Distinct impact of SIV infection in interstitial and alveolar lung macrophages on the pathogenesis of lung disease in rhesus macaques (VIR9P.1147)

Declining CD4 + T cells during HIV infection contributes to immunodeficiency, but we recently reported that increasing monocyte turnover better predicted onset of terminal disease progression to AIDS in SIV-infected rhesus macaques. Here we describe the kinetics of SIV infection on distinct lung macrophage subsets and on monocyte/macrophage turnover rates in relation to pulmonary disease progression in rhesus macaques. Monocyte and tissue macrophage turnover were monitored by in vivo BrdU injection and cell uptake. Cell-associated SIV DNA in lung tissue was quantified by qPCR and in situ hybridization. Massive SIV infection was associated with increasing death rate of shorter-lived lung interstitial macrophages (IM) with elevated monocyte turnover and progression to AIDS. Conversely, the turnover of alveolar macrophages (AM) and decreasing numbers of CD4+ T cells in lung tissue did not directly correlate with disease progression. SIV DNA levels within IM and AM of the lung increased as monocyte turnover increased, but did not change within lung CD4+ T cells regardless of the stage of disease. These data suggest that SIV infection and concurrent destruction of lung IM contribute to pulmonary pathogenesis during AIDS progression while the longer-lived AM that become infected may contribute to establishing a virus reservoir. Also, bronchoalveolar lavage (BAL) specimens contain AM but not IM, so may be insufficient for fully evaluating macrophage-mediated responses in the lung.