Thursday, July 4, 2013

The CCR5 Receptor and HIV/AIDS

The recently reported news that an AIDS patient has been successfully cured of his disease is a very exciting development in regards to global public health.  The methodology used to affect this outcome is directly related to the manner in which the human immunodeficiency virus (HIV) gains entry into its host cell.  HIV enters and ultimately kills the so-called,” T-Helper” cell that plays a critical role in adaptive human immunity.  Once a significant portion of these cells are destroyed, the patient displays the classic symptoms of AIDS – the inability to successfully fight off infections by invading micro-organisms.

In order to successfully invade its target cell, HIV must bind to specific proteins found on the surface of T-Helper cells.  One of these cell surface proteins is referred to CCR5 (CD195) – a member of the chemokine receptor family – and the protein product of the CCR-5 gene.  Chemokines are factors that are used to attract T cells to particular tissue or organ targets when battling infection.  If this protein is absent or the product of a mutated gene, HIV will fail to bind and therefore be unable to infect the target cell.  It is important to remember that viruses have an absolute requirement for access into a living cell in order to produce an infection; for, they need to exploit the intracellular processes of a living cell in order to make copies of themselves.  The molecular biology of HIV has been studied extensively and, as a consequence, this mechanism of action is well understood.

In addition, there is a percentage of the human population that is innately resistant to HIV infection even upon exposure to the virus.  This apparent insensitivity to HIV infection is readily explained by the fact that these individuals possess defective variants of the CCR-5 gene.
Thanks to the ingenuity and inventiveness of Drs. Gero Hutter, Eckard Thiel and colleagues from the Charite Hospital in Berlin Germany, an approach to a potential cure of AIDS was recognized that involves the widely used procedure of bone marrow transplantation – the first successful human bone marrow transplantation was accomplished in 1975 in Seattle pioneered by Dr. Donnall Thomas who won a Nobel Prize in Medicine for his efforts.
In this particular case, the patient presented with acute myelogenous leukemia (AML) as well as AIDS.  The protocol that was developed involved the destruction of the AIDS patient’s immune system followed by recovery using bone marrow from a suitable donor who was also immune to HIV infection on account of a defect in the CCR-5 gene as described above.  As a result of this approach, the patient became asymptomatic and free of HIV.  This is possible because all the immuno-competent cells in the human immune system repertoire are derived from progenitors found in the bone marrow and once the patient’s own immune cells were successfully replaced by the donor’s, then he became HIV resistant.

Since bone marrow transplantation has inherent risks, it is not the recommended approach for AIDS patients; unless, they also suffer from leukemia.  However, there is considerable hope in developing methodologies to use gene modification techniques to modify an AIDS patient’s own immune cells so that they would exhibit the CCR-5 gene variant and render them HIV resistant.

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