AMD is equally active against a broad
AMD3100 is equally active against a broad range of HIV-1 and HIV-2 strains, but not against simian immunodeficiency virus (SIV) strains in human PBMC (De Clercq et al., 1994). At this moment it is not clear what coreceptor SIV is using in human PBMC, but it does not seem to be CXCR-4 (Feng et al., 1996). There are some unpublished data mentioning that SIV is using CCR-5 as the coreceptor to enter the target FSLLRY-NH2 mg (Trkola et al., 1996, Wu et al., 1996). This may explain why the bicyclams are not active against SIV in human PBMC.
SDF-1 has been shown to inhibit T-tropic (not M-tropic) viruses and primary HIV isolates (Feng et al., 1996, Wu et al., 1996). Also CXCR-4 is used by HIV-2 to enter the cells (Endres et al., 1996). The 12G5 mAb was found to inhibit HIV-1 and HIV-2 infection at 1–20 μg/ml, although the ability of this mAb to block infection of T-tropic isolates of HIV-1 is highly dependent on the viral isolate and the target cell (McKnight et al., 1997). This suggests that other cofactors may be involved or that some viruses may use a different epitope on CXCR-4 that is not blocked by the 12G5 mAb.
Some individuals repeatedly exposed to HIV infection have remained uninfected and found to be homozygous for a 32-base-pair deletion in the CCR-5 receptor (Dean et al., 1996, Liu et al., 1996, Samson et al., 1996). Perhaps also mutations in CXCR-4 and other coreceptors may be identified in individuals that are less susceptible to HIV infection and/or in individuals that have been infected but also do not proceed to AIDS, the so called long-term non-progressors (Schuitemaker et al., 1994), where there is a predominance of M-tropic viruses. AMD3100, because of its strong interaction with fusin, may become an important antiviral drug in vivo, because of its potential to block the transition of M-tropic to T-tropic viruses, which always precedes the decline in CD4+ T-cells and the development of AIDS.
Introduction Autism is a neurodevelopmental disorder, and in which its main diagnostic symptoms are unfamiliar common social interactions, with intense deficiencies in social cognition in several cases (Chevallier et al., 2012, Constantino, 2011). Improper understanding of social signs and unsuitable reactions in social settings, which are intellectualized as a reduced theory of mind, mentalization, or mind blindness are features of the diagnostic symptoms of autism (Frith and Frith, 2012, Lombardo and Baron-Cohen, 2011). Current epidemiologic studies have indicated that autism is diagnosed in approximately 1% of children (Kogan et al., 2009). However, little is known about the etiology and underlying neuropathology of autism, and there are no clear biological markers for this and other related disorders. Evidence of immune dysfunction has been observed in numerous individuals with autism, with a marked activation of microglia, increased levels of proinflammatory cytokines in the brain tissue, plasma, and peripheral blood mononuclear cell (PBMC) cultures (Ashwood et al., 2008, Enstrom et al., 2010). Chemokines are classified based on the position of the conserved cysteine residues as C, CC, CXC, and CX3C subfamilies. The CC and CXC chemokines are implicated as mediators of both central nervous system (CNS) and inflammatory development (Babcock and Owens, 2003, Bajetto et al., 2002). They are potential central therapeutic targets in numerous inflammatory and autoimmune disorders because of their critical role in cell recruitment and activation during inflammation. Chemokine receptors are highly expressed on naive T cells, which play a very important role in the recirculation of lymphocytes during the development of immune responses (Unsoeld et al., 2004). They have been shown to act as functional mediators of neuroinflammatory disorders (Karpus et al., 2003). Furthermore, high levels of chemokine receptors have been found in neurons of the hippocampus and other brain regions (Van der Meer et al., 2000). A previous study showed that chemokine receptors were implicated in neuroinflammation, neural damage, and astrocyte proliferation (Louboutin et al., 2011). A possible role for chemokine receptors has been suggested in numerous behavioral impairments in individuals diagnosed with autism (Ashwood et al., 2011). The levels of chemokine receptors in autism were found to be higher in the astrocytes of the anterior cingulate gyrus, which was also noted in the cerebellum and brain tissue (Vargas et al., 2005). The expression of the mRNA transcripts of chemokine receptors was elevated in the temporal cortex of individuals with autism (Garbett et al., 2008). The migration of activated T cells into the CNS is regulated by chemokine receptors and mediated by adhesion molecules (Engelhardt and Ransohoff, 2012, Holman et al., 2011). Furthermore, the constitutive expression of chemokine receptors in the choroid plexus is proposed to act as a gateway for T cells to penetrate the uninflamed CNS (Axtell and Steinman, 2009).