Many RNA viruses, including influenza, parainfluenza, measles, coronaviruses, chikungunya, and Ebola viruses, have traditionally been considered causes of acute infections: a person becomes ill, the immune system suppresses the virus, and the infection ends. However, new research shows that this model does not always apply. Some viruses and their proteins can remain in the body for months or even years after the acute phase of disease.
Scientists at Washington University School of Medicine in the United States showed that persistent viral products in the body can lead to prolonged tissue inflammation and chronic disease. The researchers studied Sendai virus, a murine parainfluenza virus. Long after the acute infection resolved, researchers detected viral RNA and proteins in several immune cell types in the lungs, including macrophages, type 2 innate lymphoid cells (ILC2s), and dendritic cells (DCs). Removing these cells substantially reduced chronic lung inflammation.
Similar results were obtained in studies of chikungunya virus. In mice with chronic disease, viral RNA persisted in inflammatory macrophages in joint tissues. This suggests that CD4+ T cells infiltrating these tissues contribute to inflammation and may help explain why muscle and joint pain can persist long after chikungunya infection.
Clinical observations also point to the prolonged persistence of RNA viruses. For example, Ebola virus can persist in the male reproductive system and be transmitted sexually several months after infection. In people with suppressed immune systems, parainfluenza viruses may also be shed for prolonged periods, including without symptoms.
To persist after an acute infection, RNA viruses can suppress innate immune defenses, interfere with the recognition of infected cells, persist in long-lived cells, or exploit a weakened antiviral response.
Immune Mechanisms Underlying RNA Virus Persistence
RNA virus persistence largely depends on its ability to suppress or evade immune defenses.
Some viruses also form cellular condensates that can shield them from immune recognition. Viral condensates are accumulations of viral proteins and RNA inside infected cells. They are not separated from the rest of the cell contents by a membrane and serve as sites where components required for viral replication become concentrated.
Suppression of Early Antiviral Responses
RNA viruses can suppress the interferon (IFN) response – one of the main mechanisms of early antiviral defense. Type I and III interferons activate hundreds of genes that inhibit viral replication. Type I IFNs also activate immune cells: they enhance NK cell function, which contains infection at an early stage, and promote dendritic cell maturation. Dendritic cells initiate an adaptive immune response involving cytotoxic T cells, which destroy infected cells and help protect the body against reinfection.
Suppression of the IFN response allows viruses to replicate more efficiently and increases the likelihood of chronic infection. Chikungunya, measles, SARS-CoV-2, and parainfluenza viruses use this strategy. A weakened early immune response is associated with a high viral load and subsequent persistence of the virus or its components in the body:
- Chikungunya virus: in aged rhesus macaques, a weakened immune response was associated with prolonged viral persistence in the spleen.
- Measles virus: reduces T and B cell numbers, promoting viral persistence in lymphoid tissues and the brain.
- SARS-CoV-2: suppresses the IFN response and disrupts dendritic cell function. During severe infection, these abnormalities can persist for several months and are associated with the prolonged presence of viral antigens in tissues.
- Parainfluenza virus: prolonged viral shedding is particularly common in immunosuppressed individuals, especially recipients of hematopoietic cell transplants.
Regulation of MHC Expression and Function
Some RNA viruses, including hepatitis C virus, SARS-CoV-2, and chikungunya virus, disrupt major histocompatibility complex (MHC) expression and the presentation of viral antigens on infected cells. As a result, cytotoxic T cells are less able to recognize and destroy infected cells. Such cells may persist longer in the body and become viral reservoirs.
Viral Mechanisms Underlying RNA Virus Persistence
RNA viruses can acquire mutations that slow their replication and help them evade the immune response. In some persistent infections, mutations that promote cell-to-cell spread rather than viral particle production allow the virus to escape antibody detection. This mechanism has been described for measles, Ebola, and parainfluenza viruses.
Defective viral genomes can also contribute to viral persistence in the body. They limit viral replication and reduce the number of viral antigens available for immune recognition. Researchers have detected such genomes in measles, respiratory syncytial virus (RSV), and Ebola infections, including years after infection. However, their direct role in maintaining chronic infection remains unclear.
Formation of Cellular Reservoirs of Viral Products
RNA viruses can persist for prolonged periods not only in immune-privileged organs – the brain and testes – but also in many other cells and tissues. Viruses and their products have been detected in mucosal cells, sensory and muscle cells, joints, and macrophages, DCs, and ILC2s.
In the central nervous system, the immune response is limited because strong inflammation can cause swelling and damage to brain tissue. The central nervous system is therefore considered immune privileged. Researchers have detected measles virus, Ebola virus, and SARS-CoV-2 products in the brain.
In the testes, the immune response is naturally restricted to protect sperm from immune attack. These conditions allow some RNA viruses to persist there for prolonged periods. Researchers have detected Ebola, Lassa, and Zika viruses in semen months after acute infection. Subsequent sexual transmission has been confirmed for Ebola and Zika viruses.
The eyes are another immune-privileged site where the immune response is more strongly suppressed to limit inflammation-induced vision loss. Ebola virus can persist in ocular tissues for prolonged periods.
By infecting mobile lymphocytes, viruses can spread with these cells throughout the body and enter immune-privileged sites. Non-circulating immune cells – such as macrophages, which can engulf infected cells and have relatively long lifespans – may serve as reservoirs for RNA viruses.
Immune cells can serve as reservoirs and carriers of RNA viruses:
- SARS-CoV-2 persisted in macrophages for more than 200 days;
- Measles virus persisted in lymphoid tissues for up to six months;
- Chikungunya virus persisted in macrophages of joint tissues;
- Zika virus can use infected monocytes to enter the central nervous system.
RNA viruses can persist for prolonged periods not only in immune cells but also in cells of various tissues, contributing to structural and functional abnormalities. SARS-CoV-2 RNA was detected in the intestines nearly two years after infection, while RNA and viral products were detected in taste cells several months later and were associated with long-term taste disturbances. Chikungunya and Mayaro viruses persisted in muscle cells and were associated with reduced muscle fiber mass, while enteroviruses have been detected in cardiac tissue and may be associated with cardiomyopathies.
Long-Term Consequences of Viral Persistence in the Body
Prolonged persistence of RNA viruses or their components in tissues is linked to complications after acute infections. SARS-CoV-2 has been detected in the intestines, brain, and other tissues months after acute COVID-19, and its presence has been associated with gastrointestinal, neurological, and other symptoms of long COVID.
Viral persistence in the body has also been linked to complications following Ebola, measles, and chikungunya infections, including chronic fatigue syndrome. Severe infections with respiratory viruses such as RSV and parainfluenza may predispose individuals to chronic lung diseases, including asthma and chronic obstructive pulmonary disease.
Studies in mice have confirmed that prolonged persistence of parainfluenza virus products sustained chronic lung disease resembling asthma, while chikungunya virus RNA persisted in muscle and joint tissue cells and was associated with chronic inflammation of musculoskeletal tissues.
Conclusion
The view of RNA viruses as pathogens that cause only acute infections is changing. Research shows that viral RNA, altered viral genomes, and proteins can remain in the body after the acute phase. Their prolonged presence can sustain inflammation and disrupt immune and organ function. The risk of such consequences is particularly high after severe infections. Vaccination and other preventive measures may reduce this risk.
Reference
Implications of RNA virus persistence for post-acute sequelae and chronic inflammatory syndromes
