March 2006: Grants and Fellowships Announced: Understanding HIV Infection at the Start
March 7, 2006 - What happens after HIV enters the body? Under which circumstances does HIV transmission lead to infection? What chain of events occurs at the beginning of infection? amfAR, The Foundation for AIDS Research, announced nearly $1 million dollars in new grants and fellowships for scientists seeking answers to these questions – answers many scientists believe will lead to improved methods to prevent infection.
“Not enough is known about the earliest moments of HIV’s interaction with the human body,” said Dr. Rowena Johnston, amfAR’s director of research. “The more we know, the better equipped we will be to develop a broader range of interventions – drug treatments used before or shortly after exposure to the virus, a microbicide or even a vaccine – to break the link in the chain of events leading from HIV transmission to established infection.”
One of amfAR’s new grantees is Dr. Benjamin Chen, of the Mount Sinai School of Medicine in New York. Dr. Chen will study HIV-1 infection of mucosal lymphocytes and tissue in the intestines, one of the first places where the virus invariably wipes out immune cells.
“There is great mystery surrounding the viral predilection for depleting immune cells in the gut,” Dr. Chen said. “If we can work out why the virus homes in on these cells, we may be able to develop targeted strategies to obstruct this process.” Chen’s study is one of 10 projects designed to better understand, mitigate and prevent HIV transmission and infection. Some involve the investigation of gene therapy and possible vaccine and microbicide candidates.
Newly announced amfAR fellow Dr. Hoshang Unwalla of the City of Hope National Medical Center in Duarte, California, will design a novel gene therapy as a potential barrier to infection. This technique is intended to prevent HIV from infecting cells in part by taking advantage of a series of events inside the cell that is set off by the virus itself.
“Gene therapy has the potential to improve treatment for a wide range of diseases, including HIV,” said Dr. John Rossi, who will serve as a mentor for Dr. Unwalla’s study. “By supporting Dr. Unwalla, amfAR is backing the development of a truly innovative technique that might one day not only broaden HIV patients’ treatment options but could eventually have even more far-reaching implications for the treatment of other viral infections and some cancers.”
With a grantmaking philosophy that values novel approaches to the unanswered questions surrounding HIV, amfAR consistently deploys grants and fellowships at the forefront of AIDS research. Finding new ways to prevent HIV infection is one of the goals of amfAR’s research program.
The Foundation has focused prior funding cycles on vaccine and microbicides research and on mucosal HIV transmission. amfAR funded the earliest research on DNA vaccines, one of the most promising concepts being pursued today in the quest for an AIDS vaccine. More recently, amfAR supported research leading to the first detailed description of a broadly neutralizing antibody, which could be critical in the design of an AIDS vaccine, as well as pioneering research using a new technology known as siRNA to develop a microbicide.
amfAR, The Foundation for AIDS Research, is one of the world’s leading nonprofit organizations dedicated to the support of AIDS research, HIV prevention, treatment education, and the advocacy of sound AIDS-related public policy. Since 1985, amfAR has invested close to $250 million in its programs and has awarded grants to more than 2,000 research teams worldwide.
Grants
Benjamin Chen, M.D., Ph.D.
Mount Sinai School of Medicine, New York, NY
HIV-1 infection of mucosal lymphocytes and tissue explants: Regardless of whether HIV enters the body via the vagina or rectum, immune cells in the gut (including the rectum and small and large intestine) rapidly become infected, followed by a massive loss of gut immune cells. Dr. Chen hypothesizes that certain gut cells may produce chemical signals that guide the virus to the gut. He will tag individual viruses with a fluorescent protein that will allow him to see movement of the virus towards the gut cells, in a test tube environment.
Thomas Hope, Ph.D.
Northwestern University, Chicago, IL
Interaction of HIV with the macaque female genital tract: Events that occur within the first 48 hours of HIV being deposited in the vagina are not clearly understood. Dr. Hope plans to use a novel technology developed in his laboratory to visualize individual viruses as they cross the lining of the macaque vagina and cervix to infect underlying tissues. This project will provide much-needed information on the earliest events in HIV infection, particularly those that happen within minutes or a few hours of HIV entering the vagina. This information might ultimately be used to develop strategies to prevent infection in the vagina.
Dale McPhee, Ph.D.
St. Vincent’s Institute. Fitzroy, Australia
HIV-1 transmission and replicative fitness: The strains of HIV that initially infect people may differ in important respects from strains of HIV that are found later during the course of infection. Dr. McPhee hypothesizes that the specific viruses responsible for initial infection may differ in their relative fitness, or ability to reproduce. By finding generalizable characteristics of the viruses responsible for establishing infection, scientists may be better able to design an AIDS vaccine that specifically targets the types of virus that are most likely to cause initial infection.
Leonard Moise, Ph.D.
Brown University, Providence, RI
Targeting an HIV multi-epitope vaccine to dendritic cells: One problem in developing an AIDS vaccine is ensuring that the vaccine generates an immune system response that is strong enough to overcome the virus. Dr. Moise plans to test a vaccine concept that has the potential to increase vaccine strength up to 1000-fold, by chemically linking a small portion of HIV - known to generate an important but weak immune system response - to dendritic cells. Dendritic cells form part of the immune system – they play an important role in increasing the ability of HIV to infect a large number of cells, but have the potential, if manipulated correctly, to play a key role in fighting the virus.
Eva Rakasz, Ph.D.
University of Wisconsin, Madison, WI
Female genital ulcer as a portal of HIV entry: Women who have sexually transmitted infections (STIs) like herpes or syphilis are at greatly increased risk of becoming infected with HIV, yet why this is so is not completely understood. One possibility is that the immune cells fighting those infections in the vagina provide ideal targets for incoming HIV. Dr. Rakasz plans to test, in monkeys, another hypothesis, that the ulcers commonly associated with STIs like herpes or syphilis acts as portals through which the virus can gain access to tissues underneath the surface of the vagina and thereby establish generalized infection in the body.
Manish Sagar, M.D.
Harvard University, Boston, MA
Understanding the properties of transmitted HIV-1 variants: The strains of HIV that initially infect people represent only a small portion of all the viruses circulating in the body of the transmitting partner. Dr. Sagar hypothesizes that viruses responsible for initiating a new infection are specifically well-suited to reproduce in the types of cells with which the virus first comes into contact. He will determine whether the total amount and/or density of sugars on the surface of HIV are associated with the likelihood of infecting a new person. This knowledge will increase out understanding of factors that influence sexual HIV transmission and how initial infection sets the stage for the course of disease.
Fellowships
Gabriel Birrane, Ph.D. / Mentor: John Ladias, M.D.
Beth Israel Deaconess Medical Center, Boston, MA
Molecular mechanisms of the HIV-1 co-receptor CCR5 function: In the vast majority of cases, initial infection with HIV requires that the virus interact with a protein found on the surface of some human cells called CCR5. Researchers are investigating ways of preventing this interaction and thus preventing infection altogether. Dr. Birrane has identified proteins found inside cells that regulate how much CCR5 is found on a cell’s surface and where. By understanding how the presence of CCR5 is regulated, Dr. Birrane may discover a new way in which scientists could devise therapies that would decrease the amount of CCR5 on the cell surface and thus decrease the chances that the cell could become HIV infected.
Richard Haaland, Ph.D. / Mentor: Eric Hunter, Ph.D.
Emory University, Atlanta, GA
Virologic correlates of subtype-A HIV transmission: HIV can be divided into families or subtypes, some of which occur more frequently in different regions of the world. Subtype-A HIV is one of the HIV viruses found commonly in Africa. Dr. Haaland wants to understand which characteristics of this HIV subtype, especially in the surface proteins of the virus, make it more likely to be transmitted to a sex partner than other viruses. There appear to be important differences that might predict infectiousness of subtype A viruses as opposed to subtype B viruses, which are more commonly found in North America, Europe and Australia. Understanding the characteristics of viruses which viruses can more readily infect a sex partner will help in efforts to develop an AIDS vaccine.
Hoshang Unwalla, Ph.D. / Mentor: John Rossi, Ph.D.
City of Hope National Medical Center, Duarte, CA
Designing inducible Pol II systems for RNA interference of HIV: Dr. Unwalla plans to develop a gene therapy technique designed to prevent HIV from infecting cells. He has devised a system that blocks HIV from inserting itself into human DNA after it makes contact with critical proteins on the surface of vulnerable human cells. His technique has an important advantage over current gene therapy techniques in that the HIV-fighting activity is activated only after the virus makes initial contact, which may offer an additional layer of safety over gene therapy currently under clinical investigation.
Liguo Zhang, Ph.D. / Mentor: Lishan Su, Ph.D.
University of North Carolina, Chapel Hill, NC
HIV mucosal transmission in humanized mice model: One of the greatest hurdles in studying HIV, especially the events surrounding sexual transmission, is the lack of an animal model that closely resembles what happens in humans after HIV transmission. Dr. Zhang has developed a genetically engineered mouse that has many of the characteristics needed to mimic events that occur in the human vagina and rectum. These mice will be used to generate more information concerning the details of sexually transmitted HIV and have the potential to be used to test the effectiveness of candidate microbicides, substances being developed that could be applied topically to reduce the risk of HIV transmission.