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HIV
HIV Therapeutics
HIV infection causes a slowly progressing deterioration of the immune system resulting in Acquired Immune Deficiency Syndrome, or AIDS. HIV specifically infects cells that have the CD4 receptor on their surface. Cells with the CD4 receptor are critical components of the immune system and include T lymphocytes, monocytes, macrophages and dendritic cells. The devastating effects of HIV are largely due to the multiplication of the virus in these cells, resulting in their dysfunction and destruction.
UNAIDS, the Joint United Nations program on HIV/AIDS, and WHO, the World Health Organization, estimated that in 2005, 40.3 million people worldwide were infected with HIV, 43% of whom are women. There were an estimated 4.9 million new infections diagnosed and over 3 million HIV-related deaths during 2005.
At present, three classes of products have received marketing approval from the FDA for the treatment of HIV infection and AIDS: reverse transcriptase inhibitors, protease inhibitors and entry inhibitors. Reverse transcriptase and protease inhibitors inhibit two of the viral enzymes required for HIV to replicate once it has entered the cell.
Since the late 1990s, many HIV patients have benefited from combination therapy of protease and reverse transcriptase inhibitors. While combination therapy slows the progression of disease, it is not a cure. HIV's rapid mutation rate results in the development of viral strains that are resistant to reverse transcriptase and protease inhibitors. Increasingly, after years of this combination therapy, patients begin to develop resistance to these drugs. The potential for resistance is exacerbated by interruptions in dosing which lead to lower drug levels and permit increased viral replication. Interruption in dosing is common in patients on combination therapies, because these drug regimens often require more than a dozen tablets to be taken at specific times each day. An additional problem is that in many patients, the currently approved drugs produce toxic side effects, which affect a variety of organs and tissues, including the peripheral nervous system and gastrointestinal tract. As a consequence of these side effects, patients often interrupt or discontinue therapy. Our viral-entry inhibitor represents a potential new class of drugs for these patients.
Viral infection occurs when the virus binds to a host cell, enters the cell, and by commandeering the cell's own reproductive machinery, creates thousands of copies of itself within the host cell. This process is called viral replication. Our scientists and their collaborators have made important discoveries in understanding how HIV enters human cells and initiates viral replication.
In the 1980s, our founding research scientists demonstrated that the initial step of HIV infection involves the specific attachment of the virus to the CD4 receptor on the surface of human immune system cells. These researchers also showed that a specific glycoprotein, gp120, located on the surface of HIV, binds with high affinity to the CD4 receptor. Although our researchers demonstrated that binding to CD4 was necessary for HIV attachment, further discoveries showed that attachment alone is not sufficient to enable the virus to enter the cell and initiate viral replication.
Subsequently, our research scientists, in collaboration with researchers at the Aaron Diamond AIDS Research Center, or ADARC, described in an article in Nature (Nature, 1996, volume 384, pp 184-187) the discovery of a co-receptor for HIV on the surface of human immune system cells. This co-receptor, CCR5, enables fusion of HIV with the cell membrane after the virus binds to the CD4 receptor. This fusion step results in entry of the viral genetic information into the cell and subsequent viral replication. Our collaborative research further determined that the gp120 binding site on CCR5 is located in a discrete region at one end of the CCR5 molecule.
Based on our pioneering research, we believe that we are a leader in the discovery of viral entry inhibitors, a promising new class of HIV therapeutics. For the large number of patients who are failing conventional anti-retroviral or combination therapies, we believe viral entry inhibitors could become the next generation of HIV therapy.