Deciphering the mechanisms of HIV-1 exacerbation induced by Mycobacterium tuberculosis in monocytes/macrophages

SHANTI SOURIANT; DENISE KVIATCOVSKY; ISABELLE VERGNE; SANDRA INWENTARZ; OLIVIER NEYROLLES; CHRISTEL VÉROLLET; KARINE PINGRIS; AICHA BAH; PABLO GONZÁLEZ-MONTANER; MARIA DEL CARMEN SASIAIN; GEANNCARLO LUGO-VILLARINO ; LUCIANA BALBOA; BRIGITTE RAYNAUD-MESSINA; MARCELO KURODA; EDUARDO JOSE MORAÑA; ISABELLE MARIDONNEAU-PARINI

Roma

Workshop; "HIV Workshop XIII"; 2016

The Acquired ImmunoDeficiency Syndrome (AIDS) is the deadliest disease due to a single infectious agent, namely the Human Immunodeficiency Virus (HIV-1). Worsening this public health issue is the fact that HIV-1 is frequently associated with Mycobacterium tuberculosis (Mtb), the etiological agent for tuberculosis (TB). The well-known synergy between the two pathogens places an immense burden in the healthcare systems, particularly in resource-limited countries where co-infection with these pathogens are highly prevalent. Therefore, the development of new therapeutic strategies requires a better understanding of the synergistic relationship between Mtb and HIV‑1. Both pathogens are able to impair the host immune response and share monocytes/macrophages as common host target cells. Our work aims at deciphering the mechanisms by which Mtb exacerbates HIV-1 infection in monocytes/macrophages.Here, we demonstrate that treatment of human primary monocytes with pleural effusions from TB patients (PE-TB) exacerbates HIV-1 infection (i.e. number of infected cells, virus entry and replication, and formation of multinucleated giant cells), in comparison to treatment with PE obtained from patients with other pulmonary infections (PE‑nonTB). This increased HIV-1 infection is associated with a deregulator (M2c) activation program of monocytes/macrophages, characterized by the CD16+CD163+MerTK+CD169+ cell-surface marker signature, also observed on monocytes from the pleural cavity of tuberculosis patients. The establishment of an in vitro culture system, based on the utilization of supernatants from Mtb-infected primary human macrophages, allowed us to differentiate freshly isolated monocytes from healthy donor towards both the M2c activation program and the exacerbation of the HIV-1 infection of these cells, thus mimicking the effects enacted by PE-TB. Using this approach, we identified specific molecular mechanisms responsible for this HIV-1 infection amplification induced by Mtb in monocytes/macrophages, including the increased expression of HIV-1 entry co-receptors CCR5 and CXCR4, and the IL-10/STAT3 signaling pathway.