Scientists seeking to understand how to make an AIDS vaccine have found the cause of a major roadblock. It turns out that the immune system can indeed produce cells with the potential to manufacture powerful HIV-blocking antibodies - but at the same time, the immune system works equally hard to make sure these cells are eliminated before they have a chance to mature.

“These studies show that a potentially protective neutralizing antibody against a viral disease is under the control of immunological tolerance,” said Barton Haynes, M.D., director of the Center for HIV/AIDS Vaccine Immunology (CHAVI) at Duke University Medical Center and senior author of the study appearing in the online early edition of the Proceedings of the National Academy of Sciences. “This represents a new insight into the way HIV effectively evades detection by the B cell arm of the immune system and may offer new directions for vaccine design.”

Over the years, scientists have assumed that B cells - one of the first lines of defense against infection - are simply not able to “see” the HIV virus. HIV has the ability to hide its most vulnerable parts from immune system surveillance, and researchers generally assumed that helped explain why B cells often took weeks and even months to arise following infection.

But several years ago, Duke researchers hypothesized that the antibodies required to broadly neutralize HIV may not be produced in the first place because the immune system “sees” them as a potential threat - due to their similarity to antibodies that promote autoimmune disease - and destroys them.

To see if this is indeed what happens, Laurent Verkoczy, Ph.D., assistant professor of medicine at Duke and the lead author of the study, and Haynes genetically engineered a mouse that could only produce B cells containing a rare but potent broadly neutralizing human antibody that is able to block HIV infection.

Researchers found that the mouse’s immune system produced plenty of early stage B cells bearing this human neutralizing antibody on their surface but eliminated most of them before they had a chance to fully evolve into more mature B cells capable of secreting the antibody.

“This work may mean that we need to think and act very differently in envisioning how a successful vaccine may work,” said Verkoczy. “The good news is that while about 85 percent of the “right” kind of B cells are eliminated, about 15 percent survive and wind up in circulating blood, but are turned off. One goal in vaccine design may be to figure out how to wake them up so they can go to work.”

“We have now unveiled a major reason why members of this class of neutralizing antibodies are not routinely made: Our own immune systems block their production because they are perceived as potentially harmful, when in reality, they are not,” said Haynes. “This is a very unusual way the virus has developed to evade the immune system.”

Haynes says researchers plan on using the new mouse model to test ways to teach the immune system to enable the production of powerful neutralizing antibodies capable of blocking HIV.

The research was supported by the Bill and Melinda Gates Foundation, the Duke Center for AIDS Research, and grants from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

Duke colleagues who contributed to the research include T. Matt Holl, Hilary Bouton-Verville, S. Munir Alam, Hua-Xin Liao and Garnett Kelsoe. Additional co-authors include Marilyn Diaz, from the National Institute of Environmental Health Sciences and Ying-Bin Ouyang, of Xenogen Biosciences.

Source: Michelle Gailiun

Duke University Medical Center

The Hebrew University of Jerusalem Kuvin Center for the Study of Infectious and Tropical Diseases has received a $5 million grant from the Bill & Melinda Gates Foundation for research into visceral leishmaniasis in Ethiopia.

The project will be led by Prof. Alon Warburg, a vector biologist working at the Institute of Medical Research Israel-Canada at the Hebrew University’s Faculty of Medicine.

The project, entitled ‘Studies on the ecology and transmission dynamics of visceral leishmaniasis in Ethiopia’, will comprise thorough investigations to determine the drivers of transmission of Kala-Azar in endemic foci. The ecology of the sand fly vectors and their larval breeding habitats will be characterized and putative reservoir hosts will be incriminated. In parallel, genotypes and drug sensitivities of the Leishmania parasites will be studied in depth. The data gathered will be rigorously analyzed and utilized to identify the weak links in the transmission cycle in order to devise methods for control of the disease.

According to Prof. Warburg, “Visceral leishmaniasis is transmitted by small, mosquito-like insects known as sand flies. Sand flies become infected with Leishmania while sucking blood from an infected person or animal and transmit the disease during subsequent blood meals. Sand fly control is problematic because the breeding sites of their immature stages are unknown, making larval source reduction all but impossible.”

An estimated 500,000 cases of visceral leishmaniasis - also known as Kala-azar - occur annually. More than 90 percent of the cases are concentrated in the Indian sub-continent, East Africa and Brazil. The worst affected region in Africa is southern Sudan and northwest Ethiopia. Kala Azar is considered an emerging disease in Ethiopia where it is frequently associated with HIV/AIDS, a leading cause of adult illness and death. Leishmania donovani parasites multiply inside cells of the immune system producing symptoms that include an enlarged spleen and fevers. If treated with a 30-day course of intra-muscular injections, the cure rate is 95 percent. However, if left untreated, Kala-azar kills 95 percent of its victims.

Co-infection with HIV makes treatment much more complex. Because the immune system is suppressed in HIV-positive patients, Kala-azar relapses are common and patients have to be treated multiple times. Given the difficulties of treating large populations in remote areas and the bleak prospects for co-infected patients, efforts must be made to protect people living in HIV/AIDS-endemic areas from contracting Kala-azar.

This is a collaborative project with Prof. Asrat Hailu from the Faculty of Medicine and Prof. Teshome Gebre-Michael of the Aklilu Lemma Institute of Pathobiology in Addis Ababa University. Additional collaborating institutions include the Hebrew University’s Robert H. Smith Faculty of Agriculture, Food and Environment, Charles University in Prague, the Volcani Center and the Gertner Institute for Trauma and Emergency Medicine Research.

Source: Jerry Barach

The Hebrew University of Jerusalem

Michael Saag, M.D., director of the University of Alabama at Birmingham (UAB) Center for AIDS Research and a renowned leader in the establishment of best practices for human immunodeficiency virus (HIV) treatment, has been installed as chair of the board of directors of the HIV Medicine Association (HIVMA).

HIVMA is the largest professional society of physicians, scientists and health-care professionals dedicated to the field of HIV and AIDS. The organization actively promotes quality in HIV care and advocates for policies that ensure a science-based, comprehensive and humane response to the AIDS pandemic, including adequate funding for HIV research, prevention, care and provider training and resources.

A professor of medicine, Saag also directs UAB’s Division of Infectious Diseases. He is on the board of directors of the International AIDS Society-USA, and he helped author U.S. Department of Health and Human Services guidelines for antiretroviral treatments and edits the Sanford Guide to HIV/AIDS Therapy. Saag will serve a one-year term with HIVMA that ends November 2010.

Saag is credited with being the first to demonstrate the value of viral-load testing in a clinical practice. This test allows physicians to follow the response to antiretroviral treatment, just as they follow the blood-sugar response to insulin when treating diabetics. He also is among the first to perform clinical trials of several antiretroviral drugs that are approved worldwide.

Saag helped establish UAB’s 1917 Clinic, a comprehensive HIV outpatient clinic devoted to patient care and clinical-trial coordination. Opened in 1988, the clinic has grown into a hub for HIV basic science and treatment-outcomes research at UAB.

He has authored dozens of scientific manuscripts, contributed more than 50 chapters to medical textbooks and served on the editorial board of the journal AIDS Research and Human Retrovir uses. He also has served on subspecialty committees of the American Board of Internal Medicine and the American College of Physicians.

Saag earned his medical degree from the University of Louisville in Kentucky and completed a postdoctoral fellowship at UAB. He is the Jim Straley Chair in AIDS Research and an active member of the American Society of Clinical Investigation.

About the HIV Medicine Association

The HIV Medicine Association (HIVMA) is the professional home for more than 3,600 physicians, scientists and other health-care professionals dedicated to the field of HIV/AIDS. A part of the Infectious Diseases Society of America, HIVMA promotes quality in HIV care and advocates policies that ensure a comprehensive and humane response to the AIDS pandemic informed by science and social justice. For more information, visit http://www.hivma.org.

About the UAB Center for AIDS Research

The UAB Center for AIDS Research (CFAR) is one of the seven original centers established in 1988 by the federal government to stimulate research and advances in fighting AIDS and HIV. CFAR supports prevention and HIV-patient care at the 1917 Clinic and in Africa through a partnership with the Center for Infectious Disease Research in Zambia.

Source
University of Alabama at Birmingham