The CCL2/CCR2 Axis in the Pathogenesis of HIV-1 Infection: A New Cellular Target for Therapy?

Abstract

The identification of chemokine receptors as necessary co-receptors for HIV entry into target cells represented a breakthrough in the understanding of the pathogenesis of this viral infection. Since this initial discovery, it was unraveled that chemokines, in addition to their role in blocking viral entry by binding to co-receptors, have other functions in HIV pathogenesis. Indeed, chemokines can either inhibit or enhance HIV replication, and these effects may involve both entry and post-entry events of the viral life cycle. Depending on the balance of their negative versus positive effects on HIV replication and spreading, chemokines contribute to different outcomes of HIV pathogenesis. CCL2 is unique among the chemokines in that mostly enhancing effects on viral replication and pathogenesis have been reported. Either HIV infection itself or exposure to viral products can induce the expression of this chemokine and of its receptor CCR2, and high levels of CCL2/CCR2 are indeed found in HIV-infected subjects. The CCL2/CCR2 axis is tightly linked to the high level of immune activation and inflammation that is the hallmark of HIV infection even in patients undergoing antiretroviral therapy. In addition, more direct effects of CCL2 on HIV replication are becoming apparent. Thus, modulation of CCL2/CCR2-driven effects may have significant impact on HIV disease progression. In this review, we will discuss the complex interaction between CCL2/CCR2 and HIV and the emerging therapeutic approaches based on the inhibition of this axis.

Macrophages and Phospholipases at the Intersection between Inflammation and the Pathogenesis of HIV-1 Infection

“…Although this chemokine can be produced by many cell types, monocytes/macrophages are the major source of CCL2 [ 73 ]. Its expression is increased during monocyte to macrophage differentiation [ 74 ] as well as in the course of HIV-1 infection, as demonstrated by several in vitro and in vivo studies [ 75 ]. In particular, either infection itself or exposure to viral proteins can induce an increase of CCL2 production in monocyte-derived macrophages (MDMs) [ 76 , 77 ].…”

“…All together, these results uncovered a concerted gp120-mediated signaling involving PLCs as a required step for HIV-1-induced expression of CCL2 in macrophages. This chemokine not only represents a major inflammatory mediator contributing to a plethora of HIV-1-related morbidities, but also acts as a cellular factor exploited by the virus to enhance its own replication [ 75 , 76 , 80 ]. Thus, PL-mediated signal transduction pathways may be relevant for the modulation of viral replication, at least in macrophages, and, in general, for the pathogenesis of HIV-1 infection.…”

Reconnaissance of the candidate genes involved in the pathogenesis of human immunodeficiency virus and targeted by antiretroviral therapy

“…Chemokines are a large family of low‐molecular‐weight cytokines that incite employment and other parameters of leukocytes . The cell infection by HIV starts with binding to the host CD4 receptor.…”

“…Therefore, NK cells that produce CC‐chemokines of CCL3, CCL4, and CCL5 repress the HIV replication through preventing CCR5‐dependent entrance of HIV to target cells . CCL2 belongs to this family, which boosts the viral replication and pathogenesis, and its association with multiple sclerosis, rheumatoid arthritis, and nephropathies have been disclosed . The infection by HIV can cause the upregulation of CCL2 and its receptors.…”

Genetic factors influencing HIV entry into target cells

“…Белок MCP-1 является лигандом рецептора CCR2. CCL2 участвует в ряде физиологических и патологических процессов, в том числе в патогенезе ВИЧ-инфекции (СПИДа) [56,57].…”