1,720,965 research outputs found
The CCL2/CCR2 axis in the pathogenesis of HIV-1 infection: a new cellular target for therapy?
No full textThe 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
Study of the role of the CCL2/CCR2 axis in HIV-1 infection: molecular mechanisms and potential therapeutic approaches
Full text linkThe chemokine CCL2 plays a key role in chronic inflammation and tissue damage in HIV-1 infected patients. We recently demonstrated that CCL2 neutralization by specific antibodies strongly reduces HIV-1 replication in primary macrophages by inhibiting viral DNA accumulation.
In this study, we performed a global gene expression analysis by RNAseq to identify cellular factors modulated by CCL2 blocking and potentially involved in the regulation of HIV-1 replication. Our results show that 1915 and 311 genes are differentially expressed following 4 and 20 hours of treatment with anti-CCL2 antibodies, respectively. Upregulated genes include restriction factors (APOBEC3A), component of the interferon signaling, cytokines/chemokines, genes involved in vitamin D response . Downregulated genes comprise CXCR4 and some TLR family members.
Furthermore, we investigated the effect of CCL2/CCR2 blocking in vivo on APOBEC3A expression in HIV-1 infected patients treated with, Cenicriviroc, a novel CCR5/CCR2 antagonist,. The longitudinal analysis performed on samples derived from the same patient prior to treatment initiation and after 4,12,24, 48 weeks suggest an increase of APOBEC3A expression following treatment with Cenicriviroc from baseline compared to control patients treated with conventional therapy.
Overall, these data suggest that the CCL2/CCR2 axis may represent a new therapeutic target to strengthen host innate immunity thus limiting HIV-1 infection
Genome-wide analyis of the effect of CCL2 neutralization in primary human macrophages reveals modulation of host genes associated with HIV-1 infection
No full textEndogenous CCL2 is a Negative Regulator of APOBEC3A Expression in Macrophages: Role in HIV-1 Infection
No full textEndogenous CCL2 enhances HIV-1 replication in primary macrophages by suppressing APOBEC3A expression
No full textTargeting CCL2 inhibits viral DNA accumulation and induces APOBEC3A expression in HIV-infected primary human macrophages
No full textAPOBEC3A induction by CCL2 blocking in primary macrophages: molecular insight into a new potential anti-HIV therapeutic strategy
No full textSAMHD1-independent inhibition of HIV-1 DNA accumulation by endogenous CCL2 neutralization: possible role of APOBEC3A
No full textMacrophages are key targets of HIV-1 infection. We have previously described that the expression of CC chemokine ligand 2 (CCL2) increases during monocyte differentiation to macrophages and it is further up-modulated by HIV-1 exposure. Furthermore, CCL2 acts as an autocrine factor that promotes viral replication in infected macrophages. In this study, we dissected the molecular mechanisms by which CCL2 neutralization inhibits HIV-1 replication in monocyte-derived macrophages (MDM), and the potential involvement of the innate restriction factors protein sterile alpha motif (SAM) histidine/aspartic acid (HD) domain containing 1 (SAMHD1) and apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) family members. We found that CCL2 neutralization potently reduced viral DNA accumulation and the number of p24 Gag+ cells during the course of either a productive or a single cycle infection with HIV-1BaL or (VSV-G) HIV-1, respectively. In contrast, CCL2 blocking did not modify entry of HIV-1 based Virus Like Particles, thus demonstrating that the restriction involves post-entry steps of the viral life cycle. Looking for correlates of HIV-1 DNA accumulation inhibition, we found that SAMHD1 expression was not affected by CCL2 neutralization. Furthermore, CCL2 blocking reduced the percentage of p24 Gag+ cells both in the absence and in the presence of exogenous dNTPs, and restricted the transduction of macrophages with Vpx+ lentiviral particles, which determined a strong down-modulation of SAMHD1 expression. These results demonstrated that altered SAMHD1 expression or function cannot account for the CCL2 neutralization-mediated restriction of HIV-1 replication in macrophages. Conversely, a strong and selective induction of APOBEC3A transcript and protein expression was associated with the inhibition of HIV-1 replication mediated by CCL2 neutralization. Interestingly, the level of CCL2 blocking induced APOBEC3A expression was comparable to those of freshly isolated monocytes. Finally, induction of A3A was type I IFN independent, since neutralizing Abs to IFN-α or IFN-β did not abolish CCL2 blocking-mediated A3A expression. Overall, these data demonstrate that neutralization of endogenous CCL2 determines a profound restriction of HIV-1 replication in primary MDM affecting post-entry steps of the viral life cycle likely involving the up-regulated expression of APOBEC3A. These results highlight a novel mechanism which may contribute to regulate the expression of innate intracellular viral antagonists in vivo. Thus, our study may potentially lead to the development of new therapeutic strategies for enhancing innate cellular defenses against HIV-1 and protecting macrophages from infection
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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