Lung microbiome in human immunodeficiency virus infection

The lung microbiome plays a significant role in normal lung function and disease. Because microbial colonization is likely influenced by immunodeficiency, one would speculate that infection with human immunodeficiency virus (HIV) alters the lung microbiome. Furthermore, how this alteration might impact pulmonary complications now seen in HIV-infected patients on antiretroviral therapy (ART), which has shifted from opportunistic infections to diseases associated with chronic inflammation, is not known. There have been limited publications on the lung microbiome in HIV infection, many of them emanating from the Lung HIV Microbiome Project. Current evidence suggests that the lung microbiome in healthy HIV-infected individuals with preserved CD4 counts is similar to uninfected individuals. However, in individuals with more advanced disease, there is an altered alveolar microbiome characterized by a loss of richness and evenness (alpha diversity) within individuals. Furthermore, as a group the taxa making up the HIV-infected and uninfected lung microbiome are different (differences in beta diversity), and the HIV-infected population is more spread out (greater dispersion) than the uninfected population. These differences decline with ART, but even after effective therapy the alveolar microbiome in HIV-infected individuals contains increased amounts of signature bacteria, some of which have previously been associated with chronic lung inflammation. Furthermore, more recent investigations into the lung virome in HIV infection suggest that perturbations in lung viral communities also exist in HIV infection, and that these too are associated with evidence of lung inflammation. Thus, it is likely both microbiome and virome alterations in HIV infection contribute to lung inflammation in these individuals, which has important implications on the changing spectrum of pulmonary complications in patients living with HIV.

Introduction

Although the lung has traditionally been thought of as a sterile organ, the use of culture-independent microbial detection methods such as 16S ribosomal RNA gene sequencing has strongly suggested that a lung microbiome is present, both in healthy1, 2, 3 and diseased1, 4, 5 populations. Recognition of the potential impact of the human microbiome on health and disease led the National Institutes of Health (NIH) to add the Human Microbiome Project to the NIH Roadmap in 2007. In 2009, the National Heart, Lung, and Blood Institute created the Lung human immunodeficiency virus (HIV) Microbiome Project (LHMP) to better define the lung microbiome, both in healthy individuals and those with HIV infection. This project was driven by the recognition that pulmonary complications continued to be major causes of morbidity in HIV-infected individuals even in the era of highly active antiretroviral therapy (ART).⁶ Given the significant immune defects found in HIV-infected individuals, the fundamental question proposed by all sites in the LHMP consortium was whether HIV infection altered the respiratory microbiome. Almost all that is now known about the lung microbiome in HIV infection arose from work performed by investigators in this consortium, some as articles from the entire group and others as individual site research projects. In this review, we will describe what is known about the respiratory microbiome in HIV infection to date. This will include descriptions of various diversity indices in HIV-infected individuals and uninfected controls as well as the presence of over-represented or signature bacteria in the HIV-infected population. We will speculate on potential models that may explain differences in various diversity models, both between HIV-infected and uninfected individuals and changes that occur in infected individuals on ART. Finally, we will discuss how perturbations in the lung microbiome might contribute to the changing spectrum of lung complications in HIV infection in the ART era.