Theranostics 2013; 3(1):18-25. doi:10.7150/thno.5392


The Puzzling Role of CXCR4 in Human Immunodeficiency Virus Infection

Elisa Vicenzi1, Pietro Liò2, Guido Poli3,4 ✉

1. Viral Pathogenes and Biosafety, San Raffaele Scientific Institute, Milano, Italy;
2. Computer Laboratory, University of Cambridge, Cambridge, United Kingdom;
3. AIDS Immunopathogenesis Units, San Raffaele Scientific Institute, Milano, Italy;
4. Vita-Salute San Raffaele University, School of Medicine, Milano, Italy.

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Vicenzi E, Liò P, Poli G. The Puzzling Role of CXCR4 in Human Immunodeficiency Virus Infection. Theranostics 2013; 3(1):18-25. doi:10.7150/thno.5392. Available from

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The human immunodeficiency virus type-1 (HIV-1) is the etiological agent of the acquired immunodeficiency syndrome (AIDS), a disease highly lethal in the absence of combination antiretroviral therapy. HIV infects CD4+ cells of the immune system (T cells, monocyte-macrophages and dendritic cells) via interaction with a universal primary receptor, the CD4 molecule, followed by a mandatory interaction with a second receptor (co-receptor) belonging to the chemokine receptor family. Apart from some rare cases, two chemokine receptors have been evolutionarily selected to accomplish this need for HIV-1: CCR5 and CXCR4. Yet, usage of these two receptors appears to be neither casual nor simply explained by their levels of cell surface expression. While CCR5 use is the universal rule at the start of every infection regardless of the transmission route (blood-related, sexual or mother to child), CXCR4 utilization emerges later in disease coinciding with the immunological deficient phase of infection. Moreover, in most instances CXCR4 use as viral entry co-receptor is associated with maintenance of CCR5 use. Since antiviral agents preventing CCR5 utilization by the virus are already in use, while others targeting either CCR5 or CXCR4 (or both) are under investigation, understanding the biological correlates of this “asymmetrical” utilization of HIV entry co-receptors bears relevance for the clinical choice of which therapeutics should be administered to infected individuals. We will here summarize the basic knowledge and the hypotheses underlying the puzzling and yet unequivocal role of CXCR4 in HIV-1 infection.

Keywords: HIV, chemokine receptor, CCR5, CXCR4, CD4, integrin, AMD3100.