Interestingly, when a long-term intranasal immunization was performed, it has elicited specific IgA and IgG in both mucosal secretions and sera of the immunized mice. CCR5 or Targocil 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, Targocil -arrestin2 and ERK1 proteins. The signalosome degradation and the subsequent 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. Keywords: CC chemokine receptor 5, anti-CC chemokine receptor 5 antibodies, CC chemokine receptor 5 signalosome, HIV infection, HIV protection, CC chemokine receptor 5-based vaccine, CC chemokine receptor 5-based therapy Introduction 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). They consist approximately 4% of coded human genome (2) and represent one of the most important and largest groups of targets for therapeutics (3). Among them, the chemokine receptors are responsible for immune and inflammatory responses by mediation of chemotactic activity in leukocytes, even though they are expressed on a wide range of cell types, such as T and B cells, monocytesCmacrophages, granulocytes, NK, DC, astrocytes, and neurons, and Targocil also on epithelium, endothelium, vascular smooth muscle, and fibroblasts (4C8). CCR5 has also 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 Targocil (9C12). In particular, binding of viral gp120 of HIV-1 to CD4 triggers a conformational change in gp120 itself, which permits its binding to CCR5 and finally the viral entry into the cells (13, 14). CCR5 is undoubtedly the main HIV-1 and HIV-2 co-receptor, involved in virus entry and cell-to-cell spread (15); interestingly, these R5-tropic viruses (CCR5 dependent strains) are associated with the initial infection (16), while HIV strains using the CXCR4 co-receptor are detected rarely in the early infection (11, 15, 17). It Targocil is well known that chemokine receptor agonists, such as the -chemokines RANTES (CCL5), MIP-1 (CCL3), and Itgb8 MIP-1 (CCL4), inhibit HIV infection of susceptible cells (18C21). Interestingly, the number of CCR5 molecules expressed on cell surface is correlated with the levels of viral infection (13) and it has been described a variation of the level of CCR5 molecules among individuals (15), which is due to both environmental and genetic aspects. Indeed, it has been shown that high levels of CCR5, in some developing countries such as Africa, is environmentally driven and it has been hypothesized that it is due to parasitic infections (22). Whereas a CCR5-negative phenotype has been described in either some subjects, which are resistant to HIV infection (exposed to HIV but seronegative subjects, so called ESN) or in Caucasians and in other ethnic groups worldwide; the reduced or absent expression of CCR5 in these populations has been attributed to a genetic mutation, named 32, a deletion of 32 base-pair in CCR5 gene that produces a truncated form of the receptor, which is not expressed on the cell membrane (23). Several clinical studies underlined that homozygous mutation affecting the expression of CCR5 confers a total resistance against HIV infection (24C28); whereas heterozygotes for CCR532 are not associated with complete HIV protection (15) but progress slowly in the infection, most likely due to the reduction of CCR5 levels on the cell surface (29). CCR532 is spontaneous in 4C18% of Askenazi Jews and European people but it has not been found in Pacific and Asian indigenes (21, 24, 25, 28); this mutation occurs mostly like a heterozygous defect on CCR5 gene (10C20%), with the highest frequencies in Nordic European countries, and only less than 1% is a homozygous mutation, as reported in several study population (24, 25, 30C33). In addition, it has been shown that the frequency of CCR532 genotype is higher also among ESN and HIV-infected individuals who control disease progression without.