Virome in Immunodeficiency: What We Know Currently
The human virome, comprising the collective viral communities inhabiting the human body, has emerged as a critical factor in human health. Its interactions with microbial communities and the immune system are increasingly recognized as pivotal in maintaining homeostasis. In individuals with compromised immune function, the virome plays a unique role, as immunodeficiency heightens susceptibility to a diverse range of infectious diseases and alters the dynamics of viral populations. This article comprehensively explores the current understanding of the virome in immunodeficiency, focusing on its alterations, mechanisms, and clinical implications.
Introduction to Immunodeficiency and the Virome
Immunodeficiency disorders are broadly categorized into primary immunodeficiencies (PIDs) and secondary immunodeficiencies (SIDs). PIDs are caused by genetic defects affecting the development and function of the immune system, with immunoglobulin A deficiency (IgAD) being the most common. SIDs, more prevalent than PIDs, arise from external factors such as infections, treatments for autoimmune diseases, and cancer therapies. Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV) infection, is a prominent example of SID.
The human virome consists of bacteriophages, eukaryotic viruses, archaeal viruses, and plant viruses. A single human body harbors approximately 10^13 viral particles, predominantly in the gut. While most of these viruses are benign, they can become pathogenic in immunocompromised individuals, leading to opportunistic infections and disease associations. For instance, AIDS patients are prone to opportunistic infections and tumors linked to viruses. Additionally, co-infections with viruses like GB virus C (GBV-C) and human endogenous retroviruses (HERV) have been associated with disease outcomes.
Alterations of the Virome in Immunocompromised Individuals
People Living with HIV (PLWH)
HIV infection leads to the progressive destruction of CD4+ T cells, resulting in immunodeficiency. Studies in simian immunodeficiency virus (SIV)-infected animals have shown that pathogenic SIV infection is associated with significant expansion of the gut virome, particularly Adenoviridae and Picornaviridae. In PLWH, virome studies have been conducted on various samples, including stool, saliva, plasma, semen, and breast milk.
In stool samples, Adenoviridae and Anelloviridae are significantly enriched in HIV-positive individuals with CD4+ T cell counts below 200 cells/mL. This enrichment is linked to immunodeficiency rather than antiretroviral therapy (ART). Studies on the salivary virome of PLWH have detected lymphocryptovirus of Herpesviridae, which is rare in HIV-negative individuals. Plasma samples from PLWH have shown the presence of HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), GBV-C, and anellovirus, with anellovirus levels positively correlated with HIV-1 viral load and negatively correlated with CD4+ T cell counts.
Semen and cervical swab samples from PLWH without treatment have higher loads of Papillomaviridae, Anelloviridae, Genomoviridae, and Herpesviridae. Breast milk virome in HIV-infected women without ART contains cytomegalovirus (CMV) and tailed phages, but the virome remains resilient despite immunosuppression.
Organ Transplant Recipients
Organ transplant recipients require lifelong immunosuppression, increasing the risk of post-transplant complications, including secondary infections and malignancies. The virome in these patients has been studied in various body sites, including blood and lungs.
In lung transplant recipients (LTRs), the lung and plasma virome is dominated by Anelloviridae, Herpesviridae, and Coronaviridae, with higher torque teno virus (TTV) levels compared to healthy controls. TTV has been associated with primary graft dysfunction and may serve as a biomarker of immune status in LTRs. RNA viruses like human rhinovirus and parainfluenza virus have also been identified in post-lung transplant patients.
In liver transplantation (LT) recipients, the virome composition shifts from Hepadnaviridae dominance pre-transplant to Anelloviridae post-transplant. Kidney transplant recipients show the presence of Anelloviridae, Adenoviridae, Herpesviridae, and Papillomaviridae in the urinary virome, with viral transmission from donors to recipients. TTV kinetics in liver and kidney transplant recipients reflect immunosuppressive regimens and may predict CMV reactivation.
Autoimmune Diseases
Autoimmune diseases, characterized by aberrant immune responses against the body’s own tissues, have been linked to virome alterations. Studies have focused on type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), osteoarthritis (OA), and ankylosing spondylitis (AS).
In T1D, the gut virome of children shows associations with Enterovirus B (EV-B), human mastadenovirus F (HadV-F), and Coxsackie B virus (CVB). RA patients exhibit distinct virome variations in dental plaque, saliva, and fecal samples, with increased Myoviridae, Herelleviridae, and Autographiviridae and decreased Siphoviridae. SLE patients show increased Demerecviridae and Phycodnaviridae and decreased crAss-like phages in the gut virome. OA patients have decreased Siphoviridae, Myoviridae, and Microviridae, while AS patients show increased Myoviridae, crAss-like, and Microviridae and decreased Podoviridae and Siphoviridae.
Primary Immunodeficiency and Other Immunocompromised Diseases
PIDs, such as IgAD and DOCK8 deficiency, have been studied for virome alterations. IgAD patients show minimal changes in the oral virome, suggesting IgA’s limited role in maintaining virome composition. DOCK8-deficient patients exhibit higher relative abundance of eukaryotic viruses like Papillomaviridae, Polyomaviridae, and Poxviridae on the skin.
Mechanisms of Virome Alteration in Immunocompromised Status
The mechanisms underlying virome alterations in immunodeficiency are complex and involve interactions between phages, animal cell viruses, and the immune system. Phages, the most abundant component of the gut virome, may change in abundance due to alterations in their bacterial hosts. For example, HIV-infected patients show reduced gut bacterial microbiome richness and diversity, which may influence phage populations.
Phages can directly interact with the immune system, triggering responses via toll-like receptors (TLR) and exacerbating inflammation, as seen in inflammatory bowel disease (IBD). Animal cell viruses, on the other hand, can proliferate in immunocompromised individuals due to impaired immune surveillance. Some viruses, like murine astroviruses, may protect against infections through interferon signaling.
Clinical Implications of Virome Studies
Virome as a Potential Biomarker
The virome has potential as a biomarker for disease progression and immune status. In HIV infection, alterations in the enteric virome, such as the expansion of Adenoviridae, may serve as markers of disease progression. TTV levels in organ transplant recipients reflect immunosuppression and may predict complications like CMV reactivation. In autoimmune diseases, specific viral markers, such as human herpesvirus 8 and Salmonella phages, have been associated with SLE.
Virome-Driven Therapeutic Approaches
Fecal virome transplantation (FVT) and phage therapy are emerging therapeutic approaches. FVT has shown promise in treating gastrointestinal diseases, metabolic disorders, and necrotizing enterocolitis in animal models. Phage therapy has been effective in treating bacterial infections in immunocompromised patients and reducing autoimmune inflammation in RA models.
Conclusions
The virome plays a significant role in immunodeficiency, with alterations observed in various immunocompromised conditions. Understanding these changes and their mechanisms can provide insights into disease pathogenesis and lead to novel diagnostic and therapeutic strategies. Further research is needed to explore the virome’s potential as a biomarker and its applications in personalized medicine.
doi.org/10.1097/CM9.0000000000002899
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