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In light of the very strong possibility of HIV-1 growing resistant to
current drug treatments, the implications of our subject becomes clear: If a
treatment can be developed in which a patient's lymphocytes become resistant to HIV-1
infection, we will have a means of keeping most HIV infections at bay.
Potential Treatments for the M-tropic VirusWhen researchers discovered that the CCR5 protein was indeed the second receptor for HIV-1 and that a mutation in the CCR5 protein provided resistance to HIV-1 infection, many investigators began to consider the possibilities of preventing HIV-1 and CCR5 from interacting. Most efforts are focused on searching for methods of blocking CCR5. Fortunately, blocking CCR5 is not dangerous. People with the homozygous CCR5 mutation have no obvious immune dysfunction, and are generally quite healthy. Evidently, other chemokine receptors counteract the deletion. Among the therapies introduced is the delivery of natural or synthetic molecules that are capable of blocking CCR5. Such molecules include chemokines or synthetic derivatives of chemokines. Recently, an international research team developed a modified chemical derivative of RANTES (a common chemokine that binds to CCR5) that looks very promising in test-tube studies. Synthetic antibodies can also function as molecular "plugs" by specifically homing in on CCR5 and preventing HIV-1 from attaching. Additionally, researchers could theoretically use genetic engineering to provide macrophages with new genes which might prevent CCR5 from serving as a docking site for HIV-1. Alternatively, they could use genetic therapy to prevent CCR5 from being made at all. For those in the final stages of AIDS, some doctors are considering chemotherapy in an attempt to destroy all infected cells. They would then replace the patient's bone marrow with that of donors who are homozygous for the CCR5 deletion. Potential Treatments for the T-tropic VirusIn addition to methods designed to inhibit the expression of CCR5 and thus preventing the M-tropic virus from gaining a foothold, similar methods have been developed to inhibit the expression of CXCR4. CXCR4 is a T-cell chemokine receptor which facilitates fusion with HIV-1 during the T-tropic phase of HIV infection. An October 1997 article in the journal Nature Medicine reviews a study of the effects of capturing CXCR4 in the endoplasmic reticulum and preventing its expression on the cell surface. In these studies, T-cells were genetically altered (in culture) so that a chemokine called stromal derived factor (SDF) was produced. In these T-cells SDF was altered and retained in the endoplasmic reticulum . Because SDF binds to CXCR4, CXCR4 was then absorbed into the endoplasmic reticulum. With no CXCR4 expressed on the surface, the genetically altered T-cells became resistant to HIV-1 infection. However, HIV-1's high mutation rate excludes these strategies from being final solutions to HIV infection. But they are possible future treatments in the face of decreasingly effective drug therapies. More information on Treatments
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