Tuesday, March 11, 2014

Unique individual with lupus and HIV demonstrates desired immune response to HIV

Date:
Source:
Duke Medicine
Summary:
One person’s unique ability to fight HIV has provided key insights into an immune response that researchers now hope to trigger with a vaccine, according to new findings. The person had a rare combination of both lupus and HIV. Lupus, specifically systemic lupus erythematosus, or SLE, is a disease in which the immune system attacks the body's cells and tissue.

One person's unique ability to fight HIV has provided key insights into an immune response that researchers now hope to trigger with a vaccine, according to findings reported by a team that includes Duke Medicine scientists.
The person had a rare combination of both lupus and HIV. Lupus, specifically systemic lupus erythematosus, or SLE, is a disease in which the immune system attacks the body's cells and tissue.
In an analysis published March 10, 2014, in the Journal of Clinical Investigation, the Duke-led research team detailed how the individual's immune system made a desired type of neutralizing antibodies that is considered essential to an effective vaccine response.
"Over the years we have searched for and now have found one person with SLE who was also chronically infected with HIV to determine if this person could make broad neutralizing antibodies," said Barton F. Haynes, M.D., director of the Duke Human Vaccine Institute and senior author of the study. "We found that the patient did indeed make these important antibodies, and by determining how this immune response occurred, we have enhanced our understanding of the process involved."
Haynes said a huge barrier to creating an effective HIV vaccine has been the difficulty in eliciting the broad neutralizing antibody response. These antibodies arise in a few people infected with HIV, but it takes at least two years.
In 2005, Haynes found that some broad neutralizing antibodies to HIV cross-reacted with the body's tissues in a process termed autoreactivity. Autoreactive antibodies are kept in check by the body's immune tolerance controls, which sense antibodies that react with the body and prevent them from being made.
Haynes's hypothesis has been that these autoreactive broad neutralizing antibodies are not routinely made because the immune system targets them as harmful and keeps them in check. In essence, the virus has found a unique escape mechanism from neutralizing antibodies by adapting itself to look like the body's tissues.
In an autoimmune disease such as lupus, the immune tolerance controls are defective, so the broad neutralizing antibodies should be produced, the Duke team reasoned.
Haynes and colleagues, including lead author Mattia Bonsignori, M.D., assistant professor of medicine at Duke, identified an individual with both lupus and HIV and found that, after several years, the person made the desired broad neutralizing antibodies.
Remarkably, the broad neutralizing antibody found in the lupus individual was autoreactive, and reacted with similar molecules in the body called double stranded DNA, or dsDNA, that are made in individuals with lupus who do not have HIV.
"The cross-reactivity of the broad neutralizing antibody with dsDNA was very surprising and provided support for the hypothesis that broad neutralizing antibodies are similar to the autoantibodies that arise in lupus patients who are not infected with HIV," Bonsignori said.
The findings in no way suggest that individuals with lupus are immune to HIV, and they, like all individuals, should protect themselves from contracting the virus. Rather, it suggests that when individuals with lupus do become infected with HIV, they can eventually make broad neutralizing antibodies, although unfortunately too late to help them fight off the infection.
"Our study of this person with SLE and HIV has been critically instrumental in our understanding of the unusual biology of the remarkable host control of antibody responses to the conserved broad neutralizing sites of the HIV envelope," Bonsignori said. "We are hopeful that these insights in lupus will aid in our implementation of strategies for designing experimental vaccines capable of overcoming the host tolerance control of broad neutralizing antibodies."
In addition to Haynes and Bonsignori, study authors from Duke include Kevin Wiehe, Guang Yang, Daniel M. Kozink, Florence Perrin, Abby J. Cooper, Kwan-Ki Hwang, Xi Chen, Mengfei Liu, Robert J. Parks, Joshua Eudailey, Minyue Wang, Megan Clowse, Lisa G. Criscione-Schreiber, M. Anthony Moody, Feng Gao, Garnett Kelsoe, Laurent Verkoczy, Georgia D. Tomaras, Hua-Xin Liao, and David C. Montefiori. Other authors include Sabastian K. Grimm and Margaret E. Ackerman from Dartmouth College; Rebecca Lynch, Krisha McKee and John R. Mascola from the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases; and Scott D. Boyd of Stanford University.
The National Institute of Allergy and Infectious Diseases funded the study (AI067854 and AI100645).

Story Source:
The above story is based on materials provided by Duke Medicine. Note: Materials may be edited for content and length.

Journal Reference:
  1. Mattia Bonsignori, Kevin Wiehe, Sebastian K. Grimm, Rebecca Lynch, Guang Yang, Daniel M. Kozink, Florence Perrin, Abby J. Cooper, Kwan-Ki Hwang, Xi Chen, Mengfei Liu, Krisha McKee, Robert J. Parks, Joshua Eudailey, Minyue Wang, Megan Clowse, Lisa G. Criscione-Schreiber, M. Anthony Moody, Margaret E. Ackerman, Scott D. Boyd, Feng Gao, Garnett Kelsoe, Laurent Verkoczy, Georgia D. Tomaras, Hua-Xin Liao, Thomas B. Kepler, David C. Montefiori, John R. Mascola, Barton F. Haynes. An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes HIV-1. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI73441

Cite This Page:
Duke Medicine. "Unique individual with lupus and HIV demonstrates desired immune response to HIV." ScienceDaily. ScienceDaily, 10 March 2014. <www.sciencedaily.com/releases/2014/03/140310182542.htm>.

Scientists describe deadly immune “storm” caused by emergent flu infections

Scientists describe deadly immune “storm” caused by emergent flu infections

Fri, 02/28/2014 - 7:53am
Scientists at The Scripps Research Institute (TSRI) have mapped key elements of a severe immune overreaction—a “cytokine storm”—that can both sicken and kill patients who are infected with certain strains of flu virus.
Their findings, published online in the Proceedings of the National Academy of Sciences, also clarify the workings of a potent new class of anti-inflammatory compounds that prevent this immune overreaction in animal models.
“We show that with this type of drug, we can quiet the storm enough to interfere with the virus-induced disease and lung injury, while still allowing the infected host to mount a sufficient immune response to eliminate the virus,” said John R. Teijaro, an asst. prof. in TSRI’s Dept. of Immunology and Microbial Science and first author of the study.
“This study provides insights into mechanisms that are chemically tractable and can modulate these cytokine storms,” said Hugh Rosen, prof. in TSRI’s Dept. of Chemical Physiology and senior author of the study with Michael B. A. Oldstone, prof. in TSRI’s Dept. of Immunology and Microbial Science.
Calming the storm
A cytokine storm is an overproduction of immune cells and their activating compounds (cytokines), which, in a flu infection, is often associated with a surge of activated immune cells into the lungs. The resulting lung inflammation and fluid buildup can lead to respiratory distress and can be contaminated by a secondary bacterial pneumonia—often enhancing the mortality in patients.
This little-understood phenomenon is thought to occur in at least several types of infections and autoimmune conditions, but it appears to be particularly relevant in outbreaks of new flu variants. Cytokine storm is now seen as a likely major cause of mortality in the 1918-20 “Spanish flu”—which killed more than 50 million people worldwide—and the H1N1 “swine flu” and H5N1 “bird flu” of recent years. In these epidemics, the patients most likely to die were relatively young adults with apparently strong immune reactions to the infection—whereas ordinary seasonal flu epidemics disproportionately affect the very young and the elderly.
For the past eight years, Rosen’s and Oldstone’s laboratories have collaborated in analyzing the cytokine storm and finding treatments for it. In 2011, led by Teijaro, who was then a research associate in the Oldstone Laboratory, the TSRI team identified endothelial cells lining blood vessels in the lungs as the central orchestrators of the cytokine storm and immune cell infiltration during H1N1 flu infection.
In a separate study, the TSRI researchers found that they could quiet this harmful reaction in flu-infected mice and ferrets by using a candidate drug compound to activate immune-damping receptors (S1P1 receptors) on the same endothelial cells. This prevented most of the usual mortality from H1N1 infection—and did so much more effectively than the existing antiviral drug oseltamivir, although the combination of both therapies worked even better. “That was really the first demonstration that inhibiting the cytokine storm is protective,” said Teijaro.
Mapping a path forward
For the new study, Teijaro and his colleagues set out to map the major elements of the cytokine storm in H1N1 infection. To do so, they used gene knock-out techniques to breed mice that lack one or more molecular sensors of influenza virus infection and then observed the response to infection by H1N1 influenza virus.
The experiments showed that knocking out any one infection-sensing pathway has relatively modest effects on damping the cytokine and immune cell lung-infiltration response. In each case, an experimental drug compound (CYM5442) that activates S1P1 receptors knocked it down much more.
“What this shows is that our drug is working not through one selective pathway but much more broadly,” said Teijaro. “Many different cytokines are induced in this reaction, so just blocking one is surely not enough to reduce the lung disease.”
While CYM5442’s effect is broad, its action is selective on cells that bear the sphingosine-1-phosphate 1 receptor (S1P1R). Teijaro pointed out that it is also milder than those of steroids, which act indiscriminately on all lymphoid cells, and other strong immunosuppressant drugs, which may block the immune response so completely that an infecting virus ends up replicating out of control.
An optimized version of CYM5442, initially developed by Rosen and fellow TSRI chemist Ed Roberts, has been licensed to the pharmaceutical company Receptos. It is now in Phase 3 clinical trials for treating relapsing-remitting multiple sclerosis and Phase 2 trials for ulcerative colitis. Other S1P1 receptor agonists are in development for inflammatory conditions. A less-specific S1P receptor agonist—which hits S1P1, but also hits S1P3, S1P4 and S1P5, with potential off-target effects—is already approved for treating multiple sclerosis.
“We’d like to understand all the pathways through which S1P1 agonists work and, by pinpointing specific stop/start points, figure out how best to target those pathways with future drugs,” said Teijaro, who plans further studies with his colleagues to determine what other cell types are involved in orchestrating and possibly quieting the cytokine storm. “I’m hoping our work can further contribute to TSRI’s long track record of success in employing small molecule probes coupled to genetic and biochemical tools to provide biological insight into pathological disease processes