CCR5 antagonists in the treatment of HIV-infected persons: is their cancer risk increased, decreased, or unchanged

• Published in: The AIDS reader Vol. 19; no. 6; p. 218
• Main Authors: McNiff, Todd, Dezube, Bruce J
• Format: Journal Article
• Language: English
• Published: United States MultiMedia Healthcare Inc 01.06.2009
• Subjects: Anti-HIV Agents - adverse effects; CCR5 Receptor Antagonists; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; Humans; Neoplasms - chemically induced; Neoplasms - classification; Piperazines - adverse effects; Pyrimidines - adverse effects; Receptors, CCR5 - genetics; Treatment Outcome
• ISSN: 1053-0894

One of the best-understood chemokine receptors is CCR3. The CCR3 receptor is expressed primarily on eosinophils and appears to be responsible for their migration; blocking this receptor inhibits chemotaxis in vitro. Eotaxin, a ligand for the CCR3 receptor, seems to be overexpressed in patients with asthma, a disease characterized by eosinophilic hyperactivity.2 While the chemokine system regulates normal immune function and response to pathogens, it has also been exploited by various pathogens. The CCR5, CXCR4, and to a lesser extent the CCR3 receptors are utilized in conjunction with the CD4 cell surface receptor by HIV for entry into host T cells. While the exact function of CCR5 is somewhat less well understood, CCR5 seems to function in lymphocyte trafficking like other chemokine receptors. Natural killer (NK) cells and antigen-specific T cells when presented with foreign antigens secrete CCR5 ligands, such as RANTES, into the surrounding extracellular matrix. These ligands attract CCR5-positive cells, such as mature T cells, NK cells, and monocytes, to areas of infection and contribute to an immune and inflammatory response.3 RANTES, the primary ligand of CCR5, has been shown to be overexpressed in breast cancer/ and breast cancer cell lines have been shown to migrate toward RANTES.5 A study of CCR5 expression in a large sample of various subtypes of T-cell non-Hodgkin lymphomas (NHLs) shows the complex associations between the various lymphoma subtypes and expression of various chemokine receptors.6 Consistent expression of CCR5 was shown only in a small subset of NHLs, ie, anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma. In a detailed analysis of 141 patients with Tcell-associated NHLs, CXCR3 expression was typical of smaller T-cell lymphomas (eg, angioimmunoblastic lymphoma) and CCR4 expression was typical of other lymphoma types. CCR5 expression was not consistently seen in any lymphoma types. Another preclinical study of the CCR5 antagonist TAK-779 showed that TAK-779 blocked RANTES-induced cell invasion and proliferation of prostate cancer cells in cell culture.7 These studies of the prevalence of genetic mutations of CCR5 ligands in certain malignancies serve to further elucidate the potential role of CCR5 antagonism in cancer risk.913 Arguably, though they may not replicate completely the effects of blocking CCR5, because while it is tempting to assume that a mutated version of a CCR5 Iigand is unable to bind CCR5 and accordingly unable to elicit the effects of the wild-type ligand, it is possible that mutant ligands might bind receptors more avidly and may therefore either block or agonize CCR5. In the San Francisco study of pancreatic cancer, the investigators looked at RANTES mutations as well as the CCR5 delta32 mutation.12 The odds ratio of pancreatic cancer in patients with 1 mutant copy of the RANTES gene was shown to be 0.99; in patients homozygous for the RANTES mutation, the odds ratio was 0.82 - not a statistically significant difference. This article examines 3 sources of data regarding the cancer risk with the use of CCR5 antagonists in HIV-infected patients: basic science research concerning the role of CCR5 in cancer pathogenesis, epidemiological studies of cancer rates in patients with congenital lack of functional CCR5, and clinical data of cancer rates in CCR5 antagonist studies. Available preclinical evidence suggests that CCR5 is critical to the development and progression of certain tumors and that, at least theoretically, blocking CCR5 seems unlikely to increase cancer risk. Epidemiological data in non-HIV-infected persons do not show a significantly different rate of the delta-32 mutation in persons with several different malignancies compared with matched controls without malignancies. In fact, persons with HIV infection and the delta-32 mutation appear to have a decreased risk of NHL.