Important Developments in Dana-Farber's AIDS Research Program
1989
Dana-Farber Cancer Institute is designated by the National Institutes of Health as a Center for AIDS Research. There are currently 20 such centers in the United States
1990
Dana-Farber receives and subsequently has renewed a five-year, postdoctoral training grant in AIDS research from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.
1999
Dana-Farber Cancer Institute teams with Beth Israel Deaconess Medical Center and Children's Hospital to create the DFCI/BIDMC/CH Center for AIDS Research.
Breakthroughs in the Laboratory
Dana-Farber researchers study CD4 and CCR5, molecules on immune system cells targeted by the AIDS virus and used by the virus as its port of entry into human cells.
1982
Dana-Farber researchers demonstrate a marked decrease in levels of CD4, an illustration of profound immune system alterations in AIDS.
1988
Dana-Farber researchers demonstrate that free-floating, synthesized CD4 has the ability to stop the replication of the human immunodeficiency virus-1 (HIV-1) and to inhibit the binding and fusion of virally infected cells to healthy cells.
1990
Using X-ray crystallography, Dana-Farber scientists create a three-dimensional portrait of CD4 to help develop and identify substances that inhibit the attachment of HIV-1 to white blood cells called T lymphocytes and monocytes.
1996
Dana-Farber investigators identify a host cell protein, CCR5, that is necessary for clinically relevant HIV-1 strains to enter blood cells.
CCR5 and a related protein, CCR3, are shown to be used by HIV-1 to enter microglial cells, which are major target cells for HIV-1 in the brain.
Attachment of the HIV-1 gp120 envelope glycoprotein to the primary receptor, CD4, is shown to create a new binding site for the CCR5 protein, which acts as a second receptor.
1998
A region on the HIV-1 gp120 envelope glycoprotein that interacts with CCR5 and that is highly conserved in all HIV-1 strains is discovered.
1999
An unusual protein modification, sulfation, is shown to be important for the ability of human CCR5 to support HIV-1 entry.
2000
A method for purifying human CCR5 and returning it to a membrane is developed. This method may facilitate the discovery of drugs active against not only CCR5, but also many G protein-coupled receptors. The G protein-coupled receptors are important in many aspects of biology and represent targets for 30-40 percent of all drugs currently in clinical use.
2001
Dana-Farber scientists use X-ray crystallography to show that HIV-1 binds to the same region on CD4 as the natural partner for CD4, the major histocompatibility complex class II protein. This observation suggests that HIV-1 binding to CD4 might interfere with normal function of the immune system.
From 1984 to the present day, numerous discoveries concerning the genetic makeup ofHIV-1 are made.
1984
Dana-Farber is involved in mapping the entire genetic sequence of
HIV-1.
1985
DFCI scientists discover that HIV-1 possesses a powerful stimulator of its own gene expression. Later in the year, they identify this stimulator as the viral Tat protein.
Discovery of TAR, an element that binds to the TAT protein, occurs at Dana-Farber.
1986
The REV gene, which is known to regulate production of messenger RNA for certain viral proteins, is discovered.
1989
The VPU gene, which regulates release of the virus from a cell, and the VPR gene, which allows HIV-1 to infect certain non-dividing cells like macrophages, are discovered.
Work with the anti-AIDS drug AZT in mice at Dana-Farber demonstrates the following:
1986
AZT is able to prevent virus replication and the development of AIDS.
1987
AZT is very effective and causes no birth defects when given to murine retrovirus-infected pregnant mice.
When low doses of AZT are combined with interferon-alpha, AZT is much more effective in inhibiting retroviral replication in infected laboratory mice than when given alone.
Studies of the properties of the envelope protein that encircles HIV-1 occur at Dana-Farber.
1987
The regions of the HIV-1 envelope glycoproteins involved in binding of the virus to the CD4 receptor and in fusing the viral and host cell membranes are mapped.
1991
Dana-Farber researchers discover that specific regions of the viral envelope protein gp120, identical for all HIV-1, could be an important target for generating neutralizing antibodies in humans that block infection by all strains of the AIDS virus.
1998
Dana-Farber and Columbia University researchers obtain the first three-dimensional picture of the envelope glycoprotein gp120. The glycoprotein meshes with receptors on the surface of immune cells, setting HIV infection in motion.
2001
Methods for producing stable HIV-1 envelope protein complexes are developed. These complexes are shown to elicit antibodies that block the infection of clinical HIV-1 strains more effectively than the gp120 protein.
Dana-Farber scientists gain an understanding of how HIV-1 causes the destruction of the immune system and brain.
1986
Studies by Dana-Farber researchers demonstrate that the ability of the HIV-1 envelope glycoproteins to disrupt cellular membranes is responsible for the destruction of the host cell by the virus.
1992
In conjunction with the New England Primate Center, Dana-Farber scientists construct a virus that expresses the exterior envelope glycoproteins of HIV-1 and contains an inner core of a monkey virus (simian immunodeficiency virus) related to HIV. This virus, unlike HIV-1, will infect a variety of monkey species and will allow testing of vaccines for HIV-1 in readily available monkeys.
1996
A chimeric simian-human immunodeficiency virus is identified that causes rapid CD4 T-cell destruction and AIDS in monkeys.
Dana-Farber researchers identify two proteins, CCR3 and CCR5, that are important for allowing access of HIV-1 to the microglial cell, which is the major target cell for the virus in the brain.
1998
Studies of the role of apoptosis (programmed cell death) in HIV-1 dementia, a neurologic complication that causes cognitive impairment and neurologic disability in up to 30 percent of AIDS patients, are undertaken at Dana-Farber. DFCI researchers showed that HIV infection induces apoptosis in key cells in human brain cultures.
2001
The capacity of the HIV-1 envelope glycoproteins to fuse cell membranes is shown to determine how efficiently CD4-positive T cells are destroyed in monkeys infected with simian-human immunodeficiency viruses.
Dana-Farber serves as the home of several studies into the means of HIV transmission.
1991
Scientists at Dana-Farber discover that the dendritic/Langerhans cell allows for infection by the HIV-1 virus during sexual intercourse through mucous membranes found in areas such as the anus, the mouth and the genital areas, which are most susceptible to infection by sexually transmitted diseases.
1992
In collaboration with Brigham and Women's Hospital, TSI Mason Laboratories in Worcester, Massachusetts, and Tufts University School of Veterinary Medicine, Dana-Farber researchers create the first animal model to study how an AIDS virus damages the immune system of a fetus and how virus transmission from mothers to their unborn children, either during pregnancy or during birth, can be prevented.
Many molecular studies aimed at inhibiting the replication of HIV have occurred at Dana-Farber.
1991
Dana-Farber staff finds that HIV-1 itself might be used in a modified form to treat AIDS by inhibiting its own virus replication, perhaps by carrying foreign genes from one cell to another.
1992
Studies of antibodies that are able to disrupt the function of TAT, a protein that stimulates HIV-1 infected cells to produce more viral particles, take place at Dana-Farber.
1995
Dana-Farber researchers develop a system by which antibodies deliver therapeutic genes to cells by binding to surface receptors. The system is an important step toward the development of a gene therapy for HIV-1 infected patients.
Studies of new drug therapies aimed at quelling the advance of AIDS and the infections and cancers associated with it take place at Dana-Farber.
1991
Progress is made at Dana-Farber in understanding the molecular basis of the susceptibility of HIV-1 to cyclosporin, a drug that is widely used to prevent rejection of foreign tissue.
1995
Dana-Farber scientists find that an experimental AIDS vaccine that looked promising in adult monkeys proved deadly to newborn monkeys. These findings dampen researchers' hopes that a vaccine made from a weakened form of the AIDS virus might become available in the near future, but redirect scientists toward alternative vaccine strategies that may in the long run prove successful.
