Abstract
The CC chemokine receptor 5 (CCR5) is responsible for immune and inflammatory responses by mediation of chemotactic activity in leukocytes, although it is expressed on different cell types. It has been shown to act as co-receptor for the human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV). Natural reactive antibodies (Abs) recognizing first loop (ECL1) of CCR5 have been detected in several pools of immunoglobulins from healthy donors and from several cohorts of either HIV-exposed but uninfected subjects (ESN) or HIV-infected individuals who control disease progression (LTNP) as well. The reason of development of anti-CCR5 Abs in the absence of autoimmune disease is still unknown; however, the presence of these Abs specific for CCR5 or for other immune receptors and mediators probably is related to homeostasis maintenance. The majority of anti-CCR5 Abs is directed to HIV binding site (N-terminus and ECL2) of the receptor. Conversely, it is well known that ECL1 of CCR5 does not bind HIV; thus, the anti-CCR5 Abs directed to ECL1 elicit a long-lasting internalization of CCR5 but not interfere with HIV binding directly; these Abs block HIV infection in either epithelial cells or CD4+ T lymphocytes and the mechanism differs from those ones described for all other CCR5-specific ligands. The Ab-mediated CCR5 internalization allows the formation of a stable signalosome by interaction of CCR5, β-arrestin2 and ERK1 proteins. The signalosome degradation and the subsequent de novo proteins synthesis determine the CCR5 reappearance on the cell membrane with a very long-lasting kinetics (8 days). The use of monoclonal Abs to CCR5 with particular characteristics and mode of action may represent a novel mode to fight viral infection in either vaccinal or therapeutic strategies.
Highlights
The CC chemokine receptor 5 (CCR5) belongs to G protein-coupled receptors (GPCRs), which represent the largest known superfamily of signal transducers and play functional roles in the response to exposure to light and odor as well as in cellular response to different types of signaling molecules [1]
CCR5 has been implicated in hematopoiesis and it has been demonstrated that it act as co-receptor for the human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV) either independently of, or together with, the receptor CD4 [9,10,11,12]
A total of 325 healthy controls have even analyzed as well but none resulted positive for anti-CCR5 Abs, suggesting that these Abs could be elicited by low levels of viral antigenic stimulation; that could explain why these Abs have been found in exposed but uninfected subjects (ESN) and LTNP people but not in subjects who were not exposed to HIV or progressed and developed AIDS
Summary
The CC chemokine receptor 5 (CCR5) belongs to G protein-coupled receptors (GPCRs), which represent the largest known superfamily of signal transducers and play functional roles in the response to exposure to light and odor as well as in cellular response to different types of signaling molecules [1]. A total of 325 healthy controls have even analyzed as well but none resulted positive for anti-CCR5 Abs, suggesting that these Abs could be elicited by low levels of viral antigenic stimulation; that could explain why these Abs have been found in ESN and LTNP people but not in subjects who were not exposed to HIV or progressed and developed AIDS. Another hypothesis could be that anti-CCR5 Abs are elicited during other antigenic stimulations (different from HIV), which induce alterations of self-repertoire, eliciting anti-self responses. Both these findings provide an argument against the possible use of a target therapy with CCR5-specific Abs
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