send signals to activate the body’s immune response whenever they detect an intruder, such as bacteria or viruses. T cells always work in pairs, and so scientists place them in two large categories based on their function (and the molecules found on their surfaces). CD4+ T cells, referred to as helper T cells, lead the fight by identifying an infection, while CD8+ T cells go in for the kill. It’s an effective partnership, the basis of the immune system.

However, this essential system breaks down in the presence of auto-immune diseases like AIDS. When a person becomes infected with HIV, the virus attacks CD4+ T cells and then uses the stolen parts of their machinery to multiply itself and spread throughout the body. When trying to develop a vaccine for AIDS, many scientists have decided to use CD4 + T cells as a potential target because of this key role in both HIV and SIV (simian immunodeficiency virus) infection.

For Silvestri’s research project, he and his co-authors evaluated five different strategies for immunizing 36 rhesus macaques against SIV. After being given an initial shot of one of the five different vaccines, each of the monkeys received booster shots at 16 weeks and then again at 32 weeks. Next, the monkeys were exposed to a low-dose of SIV. In general, the researchers found none of the vaccines prevented an SIV infection. Oddly, all the immunized monkeys had detectable levels of circulating “killer” T cells — the CD8+ T cells — but these cells did not prevent infection. That said, at the beginning of their infections, the vaccinated animals showed a lower than expected initial viral load or level of SIV in their blood. What was the researchers’ most important finding? The monkeys had higher levels of activated CD4+T cells in their rectal mucosal tissues before becoming infected.

“The possibility that certain immunization regimens designed to protect against HIV infection and AIDS result in increased risk of virus transmission is not just a theoretical concern, because three recent large-scale clinical trials … have shown a trend toward higher infection rates in vaccinated individuals than in placebo recipients,” noted the authors in their conclusion.

Source: Carnathan DG, Wetzel KS, Yu J, et al. Activated CD4+CCR5+ T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques. PNAS. 2014.

World Health Organisation recommends that all gay men should take antiretroviral medicine to halt HIV epidemic.


The World Health Organisation has announced for the first time that all men who have sex with men should take antiretroviral drugs, in a bid to try and contain the growing rates of HIV in gay communities around the world.

Studies show that antiretroviral drug use can reduce the chance of passing on HIV by up to 92 per cent

The report says that in addition to other forms of protection like condoms and regular testing, increased use of antiretroviral drugs in the gay community could have a significant impact in stopping the spread of HIV and could prevent a million new infections in the next ten years, according to the WHO.

In the report, it says that homosexual men are 19 times more likely to have HIV than the rest of the population, and it is believed that encouraging gay men to take the antiretroviral medicine could decrease this significantly.

According to the report, HIV rates in gay communities are still on the rise

According to the report, HIV rates in gay communities are still on the riseSome scientists predict that the antiretroviral drug use for all gay men could lower the spread of HIV by 20 to 25 per cent.

Speaking after the release of the report, Gottfried Hirnschall, who heads WHO’s HIV department, said that they were seeing an “exploding epidemic” when it came to HIV rates in the gay community around the world.

He said this was largely down to a more relaxed attitude to HIV, which were the result of new drugs that made it possible to live with the disease.

He said that antiretroviral drugs could help stop this growth and supported the WHO’s recommendations.

A number of studies looking into the impact antiretroviral drugs have on preventing the transmission of HIV have shown that those who regularly take the drug have a significantly smaller chance of contracting or passing on the virus.

The Pre-Exposure Prophylaxis as HIV Prevention Among Men who Have Sex with Men (Iprex) study published in 2010, the most in-depth study into this area,  found that the use of antiretroviral drugs could reduce the risk of infection in men who have sex with men by up to 92 per cent.

As well as looking at how to best prevent the spread of HIV in the gay community, the report also focussed on other high-risk groups including transgender women, sex workers and people that inject drugs.

According to the study, transgender women and those that inject drugs are 50 times more likely to catch HIV, while sex workers are 14 times more likely to get the disease when compared with the rest of the population.

The report recommended that national agencies that deal with preventing the spread of HIV should spend more time focusing on these groups as they account for just under half of all new HIV infections worldwide.

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