Study of the role of the CCL2/CCR2 axis in HIV-1 infection: molecular mechanisms and potential therapeutic approaches

The 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.