In 2014, there were approximately 36.9 million of people living with HIV‐1 (UNAIDS, WHO). Of those only 15 million people had access to antiretroviral therapy. However, despite the successful reduction of the development of HIV/AIDS in patients receiving therapy, this population is at a higher risk to develop non‐AIDS related diseases, which are often associated with inflammatory process. It is known that HIV‐1 gp120 proteins can cause increased cytokines release that generates sustained immune activation in macrophages, which are the principal target for HIV‐1 derived R5‐ tropism strains. In our laboratory, we recently demonstrate that in human macrophages, gp120 (X4‐ derived strains) protein induces the up‐regulation of the α7 nicotinic acetylcholine receptor (α7‐nAChR), a key regulator of systemic inflammation that inhibits the production of pro‐inflammatory cytokines. Moreover, recent findings suggest that inflammation processes in HIV positive patients are characterized by high levels of α7‐nAChR in macrophages, up regulation that resulted in cholinergic anti‐inflammatory pathway (CAP) disruption. Our project therefore, examines the functional relationship between the findings with the principal objective of determining whether HIV‐1 gp120JRFL (R5‐strain) pre‐incubation, that up‐regulate α7‐nAChR in macrophages, may also affects the CAP and the mechanism that mediates this up‐regulation.We previously demonstrated that gp120IIIB disrupt this signal transduction pathway through α7 nAChRs up‐regulation however the mechanism has not been reported. Here we show that M‐tropic gp120JRFL, induces a higher level of α7 nAChRs protein in human derived macrophages leading to CAP response disruption by a previous unknown mechanism. Our results demonstrated that HIV gp120 /CD4‐CCR5 receptor complex promotes α7 nAChRs up‐regulation via a mechanism that is associated with the activation of p38‐MAPK signaling that has been shown to up‐regulates early gene (Egr1), a transcription factor known to drive the expression of α7 nAChRs. Using α7 antagonist, bupropion attenuation of pro‐inflammatory cytokines production was prevented. In contrast, treatment with Maraviroc (CCR5, receptor antagonist), results in a reduction of IL‐8 and I‐309 pro‐inflammatory cytokines levels in up‐regulated MDMs but did not affect CAP functioning in terms of ILs. Taking together, these findings suggest that HIV‐1 glycoproteins can conferred different macrophages phenotypes, in terms of the α7 nAChRs up‐regulation mediated by gp120JRFL, normal functioning of the cholinergic anti‐inflammatory response control the excessive immune responses. Hence, our data demonstrate the possible molecular mechanism that may be responsible for α7 nAChRs up‐regulation that failed in inhibiting the release of pro‐inflammatory cytokines.Support or Funding InformationNHI Grant Number 2R25GM061151‐16