Characterization of monocyte gene expression in HIV-1 infected individuals

Monocytes/macrophages (M/M) are primary HIV-1 infection targets; they support virus replication and serve as HIV-1 reservoirs. Unlike CD4 T cells that progressively diminish over the course of infection, M/M pools are not observed to be depleted. M/M in HIV-1 infected individuals also exhibit functional impairment. A majority of the observations of HIV-1 mediated M/M modulation have been made in vitro models and a single report to date has studied circulating HIV-1 monocyte gene modulation. Understanding modulation in the peripheral monocyte pool is important as it also allows us to make inferences of modulation that may occur in tissue macrophages (derived from circulating monocytes) which are not easily accessible for in vivo studies and that are ultimate targets of HIV-1 infection. We have characterized gene expression in circulating monocytes in asymptomatic and chronically infected HIV-1 subjects. We have identified gene signatures associated with TNF, CD40/CD40L, ERK/MAPKinase, G-protein signaling and PPAR and p53 transcription that would support dysregulation of major monocyte functions including inflammatory response, lipid metabolism and survival. The gene signatures persist upon repeat sampling. We present via gene network analysis pathways of chronic immune activation - including TNF, IL6 and CD40/CD40L - in association with the observed dysregulation of lipid metabolism (via PPARG inhibition) and apoptosis resistance (via p53 inhibition, activation of ERK/MAPK). We identify inflammatory, selected lipid and apoptosis related genes associated with TNF signaling networks to be shared with other non-HIV macrophage activation programs and the p53 network related apoptosis genes to be associated specifically with HIV-1 monocyte/macrophages. We identify functional consequences of constitutive gene modulation as an increased modulation in inflammation, lipid and survival gene expression following acute TLR2 stimulation of HIV monocytes and as an increased HIV-1 monocyte apoptosis resistance as compared to uninfected monocytes and to increased apoptosis in infected CD4 T cells. Further, by replicating the observations of monocyte apoptotic resistance in Sooty mangabeys (having high virus replication and minimal immune activation [2]) we infer that HIV-1 binding independent of immune activation can induce apoptosis resistance in monocytes, and further indicate monocyte apoptosis regulation to be an evolutionarily conserved feature of lentiviral pathogenesis