viruses Review The Role of Coinfections in the EBV–Host Broken Equilibrium Yessica Sánchez-Ponce 1,2 and Ezequiel M. Fuentes-Pananá 1,* 1 Research Unit in Virology and Cancer, Children’s Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico; [email protected] 2 Doctoral Program in Biomedical Science, National Autonomous University of Mexico, Mexico City 04510, Mexico * Correspondence: [email protected] or [email protected]; Tel.: +52-55-9199-7577 Abstract: The Epstein–Barr virus (EBV) is a well-adapted human virus, and its infection is exclusive to our species, generally beginning in the childhood and then persisting throughout the life of most of the affected adults. Although this infection generally remains asymptomatic, EBV can trigger life-threatening conditions under unclear circumstances. The EBV lifecycle is characterized by interactions with other viruses or bacteria, which increases the probability of awakening its pathobiont capacity. For instance, EBV infects B cells with the potential to alter the germinal center reaction (GCR)—an adaptive immune structure wherein mutagenic-driven processes take place. HIV- and Plasmodium falciparum-induced B cell hyperactivation also feeds the GCR. These agents, along with the B cell tropic KSHV, converge in the ontogeny of germinal center (GC) or post-GC lymphomas. EBV oral transmission facilitates interactions with local bacteria and HPV, thereby increasing the risk of periodontal diseases and head and neck carcinomas. It is less clear as to how EBV is localized in the stomach, but together with Helicobacter pylori, they are known to be responsible for gastric cancer. Perhaps this mechanism is reminiscent of the local inflammation that attracts different herpesviruses and enhances graft damage and chances of rejection in transplanted patients. In this review, we discussed the existing evidence suggestive of EBV possessing the potential to Citation: Sánchez-Ponce, Y.; Fuentes-Pananá, E.M. The Role of synergize or cooperate with these agents to trigger or worsen the disease. Coinfections in the EBV–Host Broken Equilibrium. Viruses 2021, 13, 1399. Keywords: EBV; HIV; beta herpesvirus; HPV; P. falciparum; H. pylori; periodontal bacteria; coinfection; https://doi.org/10.3390/v13071399 immunosuppression; lymphomagenesis Academic Editors: Sylvain Latour and Benjamin Gewurz 1. Introduction Received: 15 May 2021 The Epstein–Barr virus (EBV) is a well-adapted human virus, and its infection is exclu- Accepted: 12 July 2021 sive to our species, generally beginning in childhood and persisting throughout the life of Published: 19 July 2021 most affected adults. This adaptation probably reflects at least a hundred thousand years of viral and human coevolution, helping shape an equilibrium wherein most people live Publisher’s Note: MDPI stays neutral with the virus without showing overt evidence of malaise. Nevertheless, this virus is often with regard to jurisdictional claims in associated with severe diseases such as cancer and inflammatory and auto-immune disor- published maps and institutional affil- ders. Thus, EBV seems more of a pathobiont than a true pathogen, that is, an agent with iations. the capacity to unleash its harmful potential in dysbiotic conditions [1]. The circumstances that lead to the disturbance of the viral-host balance are more often unknown. In this review, we focused on the existing evidence indicating that EBV-opportunistic mechanisms of pathogenicity can intersect with those of other infectious agents, resulting in detonation Copyright: © 2021 by the authors. or worsening of the disease (Figure1). Licensee MDPI, Basel, Switzerland. EBV’s main route of transmission is through saliva droplets. EBV first infects the This article is an open access article lymphoepithelial tissues of the Waldeyer ring. EBV causes chronic infections oscillating distributed under the terms and between B cells and epithelial cells, the latter serving to amplify the number of infectious conditions of the Creative Commons particles released into the saliva for efficient transmission to new hosts and, most likely, Attribution (CC BY) license (https:// B cells providing the niche for persistence, particularly memory B cells [2,3]. Similar to that creativecommons.org/licenses/by/ 4.0/). for the other members of the herpesvirus family, EBV oscillates between lytic and latent Viruses 2021, 13, 1399. https://doi.org/10.3390/v13071399 https://www.mdpi.com/journal/viruses Viruses 2021, 13, x FOR PEER REVIEW 2 of 28 Viruses 2021, 13, 1399 2 of 27 latent infectious cycles, perhaps with the former prevailing more in the epithelial cells and theinfectious latter more cycles, in perhapsthe B cells, with together the former assuri prevailingng successful more persistenc in the epitheliale at the cells population and the andlatter individual more in the levels. B cells, together assuring successful persistence at the population and individual levels. FigureFigure 1. 1. SharedShared microenvironments microenvironments between between EBV EBV and and othe otherr infectious infectious agents. agents. EBV infection’s EBV infection’s main portalmain portalof entry of and entry exit and is the exit oral is mucosa, the oral wh mucosa,ere it coexists where itwith coexists the periodontal with the periodontal bacteria P. gingivalis bacteria and A. actinomycetemcomitans, and HPV. EBV persists in B cells residing in the lymphatic system, P. gingivalis and A. actinomycetemcomitans, and HPV. EBV persists in B cells residing in the lymphatic where it can cross paths with other infectious agents such as HIV, P. falciparum, or KSHV (here system, where it can cross paths with other infectious agents such as HIV, P. falciparum, or KSHV represented in the spleen as an example of a secondary lymph node). From the lymphatic system, EBV-infected(here represented cells can in the infiltrate spleen certain as an exampletissues, su ofch a as secondary the stomach lymph or cervix, node). where From EBV the lymphaticcan inter- sectsystem, with EBV-infected H. pylori and cells HPV, can respectively. infiltrate certain tissues, such as the stomach or cervix, where EBV can intersect with H. pylori and HPV, respectively. EBV is found in latently infected cells with different active transcriptional programs, EBV is found in latently infected cells with different active transcriptional programs, which are often referred to as latency programs. For instance, there is a latency III program which are often referred to as latency programs. For instance, there is a latency III program in which the virus expresses the complete repertoire of latent proteins: the EBV nuclear in which the virus expresses the complete repertoire of latent proteins: the EBV nuclear antigens EBNA1; EBNA2; the family of EBNA 3A, 3B, and 3C; EBNA-LP (leader protein), antigens EBNA1; EBNA2; the family of EBNA 3A, 3B, and 3C; EBNA-LP (leader protein), and three latent membrane proteins LMP1, LMP2A, and LMP2B. The virus progressively and three latent membrane proteins LMP1, LMP2A, and LMP2B. The virus progressively switches off the expression of these proteins, beginning with the EBNAs in latency II and switches off the expression of these proteins, beginning with the EBNAs in latency II then the EBNAs and the LMPs in latency I, except for EBNA1 whose expression is main- and then the EBNAs and the LMPs in latency I, except for EBNA1 whose expression is tained through the three transcriptional programs. EBNA1 serves to replicate the viral maintained through the three transcriptional programs. EBNA1 serves to replicate the viral genome during the cell cycle and segregates viral genomes to both the daughter cells after genome during the cell cycle and segregates viral genomes to both the daughter cells after mitosis, thus ensuring that the infection is not lost during cell replication. According to mitosis, thus ensuring that the infection is not lost during cell replication. According to thethe germinal germinal center center (GC) (GC) model model [2], [2], these these latency latency programs programs allow allow EBV EBV to to transit transit to tothe the B cellB cell differentiation differentiation pathway, pathway, changing changing from from an an activated activated to toa memory a memory state. state. Memory Memory B Viruses 2021, 13, 1399 3 of 27 B cells are quiescent long-lived cells in which EBV turns off all viral protein expression (latency 0) [3]. Although EBV also expresses several non-coding RNAs throughout all latency programs, latency 0 is most likely the least harmful and the most prevalent one in asymptomatic carriers. The remaining latencies are active in the neoplasms associated with a viral infection and, in the case of EBV-induced B cell lymphomas, these neoplasms usually phenotypically correlate with an intermediate state of the GC reaction (GCR) [3]. 2. EBV in Immunocompromised Individuals The capacity of EBV to downregulate the viral protein expression also allows it to hide from antagonistic host immune responses. Presently, the precise mechanisms and immune populations that help maintain the EBV-host equilibrium are mostly unclear. Most likely, this is importantly aided by CD8 T cells, CD4 T cells, and natural killer (NK) cells [4], since one of the most evident mechanisms of a broken equilibrium is made evident by the improper functioning of these immune cells, as it occurs after primary immunodeficiencies (inborn errors of immunity) or because of pharmacological immunosuppression in the organ- or progenitor cell-transplanted