Lung T cells in HIV infection. Driven to exhaustion?

More than 30 million people are living with HIV worldwide, the majority of whom will suffer at least one pulmonary complication during the course of their disease (1, 2). Pulmonary infections remain an important cause of morbidity and mortality. Recent studies have also identified chronic, noninfectious pulmonary disorders, such as chronic obstructive pulmonary disease (COPD), as an emerging problem in HIV-positive individuals, even in those receiving effective antiretroviral therapy (ART) (3, 4). The fundamental pathogenic process in HIV infection is the depletion of CD4 T cells, resulting in immunodeficiency and susceptibility to infection. The loss of CD4 T cells is thought to result predominantly from chronic immune activation (5, 6). In fact, the level of immune activation predicts outcomes independent of viral load and CD4 T cell counts. Chronic stimulation of T cells also drives the cells to exhaustion, an immune state characterized by increased expression of inhibitory markers and defined by the loss of effector functions (proliferative capacity, cytokine production, and cytotoxicity) (7). Even with effective viral suppression, immune activation persists at mucosal sites and predicts non–AIDS-related morbidity and mortality (6, 8). Activation of the immune system in the gut and female genital tract is associated with organ-specific immunologic defects and structural alterations that predispose HIV-positive individuals to both infectious and noninfectious disorders (9, 10). In the lung, chronic immune activation from HIV infection results in lymphocytic alveolitis (11, 12). Prior studies have documented depletion of CD4 T cells and accumulation of CD8 T cells in bronchoalveolar lavage (BAL) fluid. Lymphocytic alveolitis has been associated with increased mortality and has been implicated in the development of noninfectious pulmonary diseases (4, 13). Although there is a general understanding that HIV infection drives immune activation in the lung, a number of important questions remain: What are the mechanisms that drive lymphocytic alveolitis? What are the pathologic implications of this chronic inflammation in the lung? How are these processes altered by ART, environmental exposures, and microbes? In this issue of the Journal, Neff and colleagues (pp. 464– 473) take the first step toward better defining lymphocytic alveolitis by characterizing T cells from the BAL and blood of subjects with untreated HIV infection compared with healthy subjects (14). They demonstrate, as others have, that individuals with untreated HIV have increased numbers of BAL lymphocytes that result primarily from accumulation of CD8 T cells. Using antigen-specific T-cell stimulation, the authors show that HIV-positive subjects have a higher frequency of HIVspecific T cells in BAL compared with peripheral blood, suggesting these cells are recruited to and/or sequestered in the lung. The frequency of HIV-specific T cells correlates with the total number of T cells in the alveolar lavage. Further, HIVspecific T cells in the lung have decreased proliferation and increased levels of the inhibitory molecule programmed cell death 1 (PD-1), but not cytotoxic T-lymphocyte antigen 4 (CTLA-4) relative to blood. Finally, the authors demonstrate that PD-1 expression on the HIV-specific T cells is associated with reduced proliferation and can be reversed with PD-1 blockade. The results suggest that the HIV-specific T cells in the BAL are exhausted, and the authors conclude that the lymphocytic alveolitis seen in HIV infection is associated with an influx of dysfunctional HIV-specific T cells. Prior studies have shown that alveolitis correlates with the viral load in the BAL, so it is not surprising that the total number of T cells in the BAL directly relates to the number of HIV-specific T cells (11). Other studies have shown elevated levels of T-cellspecific chemokines (CXCL9, CXCL10) produced by alveolar macrophages, as well as increased expression of their receptor CXCR3 on lung T cells in HIV infection (15). These data, along with the data from Neff and colleagues, suggest that HIV-specific T cells recruited to the lung in response to virus are central in the development of alveolitis. The more important finding in this study is that T cells in the lung are dysfunctional. T cells in the blood of individuals with chronic HIV infection have been shown to be exhausted, with high-level expression of inhibitory receptors such as PD-1, CTLA-4, and T-cell immunoglobulin domain 3 (Tim3) (7). Whether T cells in the lung have a similar profile was not previously known. In this study, Neff and colleagues demonstrate that HIV-specific T cells in the lung have impaired proliferation that correlates to PD-1 (but not CTLA-4) expression and is reversible with PD-1 blockade. It is worth noting that the relationship between PD-1 expression and IFNg production in these cells and their cytotoxic function were not assessed. Thus, determining whether the BAL T cells are truly exhausted will require additional investigation (16). Regardless, it seems likely that alterations in the number and function of BAL T cells induced by HIV will have effects on lung immunity and homeostasis. The work by Neff and colleagues is important, as it advances our understanding of the pulmonary-specific effects of HIV and suggests that targeting exhausted T cells with novel therapies could restore normal immune responses. Perhaps the more important question is what drives the accumulation of dysfunctional T cells in the lung, and whether these cells alter the lung microenvironment in ways that contribute to pulmonary morbidity and mortality. Conversely, does HIV infection alter other cells in the lung (e.g., innate immune cells, epithelium, or endothelium) or the lung microbiome in ways that influence T-cell numbers and function? Exactly how HIV infection increases the incidence and progression of pulmonary diseases is a focus of the Investigating HIV-Associated Lung Disease Network (http://statepiaps.jhsph.edu/lamdacc/inhald/index.html), a National Heart, Lung and Blood Institute consortium formed in September 2013. The Investigating HIV-Associated Lung Disease Network brings together investigators from several disciplines in an attempt to answer these questions and to examine the effects of smoking and ART on the development of HIV-associated lung disease. Although the article by Neff and colleagues adds to our understanding of HIV-associated lymphocytic alveolitis, much EDITORIALS