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HIV study in Kenyan women: Diversity in a single immune-cell type flags likelihood of getting infected

HIV study in Kenyan women: Diversity in a single immune-cell type flags likelihood of getting infected

virally infected cellsWhen it comes to immune cells, “it takes all kinds” isn’t too bad a description of what makes for the best composition of our fighting force for warding off viruses, bacteria and incipient tumors. But in a study just published in Science Translational Medicine, Stanford infectious-disease immunologist Catherine Blish, MD, PhD, and her colleagues have found, unexpectedly, that high diversity in the overall population of one particular type of immune cells strongly correlates with an increased likelihood of subsequent infection by HIV.

The investigators had figured that diversity in so-called natural killer cells, or NK cells, would be a strength, not a detriment. “Our hypothesis was wrong,” Blish (much of whose research focuses on NK cells) told me. In this study,  it was higher, rather than lower, diversity in this immune-cell population that turned out to be associated with increased HIV susceptibility.

NK cells, fierce white blood cells that help fight viruses and tumors, harbor various combinations of receptors on their surface. Some receptors recognize signs of our other cells’ normalcy, while others recognize signs that a cell is stressed — due, say, to viral infection or cancerous mutation. On recognizing their targeted features on other cells’ surfaces, an NK cell’s “normalcy” receptors tend to inhibit it, while its stress-recognizing receptors activate it.

All told, NK cells can have many thousands of different combinations of these receptors on their surfaces, with each combination yielding a slightly different overall activation threshold. At birth, our NK cells are pretty similar to one another. But as they acquire life experience – largely from viral exposure, Blish thinks – they increasingly diverge in the specific combinations of receptors they carry on their surfaces.

From my news release on the study:

In order to assess the impact of NK-cell diversity on adult humans’ viral susceptibility, Blish and her associates turned to blood samples that had been drawn during the Mama Salama Study, a longitudinal study of just over 1,300 healthy … Kenyan women. [T]he researchers carried out a precise analysis of NK cells in the women’s blood and observed a strong positive correlation between the diversity of a woman’s NK cell population and her likelihood of becoming infected with HIV.

This correlation held up despite the women’s being statistically indistinguishable with respect to age, marital status, knowledge of sexual partners’ HIV status, history of trading sex for money or goods, sexually transmitted disease status or reported frequency of recent unprotected sex.

And the NK-diversity-dependent difference in these women’s likelihood of HIV infection was huge. From my release:

Those with the most NK-cell diversity were 10 times as likely as those with the least diversity to become infected. A 10-fold risk increase based solely on NK-cell diversity is far from negligible, said Blish. “By way of comparison, having syphilis increases the risk of contracting HIV two- to four-fold, while circumcised men’s HIV risk is reduced by a factor of 2.5 or 3,” she said.

These surprising findings  could spur the development of blood tests capable of predicting individuals’ susceptibility to viral infection.

Previously: Study: Pregnancy causes surprising changes in how the immune system responds to the flu, Revealed: Epic evolutionary struggle between reproduction and immunity to infectious disease and Our aging immune systems are still in business, but increasingly thrown out of balance
Photo by NIAID

Global Health, HIV/AIDS, Medical Education, Medical Schools, Stanford News

Stanford med student chronicles his experience working in rural Kenya

Stanford med student chronicles his experience working in rural Kenya

Hodgkinson and others in Kenya

Growing up in Kakamega, a rural county in western Kenya, medical technologies and services were extremely limited for Luqman Hodgkinson, PhD. Now a first-year Stanford medical student, Hodgkinson is spending the summer months back in his hometown conducting research and chronicling exciting new developments in medical education – the opening of the first medical school in the region.

With a population of nearly two million, Kakamega is the second largest county in Kenya behind only Nairobi. But with only 12 physician specialists, the vast majority of residents don’t have access to advanced care.

Earlier this year, Masinde Muliro University of Science and Technology (MMUST), a leading public university in Kenya, received authorization to become the very first medical school in Kakamega; it’s expected to enroll its first class of students this fall.

Hodgkinson has received a faculty position as an adjunct associate researcher at the new MMUST School of Medicine and will serve as the designated ambassador from MMUST to Stanford.

As Hodgkinson writes in his first blog entry en route to Kakamega, “Relationships are very important in medicine and this is also true for a medical school that is at the beginning of a bright future.”

His first research project in Kakamega focuses on the efficacy of community outreach programs designed to improve adherence to antiretroviral medications among adults with HIV/AIDS. Under the mentorship of Michele Barry, MD, FACP, senior associate dean for global health at Stanford, Hodgkinson is working with Emusanda Health Centre to evaluate the efficacy of these programs and demographic factors that may impact medication adherence.

He writes in his blog: “Medical research of all kinds is greatly needed in Kakamega to advance the health of the community, particularly in the area of HIV. In Kakamega County, the HIV prevalence is 5.6 percent. Addressing the local HIV pandemic is what inspired me many years ago to pursue medicine and now for the first time I am on my way to join this endeavor.”

Hodgkinson will be blogging from Kakamega throughout the summer, sharing updates from his research activities and collaborative opportunities for members of the Stanford community to get involved with the new MMUST School of Medicine. Follow along on the Center for Innovation in Global Health website.

Rachel Leslie is the communications officer at Stanford’s Center for Innovation in Global Health.

Photo – of (left to right) clinician Jorcelyne Makori, peer educator James Okwiri and Hodgkinson – courtesy of Hodgkinson

Global Health, HIV/AIDS, Infectious Disease, Public Health, Research, Rural Health

Drought causes spike in HIV infections in Africa

Drought causes spike in HIV infections in Africa

75148497_50e081cd5b_zHere in California, the drought is plenty serious. Shortages mean short showers, brown lawns, empty reservoirs and fallow fields.

But in sub-Saharan Africa, drought spreads disease, including the still-rampant HIV virus. The phenomenon is more sociological than ecological: Slim harvests slash farmers’ incomes, forcing them to find new ways to earn money. Some turn to sex, according to a new study in The Economic Journal.

As described in a recent article from Stanford’s Center on Food Security and the Environment (FSE):

Analyzing data on more than 200,000 individuals across 19 African countries, the research team finds that by changing sexual behavior, a year of very low rainfall can increase local infection rates by more than 10 percent.

That means condoms and sex education aren’t all that’s needed to thwart the epidemic’s spread, the study’s authors say. Affected farmers also need economic support and alternatives to help them weather the dry period, without sacrificing their health.

“These are the people who really suffer when the rains fail, and who are forced to turn to more desperate measures to make ends meet,” co-author Marshall Burke, PhD, a fellow at the FSE, said in the piece.

Previously: Spread of drug-resistant HIV in Africa and Asia is limited, Stanford research finds, Stanford study: South Africa could save millions of lives through HIV prevention and Changing the prevailing attitude about AIDS, gender and reproductive health in southern Africa 
Photo by Jon Rawlinson

Genetics, HIV/AIDS, Infectious Disease, Research, Stanford News

Study shows toothed whales have persisted millions of years without two common antiviral proteins

Study shows toothed whales have persisted millions of years without two common antiviral proteins

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Our ability to fend off the flu, HIV and other viruses is enhanced when proteins are produced by two “immune genes,” called MX1 and MX2. Other mammals also have these genes, but little is known about the role they play in the immune responses of these animals.

Now a study comparing the genomes and Mx genes of 60 mammal species has revealed a surprising finding: Every species in the study has functioning Mx1 and Mx2 genes except for dolphins, whales and orcas — species from a lineage of toothed whales that’s persisted for roughly 33 million years.

Gill Bejerano, PhD, a geneticist and developmental biologist, graduate student Benjamin Braun and their team wanted to know more about the status and function of Mx genes in non-human mammals. To do this, they examined and compared the part of the genome that contains the Mx genes in 60 different species including humans, cows, whales, dolphins and orcas.

I think this will open up very exciting research avenues, either to better protect the compromised whales, or to study their different viral defenses, and someday add them to our own arsenal.

The study, published this week in the Proceedings of National Sciences, showed that the Mx1 and Mx2 genes in the toothed whales (bottlenose dolphin, orca, Yangtze river dolphin and sperm whale) they tested were non-functional, and couldn’t produce the proteins that help fight viral infections. Bejerano explained the significance of this finding in our press release:

Given how important the Mx genes seem to be in fighting off disease in humans and other mammals, it’s striking to see a species lose them both and go about its business for millions of years.

To find out when in evolutionary history these genes became inactive the researchers compared the genomes of toothed whales to that of their closest ancestors, the baleen whales and hoofed mammals (ungulates). They found that the Mx genes function in baleen whales and hoofed mammals, but not in toothed whales. This means that some — perhaps all — toothed whales likely lost use of their Mx genes when this lineage split off from these ancestors about 33 million years ago (see Fig. 1).

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Evolution, Genetics, HIV/AIDS, Immunology, Infectious Disease, Research, Stanford News

Study: Chimps teach people a thing or two about HIV resistance

Study: Chimps teach people a thing or two about HIV resistance

I, personally, have never had trouble distinguishing a human being from a chimp. I look, and I know.

But I’m not a molecular biologist. Today’s sophisticated DNA-sequencing technologies show that the genetic materials of the two species, which diverged only 5 million or so years ago (an eye-blink in evolutionary time), are about 98 percent identical. Think about that next time you eat a banana.

One major exception to that parallelism: a set of three genes collectively called the major histocompatibility complex, or MHC. These genes code for proteins that sit on the surfaces of each cell in your body, where they serve as jewel cases that display bits of proteins that were once inside that cell but have since been chopped into pieces by molecular garbage disposals, transported to the cell surface and encased in one or another of the MHC proteins. That makes the protein bits highly visible to roving immune cells patrolling our tissues to see if any of the cells within are harboring any funny-looking proteins. If those roving sentry cells spot a foreign-looking protein bit, they flag the cell on whose surface it’s displayed as possibly having been infected by a virus or begun to become cancerous.

Viruses replicate frequently and furiously, so they evolve super-rapidly. If they can evade immune detection, that’s groovy from their perspective. So our MHC has to evolve rapidly, too, and as a result, different species’ MHC genes  diverge relatively quickly.  To the extent they don’t, there’s probably a good reason.

Stanford immunologist and evolutionary theorist Peter Parham, PhD, pays a lot of attention to the MHC genes. In a new study in PLOS Biology, he and his colleagues have made a discovery that may prove relevant to AIDS research, by analyzing genetic material found in chimp feces. Not zoo chimps. Wild Tanzanian chimps. As I noted in a news release about the study:

The wild chimps inhabit Gombe Stream National Park, a 13.5-square-mile preserve where they have been continuously observed from afar since famed primatologist Jane Goodall, PhD, began monitoring them more than 50 years ago.

One thing that sets the Gombe chimps apart from captive chimps, unfortunately, is a high rate of infection by the simian equivalent of HIV, the virus responsible for AIDS.

The study’s lead author, postdoc Emily Wroblewski, PhD, set up shop in a corner of Parham’s lab and extracted DNA from fecal samples legally obtained by other researchers (close contact with the animals is prohibited). Each sample could be tied to a particular Gombe-resident chimp. RNA extracted from the same sample indicated that chimp’s infection status.

Parham, Wroblewski and their colleagues found that one particular MHC gene came in 11 different varieties – astounding diversity for such a small collection of chimps (fewer than 125 of them in the entire Gombe). Surprisingly, one small part of one of those 11 gene variants was nearly identical to a piece of a protective version of its human counterpart gene, a version that seems to protect HIV- infected people slowing HIV progression to full-blown AIDS.

Why is that important? Because any piece of an MHC gene that has maintained its sequence in the face of 5 million years of intense evolutionary pressure must be worth something.

Sure enough, fecal samples from chimps with that MHC gene variant, so strikingly analogous to the protective human variant, had lower counts of virus that those from infected chimps carrying other versions of the gene.

You can believe that scientists will be closely examining the DNA sequence contained in both the human and chimp gene variant, as well as the part of the MHC protein that DNA sequence codes for. Because it must be doing something right.

Previously: Revealed: Epic evolutionary struggle between reproduction and immunity to infectious disease, Our species’ twisted family tree and Humans share history – and a fair amount of genetic material – with Neanderthals
Photo by Emily Wroblewski

Global Health, HIV/AIDS, Infectious Disease, Stanford News

Spread of drug-resistant HIV in Africa and Asia is limited, Stanford research finds

Spread of drug-resistant HIV in Africa and Asia is limited, Stanford research finds

In the last decade, millions more people in the developing world have gained access to anti-viral drugs to treat HIV, with nearly 12 million now on this life-giving treatment. But with more people on medication, there’s concern about the spread of drug-resistant strains of the virus, which can be transmitted from one individual to the next.

A new, multi-center study led by Stanford researchers offers some good news on this front: The transmission of drug-resistant strains thus far has been fairly limited in the hard-hit regions of Africa and Asia. The research involved more than 50,000 patients in 111 countries.

It is inevitable that transmitted drug resistance will increase further, so we need to continue ongoing monitoring to ensure successful, long-term treatment outcomes

“What we are showing is that the rates of transmitted drug-resistant HIV in the low- and middle-income countries most affected by HIV have increased modestly,” Stanford infectious disease expert Robert Shafer, MD, principal investigator on the study, told me. “The rate of increase in sub-Saharan Africa has been low, and an increase has not been detected in south Asia and Southeast Asia.”

Shafer is nonetheless cautious, as drug resistance remains a problem in these regions, where patients are prescribed drug regimens that are not as effective as those used in the West. And adhering to a daily regimen can be challenging for these patients, as transportation, drug supply and other issues may get in the way. Resistance can occur when there is a gap in treatment.

“It is inevitable that transmitted drug resistance will increase further, so we need to continue ongoing monitoring to ensure successful, long-term treatment outcomes for the millions of people on therapy worldwide,” Shafer said.

In the study, he and his colleagues identified four mutations that were linked to resistance to two HIV drugs, nevirapine and efavirenz. That result points to the possibility of creating a simple test that could be used to detect these mutations, he said. Clinicians then could tailor their treatment accordingly.

Another key finding was that the drug-resistant strains that did occur were not from a single line of resistant viruses, but were quite distinct. That means they developed independently, not as a result of a single transmission chain. That differs from some other microbes, such as malaria and tuberculosis, where resistant strains can move very quickly through the population.

“We are finding that the strains being detected in low-income countries are pretty much unrelated to one another,” Shafer said. “So that suggests these have not yet gained a foothold in the population and are less often being transmitted among people who have never received the drugs before.”

The study appears online today in PLoS Medicine.

Events, Global Health, HIV/AIDS, LGBT, Medicine and Society

Changing the prevailing attitude about AIDS, gender and reproductive health in southern Africa

Changing the prevailing attitude about AIDS, gender and reproductive health in southern Africa

5015384107_517a74d0b5_zDuring the 1990s and early 2000s, HIV/AIDS pummeled through southern Africa killing thousands. Although the epidemic has abated somewhat, the disease is still spreading through certain communities, including the lesbian, gay, bisexual, transgender and intersex (LGBTI) population.

In Zimbabwe, where homosexuality is illegal and President Robert Mugabe has actively spoken out against the LGBTI community, health-care provider Caroline Maposphere works behind the scenes, trying to change the prevailing attitudes and laws without sparking a homophobic backlash like that in Uganda. Maposphere, who serves as a nurse, midwife, chaplain and gender advocate, will visit the Stanford campus this evening to discuss her efforts.

“She tells great stories about how you deal with the kind of social and community issues that lie around HIV prevention and gay and lesbian health issues in a very homophobic and resource-poor environment,” said David Katzenstein, MD, a Stanford infectious disease specialist who met Maposphere in 1992 while working on the Zimbabwe AIDS Prevention Project.

Preventing the spread of HIV in Zimbabwe isn’t as simple as handing out condoms or launching an education campaign, although those are key strategies, said Maposphere. The nation is poor, has few health-care facilities of any kind and LGBTI rights are non-existent. The traditional southern Africa culture view of homosexually, which was sometimes attributed to witchcraft, further complicates the issue.

“It’s very difficult to reach out with services to groups that are not coming out in the open,” Maposphere said. “We try to reach out and remove some of the barriers through discussion rather than being outright confrontational.”

Maposphere often encounters LGBTI individuals who feel they have been shunned by God and have been excluded from their churches in the predominantly Christian nation. In an effort to offer spiritual guidance as well as health care, she earned a college degree in theology and hopes to explore the religious aspects of her work while at Stanford.

In addition, Maposphere is planning to connect with gay-rights activists here and learn effective methods for countering homophobia in her native country. “I’m very hopeful that things will change,” she said.

The free discussion begins at 7:30 PM in the Vaden Education Center on the second floor of the health center on campus.

Previously: Remembering Kenyan statesman and Stanford medical school alumnus Njoroge Mungai, In poorest countries, increase in midwives could save lives of mothers and their babiesSex work in Uganda: Risky business and In Uganda, offering support for those born with indeterminate sex
Photo by Remi Kaupp

Global Health, History, HIV/AIDS, Infectious Disease

A doctor’s dilemma: to help or hold back from treating dangerous infections

If, like me, you’ve wondered why a doctor or nurse would decide to volunteer to help patients with often fatal infectious diseases like Ebola, The New York Times Magazine ran an essay today by Stanford physician and author Abraham Verghese, MD, MACP, in which he addresses, among other issues, the tension for clinicians between self-preservation and the impulse to help.

We doctors feel the pull. But each of us has reasons to stay back, reasons that get bigger as we age

He begins with his time treating patients in a hospital in India, detailing his encounters with tuberculosis, malaria, and filariasis among other diseases, but his description of his fear of and his reflections of his encounter with his first rabies patient is poignant:

I felt terribly sorry for this man who was old enough to be my father. Squatting by his mat, I was ashamed of my earlier fear and hesitation. I was glad to spend some time with him. By the next morning he was comatose and convulsing. By nightfall, he’d transcended the mortal world.

He  goes on to discuss his work with HIV patients in the 1980s, and the fear that surrounded the disease at the time. Many physicians donned full protective gear, even though researchers had determined, even in the early days of the epidemic, that the disease wasn’t spread via casual contact. Verghese connects these fears to current fears about Ebola, but doesn’t blame physicians who are cautious. He also documents his own impulses:

I have the urge to sign up, to head to Liberia or Sierra Leone; the call for doctors seems personally addressed to me. When I tell my mother, who is in her 90s, that I am thinking of volunteering in West Africa, she clutches my hand and says: “Oh, no, no, no. Don’t go!” I’m secretly pleased.

….

We doctors feel the pull. But each of us has reasons to stay back, reasons that get bigger as we age: children, partners, parents, grants.

Verghese captures the conundrum facing doctors and nurses who want to help, but who are – for a  variety of reasons – pulled away.

Previously: Ebola: This outbreak is differentStanford physician shares his story of treating Ebola patients in Liberia and Dr. Paul Farmer: We should be saving Ebola patients

Ebola, Events, HIV/AIDS, Infectious Disease, Public Health, Stanford News

Dr. Paul Farmer: We should be saving Ebola patients

Dr. Paul Farmer: We should be saving Ebola patients

The photo says it all: A very slender, ailing man sits on the floor with his head bent, completely alone in the dark in what used to be an Ebola treatment center in West Africa.

Paul Farmer, MD, PhD, the brilliant physician and humanitarian, flashed the photo on a screen to a rapt Stanford audience last Friday to show the emaciated state of health care systems in West Africa, incapable now of treating the most basic ailments.

Every time someone dies, it’s a failure to diagnose and deliver the imperfect tools we have

“The primary determinant of outcomes is the strength of health care systems. And if this is what ETU’s (Ebola Treatment Units) look like, there are going to be a lot of fatalities,” he told the crowd of some 400 people at Stanford’s Graduate School of Business. “We should be saving most of these patients. Every time someone dies, it’s a failure to diagnose and deliver the imperfect tools we have.”

But this vast inequity in care need not exist, said Farmer, MD, PhD, a Harvard professor. He pointed to examples from his own experience, in which he and the group he co-founded, Partners in Health, helped build robust health systems in Haiti and more recently, Rwanda, saving thousands of lives.

Farmer started working in Haiti while he was a student at Harvard Medical School nearly 30 years ago. In 1998, during the peak of the AIDS epidemic there, he established the HIV Equity Initiative, which relied on community health workers to visit the homes of patients daily to check on their status and ensure that they took their antiretroviral and/or tuberculosis medications. The approach proved remarkably successful, as people rose from their deathbeds to return to normal, functioning lives.

More recently, after the 2010 quake in Haiti, his group helped to build a medical center and teaching hospital in rural Haiti; he showed a photo of the modern, expansive new facility to the Stanford audience, which applauded the work.

“This is what I think of for rural Liberia, rural Sierra Leone,” he said. “This is not rocket science. Just think what we could do if we had a lot of help with systems and partners. It just requires sticking with some of these problems for a long time.”

Previously: Ebola panel says 1.4 million cases possible, building trust key to containmentExpert panel discusses challenges of controlling Ebola in West Africa, Should we worry? Stanford’s global health chief weighs in on Ebola and Biosecurity experts discuss Ebola and related public health concerns and policy implications

HIV/AIDS, In the News

Mourning the loss of AIDS researcher Joep Lange

Stanford researchers specializing in HIV/AIDS mourned the loss today of Dutch scientist Joep Lange, MD, PhD, a leading AIDS researcher who died in the Malaysian Airlines crash yesterday in Ukraine. Lange, a virologist, was particularly well-known for his work in helping expand access to antiretroviral therapy in developing countries. He was among dozens of people on the ill-fated flight who were heading to the 20th International AIDS Conference that opens Sunday in Melbourne, Australia.

“We are all in a state of shocked disbelief here in Melbourne at the tragic loss of one of the giants in the global fight against AIDS and HIV,” Andrew Zolopa, MD, professor of medicine at Stanford, told me in an e-mail from the conference site. “I have known Joep Lange for more than 25 years – he was a friend and a colleague.  Joep was one of the early leaders in our field to push for expanded treatment around the globe – and in particular treatment for Africa and Asia… The world has lost a major figure who did so much good in his quiet but determined manner.  I am shocked by this senseless act of violence. What a terrible tragedy.”

David Katzenstein, MD, also an HIV specialist at Stanford, learned of the death while in Zimbabwe, where he has a long-standing project on preventing transmission of HIV from mother to child. He said Lange, a friend and mentor, had been a “tireless advocate for better treatment for people living with HIV in resource-limited settings. He was universally respected and frequently honored as a real pioneer in early AIDS prevention and treatment.” In 2001, Lange founded the PharmAccess Foundation, a nonprofit organization based in Amsterdam, which aims to improve access to HIV therapy in developing countries. He continued to direct the group until his death.

Lange served as president of the International AIDS Society from 2002 to 2004 and had been a consultant to the World Health Organization, the federal Centers for Disease Control and Prevention and the National Institutes of Health. He led several important clinical trials in Europe, Asia and Africa and played a key role in many NIH-sponsored studies, said Katzenstein, a professor of medicine.

“He was a gentle, thoughtful and caring physician-scientist with a keen sense of humor and a quick and gentle wit. He was constantly absorbing, teaching and thinking about the human (and primate) condition and psychology,” Katzenstein told me. “He was much loved and will be sorely missed.”

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