Latency in Viral Infections
Kaviya.L
Saveetha Dental College,
Saveetha Institute of Medical and Technical Sciences, Saveetha University.
Email id: [email protected] Muralidharan N.P
Associate professor, Department of Microbiology,
Saveetha Dental College,
Saveetha Institute of Medical and Technical Sciences, Saveetha University
Email: [email protected] Corresponding Author * Dr.MURALIDHARAN N.P
Associate professor, Department of Microbiology,
Saveetha Dental College,
Saveetha Institute of Medical and Technical Sciences, Saveetha University,
162,Poonamalle High Road, Chennai - 600077, Tamil Nadu, India Email: [email protected]
9840560487 ABSTRACT
In latent infections , overt disease is not produced but the virus is not completely eradicated.
Latency can be defined as a persistent infection with reservoirs that fail to produce infectious virus but are capable of reactivating to repeat the infection cycle. The main feature of this persistence is the failure of host immune response in the elimination of such viruses.Viral latent infections have numerous pathogenesis associated with birth defects, cancers, chronic inflammation, and immunological dysfunctions. Several external factors such as stress,environmental triggers play an important role in the reactivation of viruses .The mechanisms controlling the latency are complex and diversified among virus families, species, and strains. Vaccines are most effective in controlling the viral infections but are
active only on the reactivation of the lytic phase.In this review properties of latency, latency viral infections, reactivation can be defined. Eradicating latent virus has become an important but elusive challenge and will require a more complete understanding of the mechanisms controlling these processes and it is essential in developing future therapeutic drugs against viral infection and subsequent disease.
Keywords: Latency , Infections , Reactivation , Genes.
INTRODUCTION
A number of viruses can cause persistent infections in the host .The main feature of such persistence is the failure of host immune response in the elimination of such viruses. In latent infections ,overt disease is not produced ,but the virus is not eradicated.The latent period is known as the interval between the infection of a bacterial cell and the first release of infectious phage particles .A latent viral infections usually does not cause any noticeable symptoms . Latency can be defined as a persistent infection with reservoirs that fail to produce infectious virus but are capable of reactivating to repeat the infection cycle.(Speck and Ganem, 2010). During latency, the viral genome can either exist as a provirus that is integrated into the DNA of a host cell (proviral latency) or the use of genetic episomes (episomal latency) (Jane Flint et al., 2015),(Klein, 1976). Viral latent infections are neither innocuous nor inert. The escape of cell mediated immune response is the main cause of chronic persistent infections in viral latency (Pooggin, 2018). Viral latency can also be seen in the development of chronic disease depending on immunological response. Latency and reactivation is common among the virus family of herpes simplex viruses,cytomegalovirus, human immunodeficiency viruses,adenovirus ,Epstein Barr virus,varicella zoster virus ,paramyxovirus, hepatitis viruses.Eradicating latent reservoirs in HIV, SSPE, hepatitis B ,HSV, adenovirus infections has become more challenge in the treatment such diseases.Our team has rich experience in research and we have collaborated with numerous authors over various topics in the past decade (Ariga et al., 2018; Basha, Ganapathy and Venugopalan, 2018; Hannah et al., 2018; Hussainy et al., 2018; Jeevanandan and Govindaraju, 2018;
Kannan and Venugopalan, 2018; Kumar and Antony, 2018; Manohar and Sharma, 2018;
Menon et al., 2018; Nandakumar and Nasim, 2018; Nandhini, Babu and Mohanraj, 2018;
Ravinthar and Jayalakshmi, 2018; Seppan et al., 2018; Teja, Ramesh and Priya, 2018;
Duraisamy et al., 2019; Gheena and Ezhilarasan, 2019; Hema Shree et al., 2019;
Rajakeerthi and Ms, 2019; Rajendran et al., 2019; Sekar et al., 2019; Sharma et al., 2019;
Siddique et al., 2019; Janani, Palanivelu and Sandhya, 2020; Johnson et al., 2020; Jose, Ajitha and Subbaiyan, 2020).
LATENCY VIRUSES
The capacity for latency is a defining feature of all herpesviruses .The herpesviral infections display latency in every infected individual. The important feature of the clinical manifestations of infections are the anatomic site of latency and the frequency of latency is reversed to lytic infections (Vaishali and Geetha, 2018). The other important virus family in which exhibit latency are the retroviruses. These small, enveloped RNA viruses replicate via reverse transcription of their RNA genomes and the resulting DNA establishes persistence by integrating into the host genome (M, Geetha and Thangavelu, 2019). In the intact host, the retroviral latency occurs in HIV infection of humans, in which a small subpopulation of long- lived memory T cells can undergo this form of latent infection(Girija As and Priyadharsini J, 2019).
HERPES SIMPLEX VIRUSES
The herpesviruses resulting in human diseases include HSV, VZV, CMV, HHV-6,-7, EBV, and HHV-8. The clinical manifestations of Herpesvirus infections are usually asymptomatic or subclinical in immunocompromised populations. During the latent phase of herpes simplex virus infection the viral genomes proteins can be detected in sensory and autonomic neurons.
T and B lymphocytes are important while recovering from viral infections and are not responsible for the maintenance of latency in neurons. When the immune system is disordered or deficient, latent viruses may reactivate and cause asymptomatic infections, even fatal complications. HSV-1 infection is more common than HSV-2(Minarovits, Gonczol and Valyi-Nagy, 2006).
CYTOMEGALO VIRUSES
Cytomegalovirus infects 70-80% of healthy individuals .The peripheral blood monocytes are the major site of carriage of human cytomegalovirus DNA in healthy carriers. Human cytomegalovirus occurs particularly in immunocompromised people and there is a evidence that human immune response likewise plays an important role in limiting the dissemination of that virus .During organ transplant patients ,the dominant cause of this infection is the reactivation of transplant recipient's own CMV rather than virus transfer from
donor(Bakhareva et al., 2012).CMV-associated with end-organ diseases include colitis, pneumonitis, enteritis, hepatitis, retinitis and encephalitis, and so on. Ganciclovir is the first- line drug for the treatment of CMV diseases.
MORBIDITY AND MORTALITY
The reactivation of latent viral infections are important causes of morbidity and mortality in transplantation patients who are immunocompromised . Viruses acquired from the community, such as the respiratory and gastrointestinal viruses, are also important pathogens of post-transplant viral diseases(Rubin, 2013). Most of the viral infections present with asymptomatic conditions that result in complications in severe immunocompromised people.
Currently, molecular diagnostic methods such as PCR and viral culture are used in the diagnosis of viral infections. Rapid and early diagnosis of infection in patients can reduce infection-related morbidity and mortality.Adoptive cellular therapy is a promising method in the treatment of viral diseases.
ROLE OF MACROPHAGES AND MONOCYTES
Latency viruses group will establish the latency in the macrophage and monocyte lineage and CD4+ T cells.The cells of monocyte and macrophage lineage are unique, resistant to the cytopathic effects and spread virus for longer periods of time. In HIV-1 infection, activated peripheral blood monocytes cross the blood brain barrier and cause HIV infections in brain .Increased and expansion of monocyte activation, as well as the level of HIV-1 DNA positive monocytes (CD14+/CD16+) have been associated with HIV-1 associated neuroinflammation(Granai et al., 2020). The persistent HIV-1 replication in microglial cells and macrophages of the brain causes neuronal damage and neuroinflammation . Several efforts have been made in the analysis of reactivating latent reservoirs, enhancing cytotoxic response ,apoptosis of infected cells. In addition, circulating monocytes isolated from HIV-1 infected individuals exhibit different program cell death genes .Therefore, the determination of program cell death genes can help in targeting cells of monocytes and macrophage lineage infected with HIV-1.
LATENCY RESERVOIRS
The site and size of latent reservoirs in viruses determine the stability of latency and frequency of reactivation(Ashwin and Muralidharan, 2015). The latently infected CD4+ cells
can rekindle productive viral infection when the HAART is withdrawn The latent reservoirs of HIV estimated between 1 and 6 *106 CD4+ T cells based on rates of virus detected after disruption of antiviral therapy(Pinkevych et al., 2015)).Therefore , latent reservoir has been considered as a major obstacle to viral eradication.
Herpes simplex virus 1:
The latency reservoir of HSV1 is the trigeminal ganglion .The active occlusal disease,lacrimal gland and other tissues plays an important role in virus production which reinfects the eyes and continuously causes infections in ganglion (Johnston and Corey, 2015).
Epstein Barr virus :
The normal nasopharyngeal lymphocytes can act as a reservoir for EBV in normal individuals.It establishes an asymptomatic long-term latent infection and the reservoirs are detected chronically in saliva and blood at variable levels. Mathematical modeling predicts stable latent(Thorley-Lawson, 2015). The latently EBV-infected host cells can be destroyed by graft-versus-host reactivity, irradiation, or cytotoxic drugs ((Girija et al., 2019).
GENOME MAINTENANCE MECHANISMS
Latent viruses involved in several mechanisms to maintain viral genome integrity. For herpes viruses ,viral genome is present in the latent cells .This is expected because viruses can be reactivated from these cells (Camarena et al., 2010). In latency ,the terminal fragments of HSV1 DNA have lower mortality than in viral DNA virion . herpes viruses integrate into the host chromosome during latency, resembling HIV and retrovirus integration, but achieved through homologous recombination rather than with viral-encoded integrase(Selvakumar and Np, 2017)
EPISOMAL MAINTENANCE FACTORS
Episomal maintenance requires an epigenetic program for the control of DNA replication,viral gene expression .The metaphase chromosome is essential for episome maintenance and genome persistence in rapidly dividing cells.However, non integrating episomal genomes like EBV, KSHV, and HPV recruit the host cell replication machinery to the episome and maintain a stable episomal copy number by segregating newly replicated genomes equally to daughter cells after each cell division(Frappier, 2013),(Marickar, Geetha
and Neelakantan, 2014).Recently, a potential episome maintenance factor has been identified for HCMV latency. (Tarrant-Elorza, Rossetto and Pari, 2014).
VIRAL IMPACT ON IMMUNE SURVEILLANCE
Herpesviruses are known for their ability to establish lifelong .In the strategy of immune evasion ,viruses have evolved a variety of ways to manipulate the immune system of the host.
Most of the viruses encode homologs of cellular interleukins (IL), chemokines, or chemokine receptors(Nicholas, 2005). In HSV1 ,CD8+T cells restrict gene expression in infected neurons and preventing the production of infectious neurons .The IL-10 impairs NK cell- mediated killing of infected B-cells, interferes with CD4+ T-cell activity, and modulates cellular cytokine response(Girija, Jayaseelan and Arumugam, 2018)(Shahzan et al., 2019).
Another strategy for immune evasion is to reduce the viral antigens via the major histocompatibility complex (MHC) of infected cells(Mocarski, 2004),(Smiline, Vijayashree and Paramasivam, 2018). The manipulation of the immune system offers the reactivated virus at least partial relief from immune surveillance (Fishman, 2013).
EXTERNAL FACTORS INVOLVED IN REACTIVATION
Humans experience reactivation of herpesviruses through local trauma (e.g. in the form of surgery) systemic stress or immunocompromised .However corticosteroids treatments also influence reactivation in mice (Worrall, 1996).
Stress :
Both mental and physical stressors inhibit the activity of CD8+ T-cells through the release of neuroendocrine factors and the mechanism may link the control of HSV latency to activity in the sympathetic nervous system(Freeman et al., 2007). In the case of EBV, the latent virus harbored in B-cells can be reactivated in vitro by stimulating B-cell receptors .The changes in EBV VCA IgG were associated with stress and the EBV proteins get reactivated as a result of stress (Leger, St. Leger and Hendricks, 2011). In fact, the stress associated with space flight is sufficient to cause reactivation of latent herpesviruses, presumably by downregulating cellular immunity(Stowe et al., 2001),(Pawelec et al., 2005).
Environmental triggers :
The environmental triggers such as fever, sunlight, drugs ,UV exposure, hormonal changes, dental surgery, and cranial trauma can cause activation; but it is not known whether these stimuli act directly on the infected neuron, or indirectly by means of bodily functions(Shahana and Muralidharan, 2016). A skin trauma affecting the nerve endings of infected neurons may cause a similar reactivation. In order to maintain latency, the neuron must be functional, active, and healthy(Wilson and Mohr, 2012).
ROLE OF VACCINES DURING LATENCY
Vaccines are the most efficient and cost effective in controlling the viral infections.But viral vaccines are completely ineffective during latency ,but active only on the reactivation of lytic phase (Pratha, Ashwatha Pratha and Geetha, 2017) vaccines must target the viral proteins during latency ,it might be more effective in preventing the recurrent infections .The successful α-herpesvirus antivirals available is targeted towards the viral proteins .During latency, the virus does not express genes coding for virus proteins, including both DNA- polymerase and thymidine kinase(Paramasivam, Vijayashree Priyadharsini and Raghunandhakumar, 2020).Particularly the vaccine targeting CD8+ T cells are more effective in HSV1 infections (Priyadharsini et al., 2018a). Although vaccination against herpes viruses has been difficult, advancements have been made .HSV was the very first infections to be treated successfully using antiviral compounds, proving that a viral disease could be successfully treated in this way(Priyadharsini et al., 2018b). Vaccines will prevent the establishment of latency to an extent, preventing the virus from gaining entry into the host cell by the circulating antibodies. Our institution is passionate about high quality evidence based research and has excelled in various fields ( (Pc, Marimuthu and Devadoss, 2018;
Ramesh et al., 2018; Vijayashree Priyadharsini, Smiline Girija and Paramasivam, 2018;
Ezhilarasan, Apoorva and Ashok Vardhan, 2019; Ramadurai et al., 2019; Sridharan et al., 2019; Vijayashree Priyadharsini, 2019; Chandrasekar et al., 2020; Mathew et al., 2020; R et al., 2020; Samuel, 2021)
POTENTIAL FOR NEW THERAPIES IN VIRAL INFECTIONS
The use of the CRISPR/Cas9 genome editing to selectively delete or mutate latent virus DNA(Williamson et al., 2018). CRISPR/Cas9 is potentially used in antiviral therapy by targeting the viral genome of the herpes viruses (Wang and Quake, 2014) . Lytic reactivated
viruses can be selectively targeted by existing antiviral drugs and as adjuvants for immunological therapies(Shirakawa et al., 2013). Additionally,current therapies are used to limit the latent infections efficacy and cannot eradicate the viruses . Consequently, latently infected cells with cytomegalovirus are more sensitive to chemotoxic agents.(Weekes et al., 2013). These therapies are target to viral-specific noncoding RNAs associated with latent infection(Saayman et al., 2015). These play key roles in regulating virus latency, this approach could have high therapeutic potential.
CONCLUSION :
This review is far from comprehensive or complete and yet hopefully shows the enormous complexity of viral latency and its regulation at the genetic and epigenetic levels. This information provides a great opportunity for the development of innovative and highly selective therapeutic intervention. As viral latency is responsible for life-long pathogenesis and mortality risk, the tasks ahead are in sight, but challenges remain.
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