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Review
.2022 Jan 4:12:808722.
doi: 10.3389/fimmu.2021.808722. eCollection 2021.

Pulmonary Immune Dysregulation and Viral Persistence During HIV Infection

Affiliations
Review

Pulmonary Immune Dysregulation and Viral Persistence During HIV Infection

Yulia Alexandrova et al. Front Immunol..

Abstract

Despite the success of antiretroviral therapy (ART), people living with HIV continue to suffer from high burdens of respiratory infections, lung cancers and chronic lung disease at a higher rate than the general population. The lung mucosa, a previously neglected HIV reservoir site, is of particular importance in this phenomenon. Because ART does not eliminate the virus, residual levels of HIV that remain in deep tissues lead to chronic immune activation and pulmonary inflammatory pathologies. In turn, continuous pulmonary and systemic inflammation cause immune cell exhaustion and pulmonary immune dysregulation, creating a pro-inflammatory environment ideal for HIV reservoir persistence. Moreover, smoking, gut and lung dysbiosis and co-infections further fuel the vicious cycle of residual viral replication which, in turn, contributes to inflammation and immune cell proliferation, further maintaining the HIV reservoir. Herein, we discuss the recent evidence supporting the notion that the lungs serve as an HIV viral reservoir. We will explore how smoking, changes in the microbiome, and common co-infections seen in PLWH contribute to HIV persistence, pulmonary immune dysregulation, and high rates of infectious and non-infectious lung disease among these individuals.

Keywords: CD8 T-cell dysfunction; HIV; HIV reservoir; alveolar macrophage (AM); alveolar macrophages; lungs; mucosal immunity; pulmonary immunity.

Copyright © 2022 Alexandrova, Costiniuk and Jenabian.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Pulmonary inflammation drives immune dysregulation and reservoir persistence in people living with HIV. Even during the era of antiretroviral therapy (ART), people living with HIV (PLWH) continue to suffer from high burdens of pulmonary illnesses. Inflammation is likely the biggest driver of pulmonary pathologies and lung HIV reservoir persistence in these individuals. Apart from the virus itself, which is seeded into the lung within the first few weeks of infection, other factors also contribute to pulmonary immune perturbations in PLWH even during ART, such as smoking, co-infections, changes in the microbiome, and compromised integrity of mucosal barriers. Collectively, these fuel chronic inflammatory state and pulmonary immune activation characterized by high levels of pro-inflammatory cytokines (RANTES, TNF-β, IFN-γ, IL-6, IP-10), which in turn lead to immune cell recruitment to the lung tissue, typically presenting as CD8 T-cell lymphocytic alveolitis. These CD8 T-cells appear as functionally impaired and fail to remove lung HIV reservoir that continues to persist in mucosal CD4+ T-cells and CD4-CD8- Double Negative (DN) T-cells, as well as alveolar macrophages (AMs). A vicious cycle of immune activation and residual viral replication ensues further exacerbating pulmonary immune abnormalities, such as pro-inflammatory AM polarization, extracellular matrix destruction caused by increased production of matrix metalloproteinases (MMPs), further CD8 T-cell recruitment, and increased neutrophil count. In an attempt to counteract this inflammatory process, immunoregulatory arm of the immune system could further contribute to increased risk of pulmonary co-morbidities: accumulation of immunosuppressive regulatory T-cells (CD73+CD39+Treg) might be implicated in higher lung cancer risk and higher levels of TGF-β could be the primary driver of irreversible pulmonary fibrosis. [Images adapted from Servier Medical Art licensed under CC 3.0 (smart.servier.com)].
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