Small alveolar macrophages are infected preferentially by HIV and exhibit impaired phagocytic function

Abstract

HIV-1-infected persons are at higher risk of lower respiratory tract infections than HIV-1-uninfected individuals. This suggests strongly that HIV-infected persons have specific impairment of pulmonary immune responses, but current understanding of how HIV alters pulmonary immunity is incomplete. Alveolar macrophages (AMs), comprising small and large macrophages, are major effectors of innate immunity in the lung. We postulated that HIV-1 impairs pulmonary innate immunity through impairment of AM physiological functions. AMs were obtained by bronchoalveolar lavage from healthy, asymptomatic, antiretroviral therapy-naive HIV-1-infected and HIV-1-uninfected adults. We used novel assays to detect in vivo HIV-infected AMs and to assess AM functions based on the HIV infection status of individual cells. We show that HIV has differential effects on key AM physiological functions, whereby small AMs are infected preferentially by the virus, resulting in selective impairment of phagocytic function. In contrast, HIV has a more generalized effect on AM proteolysis, which does not require direct viral infection. These findings provide new insights into how HIV alters pulmonary innate immunity and the phenotype of AMs that harbors the virus. They underscore the need to clear this HIV reservoir to improve pulmonary immunity and reduce the high incidence of lower respiratory tract infections in HIV-1-infected individuals.

Asymptomatic HIV-infected Individuals on Antiretroviral Therapy Exhibit Impaired Lung CD4+T-Cell Responses to Mycobacteria

“…In high transmission regions, most TB cases in HIV-individuals result from recent Mycobacterium tuberculosis (Mtb) infection indicating that in these individuals the lung is more permissive for the establishment or progression of primary infections (3). Recent studies have reported that alveolar macrophage (AM) proteolytic function and mycobacterial antigen-specific Th1 CD4 1 T-cell responses in the lung are impaired in asymptomatic HIV-infected, antiretroviral therapy (ART)-naive persons (4)(5)(6). These findings indicate that HIV alters both innate and adaptive immunity in the lung to render HIV-infected individuals incapable of mounting adequate pulmonary immune responses to control Mtb.…”

“…Recently, we reported that AM phagosomal proteolysis function is impaired in asymptomatic HIV-infected ART-naive adults (6). To determine whether use of ART is associated with improvement in this functional defect, we used the flow cytometry-based reporter bead assay to measure phagosomal proteolysis in AM Next, we investigated Th1 and Th17 mycobacteria-and influenza-specific CD4 1 T-cell responses in BAL and peripheral blood using an intracellular cytokinestaining assay.…”

“…Phagosomal proteolysis in AM was measured using a flow cytometry-based reporter bead assay as described previously (6,13). The readout for the assay was Activity Index, which was calculated by first determining the ratio of median fluorescence intensity of the reporter over calibration flour at 10-minute and 240-minute time points, and then dividing the ratio at 240 minutes by ratio at 10 minutes.…”

Impact of HIV infection and smoking on lung immunity and related disorders

“…This has been attributed to several mechanisms, including 1) resilience of airway Th1 and Th17 cells [21,23] as well as large, as opposed to small, alveolar macrophages [24] to HIV infection and dysfunction; 2) relatively high frequencies of mucosal HIV-specific polyfunctional CD4 + T-cells in the lungs; 3) a lesser mass of HIV-susceptible secondary lymphoid tissue relative to that of the GIT [20]; and 4) the apparent efficacy of the pulmonary HIV-specific cytotoxic T-cell response, manifested clinically as an alveolitis [25].…”

Imaging HIV-1 Genomic DNA from Entry through Productive Infection

“…These approaches have provided valuable insights into intranuclear transport and integration site selection in infected cell nuclei. RNA FISH approaches have been utilized to monitor HIV-1 expression at the single-cell level in samples from infected patients, providing new insights in the tissue distribution of productively infected cells (28) and, when combined with DNA FISH, potential latent cell reservoirs in the body (29).…”