To explain cancer biology, use metaphors

An expert on doctor-patient communication says: let the explanatory metaphors Read more

Enhanced verbal abilities in the congenitally blind

Congenitally blind study participants displayed superior verbal, but not spatial abilities. Possibly reflects their greater reliance on verbal information, and the recruitment of the visual cortex for verbal Read more

Three remarkable Emory case reports from #ACC17

Three remarkable case reports being presented at the American College of Cardiology meeting, including cardiac electrical storm, reverse Takotsubo and congenital heart Read more

AIDS

Clues to how anti-integrin antibody suppresses SIV

In October 2016, Emory and NIAID researchers published results in Science that surprised the HIV/AIDS field.

They showed that treatment with an antibody, on top of antiretroviral drugs, could lead to long-term viral suppression in SIV-infected monkeys. A similar antibody is already approved for Crohn’s disease, and a clinical trial has begun at NIAID testing the effects in people living with HIV.

The HIV/AIDS field is still puzzling over a study led by Emory pathologist Tab Ansari.

All that was achieved even though HIV/AIDS experts are still puzzled by how the antibody works. Last week, Christina Guzzo,with NIAID director Anthony Fauci’s lab, presented new data at the Conference on Retroviruses and Opportunistic Infections in Seattle that provide some clues. But the broader issue of “what is the antibody doing?” is still open.

Let’s back up a bit. The antibody used in the Science paper targets a molecule called integrin alpha 4 beta 7, usually described as a “gut homing receptor” for CD4+ T cells, which are ravaged by HIV and SIV infection.  Study leader Aftab Ansari (right) and Fauci have both said their idea was to stop T cells from circulating into the gut, a major site of damage during acute viral infection.

Integrin alpha 4 beta 7 was also known to interact with the HIV envelope protein. Accordingly, it is possible to imagine some possibilities for what an antibody against integrin alpha 4 beta 7 could be doing: it could be driving T cells to different places in the body or affecting the T cells somehow, or it could be interfering with interactions between SIV and the cells it infects.

The new data from NIAID say that integrin alpha 4 beta 7 is found on the virus itself. This finding makes sense, because SIV and HIV are enveloped viruses — they steal the clothes of the cells they infect and emerge from. [Integrin alpha 4 beta 7 also appears to help the virus be more infectious in the gut, Guzzo’s presentation says.]

So a third possibility appears: the anti-alpha 4 beta 7 antibody is mopping up virus. Perhaps it’s acting like a virus-neutralizing antibody or the anti-CD4 antibody ibalizumab — CD4 is the main viral receptor on T cells. It could explain why the anti-integrin antibody’s effect is so durable; HIV/SIV can mutate to escape neutralizing antibodies directed against the viral envelope protein, but it can’t mutate the clothes it steals! Read more

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Background links on SIV remission Science paper

This was the first consistent demonstration of post-treatment immune control in monkeys infected with SIV, without previous vaccination. Long-term post-treatment control of HIV has been reported in only a handful of people treated soon after infection. To learn more, check out these links.

Transient SIVmac remission induced by TLR7 agonist, reported at 2016 CROI conference

Immune control of SIVagm, no antiretroviral drugs necessary. Model of “elite controllers.”

Immune clearance of SIVmac; prior CMV-based vaccination necessary.

Post-treatment control of HIV – VISCONTI study. Roundup of HIV remission cases, from Treatment Action Group. Read more

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The cure word, as applied to HIV

HIV researchers are becoming increasingly bold about using the “cure” word in reference to HIV/AIDS, even though nobody has been cured besides the “Berlin patient,” Timothy Brown, who had a fortuitous combination of hematopoetic stem cell transplant from a genetically HIV-resistant donor. Sometimes researchers use the term “functional cure,” meaning under control without drugs, to be distinct from “sterilizing cure” or “eradication,” meaning the virus is gone from the body. A substantial obstacle is that HIV integrates into the DNA of some white blood cells.

HIV cure research is part of the $35.6 million, five-year grant recently awarded by the National Institutes of Health to Yerkes/Emory Vaccine Center/Emory Center for AIDS Research. Using the “shock and kill” approach during antiviral drug therapy, researchers will force HIV (or its stand-in in non-human primate research, SIV) to come out of hiding from its reservoirs in the body. The team plans to test novel “latency reversing agents” and then combine the best one with immunotherapeutic drugs, such as PD-1 blockers, and therapeutic vaccines.

The NIH also recently announced a cluster of six HIV cure-oriented grants, named for activist Martin Delaney, to teams led from George Washington University, University of California, San Francisco, Fred Hutchinson Cancer Research Center, Wistar Institute, Philadelphia, Beth Israel Deaconess Medical Center and University of North Carolina. Skimming through the other teams’ research plans, it’s interesting to see the varying degrees of emphasis on “shock and kill”/HIV latency, enhancing the immune response, hematopoetic stem cell transplant/adoptive transfer and gene editing weaponry vs HIV itself.

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Everything in moderation, especially TH17 cells

I was struck by one part of Mirko Paiardini’s paper that was published this week in Journal of Clinical Investigation. It describes a treatment aimed at repairing immune function in SIV-infected monkeys, with an eye toward helping people with HIV one day. One of the goals of their IL-21 treatment is to restore intestinal Th17 cells, which are depleted by viral infection. In this context, IL-21’s effect is anti-inflammatory.

However, Th17 cells are also involved in autoimmune disease. A recent Cell Metabolism paper from endocrinologist Roberto Pacifici and colleagues examines Th17 cells, with the goal of treating bone loss coming from an overactive parathyroid. In that situation, too many Th17 cells are bad and they need to be beaten back. Fortunately, both an inexpensive blood pressure medication and a drug under development for psoriasis seem to do just that.

Note for microbiome fans: connections between Th17 cells and intestinal microbes (segmented filamentous bacteria) are strengthening. It gets complicated because gut microbiota, together with Th17 cells, may influence metabolic disease and Th17-like cells are also in the skin — location matters.

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HIV vaccine news: a glass half full

This week, researchers from Yerkes and Emory Vaccine Center led by Cindy Derdeyn published a paper that I first thought was disturbing. It describes how monkeys vaccinated against HIV’s relative SIV (simian immunodeficiency virus) still become infected when challenged with the virus. Moreover, it’s not clear whether the vaccine-induced antibodies are exerting any selective pressure on the virus that gets through.

But then I realized that this might be an example of “burying the lead,” since we haven’t made a big hoopla about the underlying vaccine studies, conducted by Rama Amara. Some of these studies showed that a majority of monkeys can be protected from repeated viral challenge. The more effective vaccine regimens include adjuvants such as the immune-stimulating molecules GM-CSF or CD40L (links are the papers on the protective effects). Read more

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Bits from HIV + Aging conference

What conferences like the HIV + Aging meeting recently held by Emory in Decatur offer the visiting writer: anecdotes that illustrate issues of clinical care.

To illustrate her point that assumptions about who is likely to develop a new HIV infection may lead doctors to miss possible diagnoses, keynote speaker Amy Justice from Yale described a patient who was seen last year at Yale-New Haven Hospital.

A 60 year old man reported fatigue and had lost 40 pounds over the course of a year. Despite those symptoms, and the discovery of fungal and viral infections commonly linked to HIV/AIDS, it took nine months before a HIV test was performed on the patient, a delay Justice deplored.

Sex and substance abuse do not end at age 50, she said, citing data showing that the risk of HIV transmission can be greater among older adults, and that substance abuse is more likely among adults who are HIV positive compared to those who are HIV negative.

Justice also highlighted the issue of polypharmacy (interactions between prescription drugs at the same time), a concern even in people who are not living with HIV. Common blood pressure medications taken by older adults to prevent heart disease have been suspected of increasing the risk for falls. That’s a problem especially for people living with HIV, because HIV infection has been linked to weakened bone. Read more

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From Berlin to Yerkes

Yerkes immunologist Guido Silvestri and colleagues have a paper in PLOS Pathogens shedding light on the still singular example of Timothy Brown, aka “the Berlin patient”, the only human cured of HIV. Hat tip to Jon Cohen of Science, who has a great explanatory article.

Recall that Brown had lived with HIV for several years, controlling it with antiretroviral drugs, before developing acute myeloid leukemia. In Berlin, as treatment for the leukemia, he received a bone marrow transplant — and not just from any donor; the donor had a HIV-resistance mutation. What was the critical ingredient that enabled HIV to be purged from his body?

Conditioning: the chemotherapy/radiation treatment that eliminates the recipient’s immune system before transplant? HIV-resistant donor cells? Or graft-vs-host disease: the new immune system attacking the old?

Silvestri and colleagues performed experiments with SHIV-infected non-human primates that duplicate most, but not all, of the elements of Brown’s odyssey. The results demonstrate that conditioning, by itself, does not eliminate the virus from the body. But in one animal, it came close. Frustratingly, that animal’s kidneys failed and researchers had to euthanize it. In two others, the virus came back after transplant.

A critical difference from Brown’s experience is that monkeys received their own virus-free blood-forming stem cells instead of virus-resistant cells. Cohen reports that Silvestri hopes to do future monkey experiments that test more of these variables, including transplanting the animals with viral-resistant blood cells that mimic the ones that Brown received. 

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Contraception and HIV risk

Does hormonal contraception increase the risk for a woman to acquire HIV from an infected partner?

This topic, with implications for public health in countries where HIV risk is high, has been contentious. Some previous studies had found the answer to be yes, for methods involving injectable progesterone such as Depo-Provera. This led the World Health Organization in 2012 to advise women using progesterone-only injections to use condoms to prevent HIV infection.

At the recent AIDS 2014 meeting in Australia, Emory epidemiologist Kristin Wall presented data from public health programs in Zambia. This is another study emerging from the Zambia-Emory HIV Research Project directed by Susan Allen.

Wall’s presentation is available here.

Studying 1393 heterosexual couples with a HIV-positive male partner over 17 years, Wall and her colleagues found no significant difference in incidence rate per 100 couple years between hormonal and non-hormonal forms of contraception. Read more

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Fighting HIV, biomedical and behavioral hand in hand

In the HIV/AIDS arena, the idea of “treatment as prevention” has been gaining strength. Multiple studies have shown that treatment with anti-retroviral drugs can dramatically reduce the likelihood that someone infected with HIV will be able to pass the virus to someone else.

However, a recent strategy document for HIV/AIDS prevention developed by a International Antiviral Society–USA panel, co-led by Rollins Global Health chair Carlos Del Rio, puts biomedical interventions hand in hand with psychosocial measures such as couples counseling and treatment for drug dependence.

Why? Because people everywhere can have trouble sticking to antiretroviral treatment, even if drugs are available. And couples counseling by itself is valuable.

A powerful example of how this plays out, and of the importance of couples counseling to the effectiveness of antiretroviral drugs in prevention, comes from a recent presentation from Emory epidemiologist Kristin Wall at the AIDS 2014 meeting in Australia. The website NAM Aidsmap had a helpful write-up of her presentation, which is available here. Thanks to co-author Susan Allen for alerting us to this.

CVCT (couples voluntary counseling and treatment) greatly enhanced the preventive effect of antiretroviral treatment, when compared to treatment without counselling, Wall’s analysis of a large cohort of couples in Zambia showed. 

Update: Allen points out that couples counseling by itself was effective in helping people avoid HIV, with a 75 percent reduction in incidence for couples where the HIV+ partner was not receiving antiviral therapy or with HIV negative couples.  Read more

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HIV discordant couples

On Thursday, NPR had a nicely done story on discordant couples (one partner is HIV positive, the other is HIV negative) in Kenya.

It provided a reminder of Susan Allen’s work in Rwanda and Zambia with discordant couples. It also very simply laid out the policy issues connected with treating discordant couples:

Medical workers are extremely interested in discordant couples for two reasons. One is that almost half of new infections in Kenya happen in these relationships. It’s one place where HIV is spreading. The second reason is that when couples are open with each other about their HIV status, managing HIV is more successful…

The World Health Organization now recommends that any HIV-positive individual in a discordant relationship be supplied HIV treatment. But discordant couples are still being treated on an ad hoc basis in Kenya, primarily because the funding for the medication just isn’t there.

Allen’s research provided critical data about HIV transmission and prevention methods, and led to the adoption of the WHO guidelines mentioned in the story. She has said that the WHO guidelines were designed to help partners in a stable relationship work together to prevent the uninfected person from getting the virus and that low-tech, inexpensive prevention methods like condoms are just as important as antiretroviral therapy in this effort.

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