Abstract
The immune and sympathetic nervous systems are major targets of human, murine and simian immunodeficiency viruses (HIV-1, MAIDS, and SIV, respectively). The spleen is a major reservoir for these retroviruses, providing a sanctuary for persistent infection of myeloid cells in the white and red pulps. This is despite the fact that circulating HIV-1 levels remain undetectable in infected patients receiving combined antiretroviral therapy. These viruses sequester in immune organs, preventing effective cures. The spleen remains understudied in its role in HIV-1 pathogenesis, despite it hosting a quarter of the body’s lymphocytes and diverse macrophage populations targeted by HIV-1. HIV-1 infection reduces the white pulp, and induces perivascular hyalinization, vascular dysfunction, tissue infarction, and chronic inflammation characterized by activated epithelial-like macrophages. LP-BM5, the retrovirus that induces MAIDS, is a well-established model of AIDS. Immune pathology in MAIDs is similar to SIV and HIV-1 infection. As in SIV and HIV, MAIDS markedly changes splenic architecture, and causes sympathetic dysfunction, contributing to inflammation and immune dysfunction. In MAIDs, SIV, and HIV, the viruses commandeer splenic macrophages for their replication, and shift macrophages to an M2 phenotype. Additionally, in plasmacytoid dendritic cells, HIV-1 blocks sympathetic augmentation of interferon-β (IFN-β) transcription, which promotes viral replication. Here, we review viral–sympathetic interactions in innate immunity and pathophysiology in the spleen in HIV-1 and relevant models. The situation remains that research in this area is still sparse and original hypotheses proposed largely remain unanswered.
Highlights
As of 2017, an estimated 38 million people in the world are living with human immunodeficiency virus-1 (HIV-1), the pathogen in acquired immunodeficiency syndrome (AIDS) [1,2]
Despite the large number of people living with HIV-1, life span is increasing in patients treated with combination antiretroviral therapies [2]
HIV-infected individuals with constitutively high activity of the autonomic nervous system before antiretroviral therapy experienced lower suppression of plasma viral load and poorer 3-month CD4+ T cell recovery [14,70]. This finding is consistent with physiological concentrations of catecholamines (10−8 to 10−5 M) significantly augmenting HIV-1 replication in vitro [71], a response mediated by the β2-adrenergic receptors (ARs)-cAMP-protein kinase A (PKA) signaling pathway [70]
Summary
As of 2017, an estimated 38 million people in the world are living with human immunodeficiency virus-1 (HIV-1), the pathogen in acquired immunodeficiency syndrome (AIDS) [1,2]. HIV-infected individuals with constitutively high activity of the autonomic nervous system before antiretroviral therapy experienced lower suppression of plasma viral load and poorer 3-month CD4+ T cell recovery [14,70] This finding is consistent with physiological concentrations of catecholamines (10−8 to 10−5 M) significantly augmenting HIV-1 replication in vitro [71], a response mediated by the β2-AR-cAMP-protein kinase A (PKA) signaling pathway [70] (see Figure 2). A more recent study in adult rhesus macaques finds that a β-AR antagonist enhances the density of sympathetic innervation, an effect associated with higher SIV gene expression in lymph nodes [22] This is further supported by findings that HIV-1-positive patients that had constitutively high autonomic activity prior to cART had less reduction in plasma viral load and less CD4+ T cell recovery during the 3–11 months of cART therapy. Both of these alternative mechanisms of cell death release molecules that further drive inflammation in the HIV-1-infected spleen
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