Abstract and Introduction
The chemokine receptors CCR5 and CXCR4 are the two major coreceptors for HIV entry. Numerous efforts have been made to develop a new class of anti-HIV agents that target these coreceptors as an additional or alternative therapy to standard HAART. Among the CCR5 inhibitors developed so far, maraviroc is the first drug that has been approved by the US FDA for treating patients with R5 HIV-1. Although many CXCR4 inhibitors, some of which are highly active and orally bioavailable, have also been studied, they are still at preclinical stages or have been suspended during development. Importantly, the interaction between CXCR4 and its ligand SDF-1 is involved in various disease conditions, such as cancer cell metastasis, leukemia cell proliferation, rheumatoid arthritis and pulmonary fibrosis. Therefore, CXCR4 inhibitors have potential as novel therapeutics for the treatment of these diseases as well as HIV infection.
Approximately 34 million people are currently living with HIV, and 2 million people died due to AIDS or AIDS-related diseases in 2008. After the introduction of HAART in 1996, which combines HIV-1 reverse transcriptase and protease inhibitors, the morbidity and mortality associated with HIV-1 infection decreased dramatically[1,2] due to sustained reductions in HIV-1 plasma levels and significant increases in the number of CD4+ T cells.[3–5] However, there are still several remaining problems associated with HAART that need to be overcome, such as the emergence of drug-resistant mutants and drug-related side effects. One approach to overcome these issues is to develop new reverse transcriptase or protease inhibitors that are effective against known drug-resistant mutations. Indeed, a new protease inhibitor, darunavir (TMC114), has been approved by the US FDA for the treatment of HIV/AIDS patients harboring multidrug-resistant HIV-1 variants that do not respond to existing HAART regimens. In addition, etravirine (TMC125), a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), has been recently approved by the FDA for the treatment of HIV infection in adults when other antiretroviral drugs have failed. Multiple mutations are required for HIV-1 to become resistant to etravirine in comparison to first-generation NNRTIs. An alternative approach is to discover new anti-HIV drugs that are directed against a novel target and have a unique mechanism of action. In 2003, the FDA approved enfuvirtide, previously known as T-20, which targets HIV-1 gp41. Enfuvirtide is classified as a fusion inhibitor, which blocks fusion between the HIV-1 envelope and the target cell membrane. Although the drug must be administered parenterally, it is also effective against a multidrug-resistant HIV-1 strain.[8,9] In addition, the FDA approved the integrase inhibitor raltegravir in 2007 for use in highly treatment-experienced patients. In addition, other anti-HIV-1 drug candidates have been explored as well, such as the maturation inhibitor bevirimat (PA-457).
After the chemokine receptors CCR5 and CXCR4 were found to be the major HIV-1 coreceptors together with the primary receptor CD4, numerous efforts were made to test whether chemokines, chemokine derivatives, or small-molecule inhibitors against chemokine receptors had the potential to be a new class of anti-HIV-1 agent. In particular, many receptor antagonists against CCR5 have been developed as anti-HIV-1 drugs. Among them, maraviroc was approved by the FDA in 2007 for the treatment of R5 HIV-1 in treatment-experienced adult patients and is used in combination with other antiretroviral treatments. Several classes of CXCR4 antagonists have also been developed, although all have yet to reach clinical testing. However, other clinical applications for CXCR4 inhibitors in addition to anti-HIV therapy have been considered, as the interaction between CXCR4 and its ligand SDF-1 is also involved in several other diseases, such as cancer metastasis, rheumatoid arthritis (RA) and pulmonary fibrosis. In addition, recent research on bicyclam AMD3100, a well-known CXCR4 antagonist, has revealed that it specifically increases CD34+ hematopoietic stem cell numbers in peripheral blood. A Phase III trial for AMD3100 as a stem cell mobilizer has been successfully completed. In this review, we will highlight the role of CXCR4 in HIV infection and introduce the history and present status of various CXCR4 inhibitors. In addition, we will also describe the potential of CXCR4 as a therapeutic target in diseases other than HIV infection.
Future Microbiol. 2010;5(7):1025-1039. © 2010 Future Medicine Ltd.
Cite this: Role of CXCR4 in HIV Infection and its Potential as a Therapeutic Target - Medscape - Jul 01, 2010.