Role of CXCR4 in HIV Infection and its Potential as a Therapeutic Target

Tsutomu Murakami; Naoki Yamamoto

Future Microbiol. 2010;5(7):1025-1039.

Abstract and Introduction

Abstract

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.

Introduction

Approximately 34 million people are currently living with HIV, and 2 million people died due to AIDS or AIDS-related diseases in 2008.^[201] 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.^[6] 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.^[7] 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.^[10] In addition, other anti-HIV-1 drug candidates have been explored as well, such as the maturation inhibitor bevirimat (PA-457).^[11]

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.^[12] 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.^[13] 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.

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Table 1. CXCR4 and CCR5 inhibitors tested in HIV and other applications
Compound	Company	Stage of development	Disease	Note
*CXCR4 inhibitors*
ALX40-4C	NPS Allelix	Terminated (Phase I/II)	HIV	No apparent effect was observed on viral load
AMD3100	AnorMED	Terminated (Phase I/II)	HIV	Little effect was observed on viral load
AMD3100 (plerixafor)	Genzyme	Approved by US FDA	Stem cell mobilizer	Use in combination with G-CSF
AMD070	Genzyme	Suspended (Phase I/II)	HIV	A derivative of AMD3100 that can be orally administered. Liver histology changes were observed in long-term preclinical toxicity experiments.
T140	Kyoto University	Preclinical	HIV, cancer metastasis, leukemia, rheumatoid arthritis	A downsized analog of T22 peptide that specifically inhibits CXCR4
KRH-3955	Kureha	Preclinical	HIV, cancer metastasis	A highly potent, orally bioavailable CXCR4 antagonist
*CCR5 inhibitors*
TAK-652 (TBR-652)	Takeda/Tobira	Phase II	HIV	A potent, orally bioavailable CCR5 antagonist
Aplaviroc	Ono	Terminated (Phase II/III)	HIV	Aplaviroc's development was stopped because of hepatotoxicity
Maraviroc	Pfizer	Approved by US FDA	HIV	The first FDA-approved CCR5 antagonist
PF-232798	Pfizer	Phase II	HIV	A second-generarion Pfizer oral CCR5 antagonist
Vicriviroc	Schering-Plough/Merck	Terminated (Phase III)	HIV	Vicriviroc did not meet the primary efficacy endpoint
INCB9471	Incyte	Phase II	HIV	A new class of oral CCR5 antagonist

G-CSF: Granulocyte colony-stimulating factor.

Sidebar

Executive Summary

Identification of chemokine receptors as coreceptors for HIV-1 entry

CXCR4 and CCR5 are the two major coreceptors for HIV-1 infection.
Coreceptors are responsible for a crucial step between Env binding to the receptor CD4 and membrane fusion mediated by the gp41 fusion peptide.

Determinants of HIV cell tropism & chemokine receptor usage

The V3 loop of HIV-1 gp120 is a primary determinant of cell tropism and chemokine receptor usage, whereas the V1/V2 region is involved in effective entry of the virus.

Impact of nonfunctional chemokine receptor alleles on HIV resistance & disease progression

Homozygotes and heterozygotes for CCR5 d32, which are prevalent in European populations, exhibit a strong resistance to HIV infection and delayed progression to AIDS, respectively.
A single-nucleotide polymorphism in CCR2b, one of the minor coreceptors for HIV, is associated with delayed progression to AIDS in either homozygote or heterozygote individuals.

Coreceptor-targeted anti-HIV therapy

inhibitors:
- The bicyclam AMD3100 is a well-known small molecule CXCR4 antagonist that strongly and specifically inhibits X4 HIV-1 infection. Tetrahydroquinoline-based AMD070 is a potent and specific X4 HIV-1 inhibitor with high oral bioavailability;
- T22, an 18-mer anti-X4 HIV peptide, was designed from self-defense peptides isolated from horseshoe crabs. T140, a downsized analog of T22, has stronger anti-HIV activity than T22;
- KRH-1636, which strongly and specifically inhibits X4 HIV-1 infection, is a novel small nonpeptide CXCR4 antagonist. KRH-3955, a derivative of KRH-1636, is much more potent than KRH-1636 and is orally bioavailable.
CCR5 inhibitors:
- Among the CCR5 inhibitors that have been developed, maraviroc is the only one that has been approved for use in treatment-experienced adult patients with R5 HIV-1 infection in combination with other antiretroviral drugs.

Resistance to coreceptor inhibitors

Generation of HIV-1 strains resistant to coreceptor inhibitors in vitro seems difficult and time-consuming compared with generation of strains resistant to antiretrovirals that target viral proteins such as reverse transcriptase.
Experiments using cells that expresses both CXCR4 and CCR5, such as human peripheral blood mononuclear cells, rarely result in the selection of drug-resistant viruses that change coreceptor usage.

Other applications of CXCR4 inhibitors

Anticancer:
- Many CXCR4 inhibitors have been shown to significantly reduce metastasis of various cancers such as ovarian carcinoma, melanoma, prostate cancer and breast cancer;
- The CXCR4 inhibitors KRH-1636 and KRH-3955 are highly potent in antagonizing SDF-1α-mediated chemotaxis of cancer cells.
Antiarthritis & allergy:
- CXCR4 inhibitors AMD3100 and T140 are effective in mitigating rheumatoid arthritis and/or pulmonary fibrosis in animal models for these diseases.
Hematopoietic stem cell mobilization:
- AMD3100 (now known clinically as plerixafor) induces the rapid and reversible mobilization of hematopoietic stem cells from bone marrow into the circulating blood in synergy with granulocyte colony-stimulating factor.

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