One of the continuing mysteries of the HIV/AIDS epidemic is why women usually develop lower viral levels than men following acute HIV-1 infection but progress faster to AIDS than men with similar viral loads.
Now a research team based at the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard has found that a receptor molecule involved in the first-line recognition of HIV-1 responds to the virus differently in women, leading to subsequent differences in chronic T cell activation, a known predictor of disease progression. Their paper, which will be published in an upcoming issue of Nature Medicine, is receiving early online release.
"This study may help to account for reported gender differences in HIV-1 disease progression by demonstrating that women and men differ in the way their immune systems respond to the virus," says Marcus Altfeld, MD, PhD, of the Ragon Institute and the MGH Division of Infectious Disease, the study's senior author. "Focusing on immune activation separately from viral replication might give us new therapeutic approaches to limiting HIV-1-induced pathology."
It has become apparent in recent years that HIV-1-infected patients with a high level of immune activation progress to AIDS more rapidly. Why this happens is an area of intense investigation. To explore whether gender-based differences in immune activation were responsible for faster disease progression in women, the Ragon Institute team and their collaborators focused on plasmacytoid dendritic cells (pDCs), among the first cells of the immune system to respond to HIV-1 and other viral pathogens. Earlier studies indicated that pDCs recognize HIV-1 using a receptor called Toll-like receptor 7 (TLR7), leading to production of interferon-alpha and other important immune system molecules.
After initial in vitro experiments showed that a higher percentage of pDCs from uninfected women produced interferon-alpha in response to TLR7 stimulation by HIV-1 than did cells from uninfected men, the researchers examined whether women's hormone levels had any effect on pDC activation. Supporting previous evidence that progesterone may modulate pDC activity, the researchers found that pDCs from postmenopausal women produced levels of interferon-alpha in response to HIV-1 that were closer to levels observed in men. They also found that, in premenopausal women, higher progesterone levels correlated with increased activation of pDCs in response to HIV-1.
Since it is known that the activation of T cells predicts the progression of HIV-1 infection to AIDS, the research team conducted a series of in vitro experiments showing that the stimulation of pDCs in response to HIV-1 led to the subsequent activation of CD8+ T cells by means of interferon-alpha secretion. They then tested blood samples taken from a group of chronically HIV-1-infected women and men prior to treatment initiation and confirmed that women had higher levels of CD8+ T cell activation than did men with the same blood levels of HIV-1.
"Taken together, these results support a model in which the same amount of virus induces stronger pDC activation in women than in men. While stronger activation of the immune system might be beneficial in the early stages of infection, resulting in lower levels of HIV-1 replication, persistent viral replication and stronger chronic immune activation can lead to the faster progression to AIDS that has been seen in women," Altfeld explains.
He adds that the study's results raise a number of important new questions, including exactly how sex hormones modulate the TLR7-mediated response of pDCs to HIV-1 and whether anti-TLR agents may help reduce immune activation in chronic HIV-1 infection. His team is beginning preliminary laboratory studies of the ability of TLR antagonists to reduce HIV-1-induced activation of pDCs.
Altfeld is an associate professor of Medicine at Harvard Medical School and director of the Innate Immunity Program at the Ragon Institute of MGH, MIT and Harvard. Co-lead authors of the Nature Medicine paper are Angela Meier, MD, PhD, and J. Judy Chang, PhD, of the Ragon Institute. Additional co-authors are Harlyn Sidhu, Tom Fang Wen, Robert Lindsay, Suzane Bazner, Hendrik Streeck, MD, and Galit Alter, PhD, Ragon Institute; Gregory Robbins, MD, MGH Division of Infectious Diseases; Ronald Bosch, PhD, Ellen Chan, PhD, and Liliana Orellana, Harvard School of Public Health; Richard Pollard, MD, University of California at Davis Medical Center; Smita Kulkarni, PhD, Jeffrey Lifson, MD, and Mary Carrington, PhD, National Cancer Institute; and Donna Mildvan, MD, Beth Israel Medical Center, New York. The study was supported by grants from the National Institute of Allergy and Infectious Diseases, the Harvard Center for AIDS Research, the Bill & Melinda Gates Foundation, the Doris Duke Charitable Foundation, and the National Cancer Institute.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.
Sue McGreevey | EurekAlert!
Further reports about: > Aids > Disease > Foundation > HIV > HIV-1 > HIV-1-induced > HIV-1-infected > Infectious > Infectious Diseases > MGH > Medical Wellness > Nature Immunology > T cell activation > T cells > blood sample > cell activation > immune activation > immune system > menopausal women > viral replication
Deep Brain Stimulation Provides Sustained Relief for Severe Depression
19.03.2019 | Universitätsklinikum Freiburg
AI study of risk factors in type 1 diabetes
06.03.2019 | University of Gothenburg
Nano- and microtechnology are promising candidates not only for medical applications such as drug delivery but also for the creation of little robots or flexible integrated sensors. Scientists from the Max Planck Institute for Polymer Research (MPI-P) have created magnetic microparticles, with a newly developed method, that could pave the way for building micro-motors or guiding drugs in the human body to a target, like a tumor. The preparation of such structures as well as their remote-control can be regulated using magnetic fields and therefore can find application in an array of domains.
The magnetic properties of a material control how this material responds to the presence of a magnetic field. Iron oxide is the main component of rust but also...
Due to the special arrangement of its molecules, a new coating made of corn starch is able to repair small scratches by itself through heat: The cross-linking via ring-shaped molecules makes the material mobile, so that it compensates for the scratches and these disappear again.
Superficial micro-scratches on the car body or on other high-gloss surfaces are harmless, but annoying. Especially in the luxury segment such surfaces are...
The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.
A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...
Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.
"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...
New research group at the University of Jena combines theory and experiment to demonstrate for the first time certain physical processes in a quantum vacuum
For most people, a vacuum is an empty space. Quantum physics, on the other hand, assumes that even in this lowest-energy state, particles and antiparticles...
11.03.2019 | Event News
01.03.2019 | Event News
28.02.2019 | Event News
21.03.2019 | Life Sciences
21.03.2019 | Physics and Astronomy
21.03.2019 | HANNOVER MESSE