Alveolar macrophage dysfunction and increased PD-1 expression during chronic SIV infection of rhesus macaques

Abstract

Abstract HIV infected individuals have been shown to be predisposed to pulmonary infections even while receiving anti-retroviral therapy. Alveolar macrophages (AMs) play a critical role in innate immunity of the lung, but their functional and immunological attributes after infection remain contradictory. Here, we use flow cytometry and phagocytosis assays to document phenotypic and functional responses of SIV infected rhesus macaque AMs. We assessed AMs by sampling bronchoalveolar lavage (BAL) from acute through chronic phases of SIV infection and compared these to BAL samples taken from naïve macaques. We found that expression of pro-inflammatory cytokines TNF-□, IL-6, IL-1β and the chemokine RANTES by AMs drastically increased at 2 weeks post-infection compared to naïve animals (p<0.0001 for all) and was quickly followed by a significant drop as infection progressed into the chronic phase of infection. We further show that AMs from chronically infected macaques have diminished capacity to perform SIV-specific antibody-dependent phagocytosis (ADP). Moreover, SIV infection was associated with reduced AM FcγRIII expression, which negatively correlated with viral load (r=−0.6819; p=0.0013). Importantly, PD-1 was shown to be expressed on AMs and showed a strong trend toward correlation with plasma viral load (r=0.8266; p=0.0583), indicating that similar to T-cells, PD-1 expression on AMs may also be associated with disease progression. These findings provide new insight into the dynamics of SIV infection leading to AM dysfunction and alteration of pulmonary innate immunity. Our results suggest new pathways to exploit in developing therapies targeting pulmonary disease susceptibility in HIV-infected individuals.