The January Community Forum focused on the next generation of treatments for HIV. Dr. John Moore of the Weill Medical College of Cornell University presented information on fusion inhibitors, drugs that work by preventing HIV from entering T-cells. Dr. Mark Muesing focused on integrase inhibitors, drugs that work by blocking the reproduction of HIV once it is inside the T-cell. These treatments are still in early stages of development, but will likely be the next options for HIV treatment.
Our current treatments, nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs) and protease inhibitors (PIs), target two enzymes that HIV uses to reproduce itself inside a T-cell. By prohibiting these enzymes from working properly, these medications block the reproduction of HIV. Unfortunately, HIV can mutate, which may confer resistance to the medications.
Researchers working on new treatments have located new targets. Two of the targets are proteins on the surface of the HIV virus. These proteins are called gp41 and gp120, and these proteins allow HIV to attach itself to a T-cell and begin the process of inserting itself into the cell. gp41 connects to one of two receptors on the T-cell surface -- either CCR5 or CXCR4. CCR5 and CXCR4 normally serve as chemokine receptors. Chemokines are chemicals that signal T-cells to move to the site of an infection, causing inflammation. HIV takes over these receptors for its own purpose of infecting the T-cell. gp120 connects to the CD4 receptor on the T-cell. When both of these proteins on the virus are connected, gp41 pierces the T-cell membrane and HIV fuses with the T-cell.
Several drugs that bind to gp41 and block its action are in clinical trials. Furthest along is T-20, also called pentafuside, which was discovered at Duke University laboratories and is being developed by Triangle Pharmaceuticals in North Carolina. T-20 has shown antiviral activity in patients who are highly resistant to current treatments. Dr. Moore stated that the main disadvantage to T-20 is that is must be injected subcutaneously (under the skin). T-20 would not enter the bloodstream if it were taken orally -- it would be digested in the stomach because it is a protein. T-1249, also being developed by Triangle, uses the same mechanism of action but has a more complex structure, which may be beneficial in decreasing resistance to the compound. Another gp41 inhibitor called the 5-Helix that is not in clinical trials yet may also be an effective fusion inhibitor.
A compound called PRO 542 that binds gp120 to prevent fusion is in preclinical development. This compound contains fragments of the CD4 protein so that the virus will bind PRO 542 instead of the CD4 receptor on the T-cell.
Another way to prevent fusion is to block the CCR5 and CXCR4 receptors. Dr. Moore explained that there are two types of HIV that can infect T-cells, known as the M-tropic viruses and the T-tropic viruses, and that they cause disease progression at different rates because of their effect on T-cells. HIV-infected T-cells can form syncytium, altered T-cells that fuse together and die rapidly. The M-tropic viruses (which cause 90% of sexually acquired HIV infections) are non-syncytium inducing (NSI), leading to slower disease progression. T-tropic viruses, on the other hand, are syncytium inducing, and therefore cause more rapid disease progression. People who are infected with M-tropic virus eventually have a mutation to T-tropic strains, which causes disease progression. Interestingly, T-tropic strains use the CXCR4 receptor to infect T-cells while M-tropic strains use CCR5 to infect cells. Some people have a genetic mutation and have no CCR5 receptors. This mutation may make them resistant to HIV infection, although this is by no means a guarantee against infection -- safer behavioral practices are still the best prevention method.
Several agents targeting CCR5 and CXCR4 are in early development. Dr. Moore mentioned PRO 140, an antibody that binds to CCR5, as one example of a CCR5 inhibitor. Another early candidate is TAK 779, a non-protein CCR5 antagonist. AMD 3100 is being developed as a CXCR4 inhibitor, and has been tested in small Phase I clinical trials.
The second topic of the evening was the role of the integrase enzyme in HIV reproduction within the T-cell. Dr. Muesing explained that integrase action results in the irreversible incorporation of an "instruction list" on how to make HIV into the T-cell chromosomal DNA. This is how a retrovirus like HIV uses its host to make copies of itself before destroying the host cell. Integrase is of great interest because it is the last enzyme target in HIV for drug development -- treatments that block the action of protease and reverse transcriptase are currently available.
Integrase works within the nucleus of the T-cell. Its structure and mechanism of action are not well understood. Scientists know that integrase has three domains, and that it cleaves the viral DNA to activate the ends, allowing the viral DNA to be incorporated into the host cell DNA. Dr. Muesing is interested in the tests used to detect compounds that inhibit integrase functions. He hopes to see compounds in development soon.
As more people develop resistance to PIs and NRTIs/NNRTIs, treatments from different classes will become indispensable tools. We will certainly hear more about fusion and integrase inhibitors as their development continues.