HCMV and the Immune System PDF

HCMV and the Immune System MICRG 1553 - Session 30 Lisa Kronstad, Ph.D. [email protected] October 30, 2024, 8:00 AM Cholla D Learning Objectives Identify the structural characteristics and infection cycles for CMV including the types of diseases, populations at risk and route...

HCMV and the Immune System MICRG 1553 - Session 30 Lisa Kronstad, Ph.D. [email protected] October 30, 2024, 8:00 AM Cholla D Learning Objectives Identify the structural characteristics and infection cycles for CMV including the types of diseases, populations at risk and route of entry and exit (transmission) Describe how CMV infections in hematopoietic cell transplant (HCT) patients, and its treatment by adoptive cellular therapy, demonstrates the importance of T cells, particularly CD8 T cells, in the control of viral infectious in humans Describe how defects of CD4 and CD8 T cell immunity in uence the control of CMV infections in humans List mechanisms by which CMV evades innate and adaptive immune mechanisms Describe why congenital CMV infection is an important goal of vaccination and outline the challenges faced by CMV vaccine development 2 fl Lecture Outline Patient Case Transplant Cytomegalovirus Virology Cytomegalovirus Disease Immune Response to Cytomegalovirus Cytomegalovirus Immune Evasion Cytomegalovirus treatment, prevention, and vaccine development Return to Patient Case 3 Patient Case 19-year-old woman with idiopathic aplastic anemia, e.g. failure to produce red blood cells (RBCs), platelets, and myeloid cells by bone marrow. Undergoes peripheral stem cell transplantation from an HLA- matched, unrelated donor Transplant recipients remain profoundly immunocompromised until donor marrow engrafts 4 Patient Case Prior to the transplant, patient was found to be Human Cytomegalovirus (HCMV) antibody positive indicating she is infected with this virus Does not recall any illness attributable to HCMV and does not know when she became infected The organ donor is HCMV-negative based on this serology test 5 Patient Case 8 days prior to transplant, receives intravenous ganciclovir, an anti-viral drug that inhibits herpesvirus DNA synthesi Also receives highly immunosuppressive graft-vs-host disease prophylaxis because the donor is unrelated 6 https://www.nejm.org/doi/full/10.1056/NEJM199112053252303 s Patient Case Ganciclovir stopped 100 days post-transplant Six months after transplant, the patient develops dyspnea (trouble breathing) over 1 week Chest radiograph and CT scan indicate pneumonia 7 Patient Case Diagnosis - HCMV Despite maximal therapy (high dose of I.V. ganciclovir, foscarnet, and HCMV immune globulin) she dies from respiratory failure. What HCMV-speci c immune response was most likely lacking in this patient that allowed late-onset Classic "Owl eye inclusion bodies" nding on HCMV pneumonia to occur? histopathology of tissue from lung biopsy How does HCMV persist without causing symptoms in an immunocompetent host? 8 fi fi Lecture Outline Patient Case Transplant Cytomegalovirus Virolog Cytomegalovirus Disease Immune Response to Cytomegalovirus Cytomegalovirus Immune Evasion Cytomegalovirus treatment, prevention, and vaccine development Return to Patient Case 9 y Herpesviridae Family; HHV-5/CMV The ability to establish lifelong latent infections is a defining characteristic of herpesviruses T cell compartment often exceeds 10% anti-HCMV in infected individuals doi: 10.3389/ mmu.2017.00733 fi Cytomegalovirus Properties CMV (HHV-5) Enveloped, dsDNA virus Largest genome of any virus known to infect humans Global prevalence: ~60% in developed countries, ~90% in developing countries CMV Epidemiology Enter: Person-to-Person transmission Saliva and urine of young children major source of virus, also spread sexually, by blood transfusion or organ transplantation Asymptomatic transmission About 1:200 babies are born with congenital CVM infection; 1:5 of these https://www.sofivagenomics.com.tw/en/Product/6/3/item/32 will have long-term health problems CMV: Infection Cycle Primary viremia - virus seeds the lung, spleen, and liver Secondary viremia infects to infection of other tissues including salivary glands, kidneys and breasts Exit: the virus can now exit through saliva, urine and breast milk https://www.mdpi.com/1999-4915/10/7/383/htm CMV: Infection Cycle HCMV productive Infectio Cell dies Virus produced Immune control by recognition of multiple proteins only expressed during lytic replication https://www.mdpi.com/1999-4915/10/7/383/htm n CMV: Infection Cycle Latenc Persistence of viral genome in the absence of virus production coupled with ability to reactivate HCMV establishes latent infections in bone marrow hematopoietic progenitor cells Limited immune control because very few proteins expressed Inflammation-associated signaling is likely a key driver of reactivation https://www.mdpi.com/1999-4915/10/7/383/htm y Cytomegalovirus Owl eye CMV (HHV-5) Produces a characteristic CPE with massive cell enlargement = cytomegal Histopathological detection of Owl's eye inclusions https://www.pathologyoutlines.com/topic/ liverCMV.html Obtained from: TA Kokjohn, Ph.D. o Lecture Outline Patient Case Transplant Cytomegalovirus Virology Cytomegalovirus Diseas Immune Response to Cytomegalovirus Cytomegalovirus Immune Evasion Cytomegalovirus treatment, prevention and vaccine development Return to Patient Case 17 e Cytomegalovirus (CMV) Disease Infection in immunocompetent individuals is typically asymptomatic or causes mononucleosis Common cause of congenital infection ToRCHeS panel A major cause of morbidity/ mortality in immunocompromised patient AIDS patients Transplant patients s s CMV in Immunocompetent Patients Asymptomatic (common) or mild infectious mononucleosis syndrome (rare) "Flu"-like illness Controlled by vigorous immune response that prevents the high viral loads required to cause end-organ diseas Specific organ involvement https://www.mja.com.au/journal/2014/201/10/ cytomegalovirus-disease-immunocompetent-adults e CMV Congenital Infections Primary or reactivation disease in pregnant women Some sources: contact with infected urine & saliva, sex, blood, organ transplantation Maternal Manifestations: Asymptomatic or mononucleosis wikipedia Neonatal Manifestations: Blueberry muffin ras Hearing loss Leading infectious cause Seizures Petechial rash "blueberry muffin" h CMV in Immunocompromised Patients Serious and potentially fatal manifestations in AIDS and transplant patients Linear ulcers Colitis, Retinitis, Esophagitis, Encephalitis, Pneumonitis (CREEP) CMV retinitis is the most common CMV Retinitis and can progress to blindness cotton-wool "sightomegalovirus" spots Lecture Outline Patient Case Transplant Cytomegalovirus Virology Cytomegalovirus Disease Immune Response to Cytomegaloviru Cytomegalovirus Immune Evasion Cytomegalovirus treatment, prevention and vaccine development Return to Patient Case 22 s CMV is constantly reactivating from latency HCMV latency and reactivation are both continuously occurring and the immunocompetent host immune response kills cells supporting viral replication, thus preventing the high titers required for end-organ disease Upon becoming immunocompromised, reactivation is still occurring but the loss of immune function allows the virus to replicate unchecked, leading to viremia and disease Often a concomitant inflammatory state driven by co-infections exacerbates the situation Immunosuppression likely releases the brake rather than representing the trigger https://www.mdpi.com/1999-4915/10/8/444 Host Response to Primary HCMV Infection Intracellular cytokine staining of antigen-specific T cells Primary Infection: first encounter with any strain of the virus Primary HCMV infection after renal transplant results in rapid appearance of HCMV-specific TH1 CD4+ helper T cells secrete IFN-γ critical for control of infection in mouse CMV model T cells appear shortly after CMV detected in the blood Secondary infection: A person already infected becomes infected with another HCMV strain (from Rentenaar et al., J. Clin. Invest. 105:541, 2000) Host Response to CMV Infection involves effector CD8+ T cells The surface protein pattern of HCMV-specific CD8+ T cells indicated they are effector cells rather than resting memory cells i.e. have license to kill Contrasts with similar analysis of influenza-specific CD8+ T cells One year after flu season, flu-specific CD8+ T cells are at a much lower frequency and are quiescent memory cell CMV likely constantly attempting to undergo productive infection, and is only held in check by T cell immunity s HCMV-specific CD8 T cell-mediated cytotoxicity HCMV+ transplant patients who develop HCMV-specific CD8 cytotoxic T cell response after transplant are at low risk of developing pneumonia HCMV-specific T cells have been grown in vitro from donors for transplant patients Adoptive transfer of HCMV-specific CD8+ T cell via infusion provide substantial protection from death or serious disease from HCMV Provides direct evidence of the importance of viral-specific CD8+ T cells in controlling human herpesvirus HCMV-specific CD4 T cells Likely important in limiting duration of viral shedding into epithelial secretions and preventing tissue dissemination e.g. to CNS Most clearly indicated by patients with HIV and a low CD4+ T cell count (AIDS) Even though CD8+ T cell number often only moderately decreased in AIDS patients, they remain at high risk for chorioretinitis, GI disease etc. Emphasizes the role of CD4+ T cells in maintaining functional CD8+ T cells No data that patients with X-linked agammaglobulinemia have poorly controlled CMV Antibodies may not be as important Patients who are chronically infected with HCMV and are receiving long-term therapy with rituximab (anti-CD20 monoclonal antibody) have an acquired lack of B-cell immunity but do not have increased activity of HCMV infection Lecture Outline Patient Case Transplant Cytomegalovirus Virology Cytomegalovirus Disease Immune Response to Cytomegalovirus Cytomegalovirus Immune Evasion Cytomegalovirus treatment, prevention, and vaccine development Return to Patient Case 28 CMV Immune Evasion and Immunomodulation More than 30% of proteins ended by HCMV may be involved in immune evasion Downregulation of MHC class I to limit CD8+ T cell recognition Expression of viral IL-10 to downregulate MHC Class II Downregulation of NK cell activating ligands Disable the interferon response Interfere with sensing of viral DNA by PRRs Produce chemokine mimics to recruit immune cells https://www.nature.com/articles/s41579-021-00582-z CMV Immune Evasion https://www.nature.com/articles/s41579-021-00582-z Type I IFN mediate important anti-viral effects HCMV pp65 blocks type I IFN production via multiple mechanisms https://www.nature.com/articles/s41579-021-00582-z CMV antagonizes the ability of IFN-γ to upregulate Class II IFN-γ signaling involves activation of JAK1/JAK2 JAK1 phosphorylates STAT1 STAT1 forms homodimers that travel to the nucleus to regulate genes, e.g. MHC class II HCMV downregulates JAK1, blocking this process Virally encoded IL-10 blocks T cell activation HCMV exploits the anti-inflammatory IL-10 signaling pathway by expressing a function viral IL-10 homolog Inhibition of MHC class II antigen presentation Block effects of IFN-γ signaling Lecture Outline Patient Case Transplant Cytomegalovirus Virology Cytomegalovirus Disease Immune Response to Cytomegalovirus Cytomegalovirus Immune Evasion Cytomegalovirus treatment, prevention, and vaccine developmen Return to Patient Case 34 t CMV: Treatment and Prevention Treatmen Ganciclovir (valganciclovir) for solid organ graft patients and those with severe disease; prophylactic therapy Nucleoside analog that inhibits viral DNA synthesis Immune globulin (CytoGam) for transplant patients, persons with severe disease or primary infections discovered during pregnancy Preventio Education of parents and/or those working with children to break the chain of transmission Good personal hygiene and fomite disinfection t n HCMV Vaccine Challenges Adaptive immunity not able to sterilize (clear) HCMV infection (or that of other herpesviruses) Established robust adaptive immunity only partially effect for preventing infection with new HCMV strains Suggests that a live attenuated HCMV viral vaccine will fail, if goal is to prevent infection Therapeutic vaccination - to increase T cell immunity in those already infected more likely to be successful Better understanding of the events in primary infection vs. reactivation will be important for future vaccine development Lecture Outline Patient Case Transplant Cytomegalovirus Virology Cytomegalovirus Disease Immune Response to Cytomegalovirus Cytomegalovirus Immune Evasion Cytomegalovirus treatment, prevention, and vaccine development Return to Patient Case 37 Back to the case Recipients of non-autologous grafts are severely immunocompromised, e.g., due to treatments for graft rejection and GVHD, and delayed T-cell reconstitution HCMV pneumonia is a common and life-threatening complication that can occur due to the reactivation of latent infection or new infection from the transplant. Case is typical in that prior to immunosuppression HCMV infection is often asymptomatic, and it is unclear exactly when HCMV infection occurred. Suppression of HCMV by drugs such as ganciclovir can reduce incidence of pneumonia. But, even a relatively long course of such therapy may not be sufficient to prevent this complication if T cell reconstitution is delayed. Back to the case Take Home Messages CMV is an enveloped dsDNA virus that can undergo latency and reactivation, is transmitted via urine, saliva, sex, and organ transplants, and can cause severe disease in neonates and potentially fatal end-organ disease in and in the immunocompromised Transplant patients who receive HCMV-speci c CD8+ T cells via infusion receive substantial protection from death or serious disease from HCMV, illustrating the key role of this cell type in the immunological control of this virus AIDS patients with low CD4 T cell counts are at risk of CMV disease, in particular CMV retinitis, emphasizing the role of CD4 T cells in maintaining functional CD8+ T cells CMV encodes immune evasion proteins including those involved in impairing class I and II antigen presentation and inhibiting NK cell activation, disabling the interferon response, interfering with sensing of viral DNA by PRRs, and producing chemokine mimics to recruit immune cells Immunoevasive mechanisms account not only for the lack of sterilizing immunity but also the lack of protection from re-infection with new HCMV strains - thus the correlates of protection remain unknown and thus dif cult to recapitulate in a vaccine 40 fi fi Please complete TopHat discussion assignment One “Muddiest point” - area of confusion? SUPER happy to answer questions - Of ce is 360D Dr. D. Science Hall! Seriously talking about this stuff is my favorite thing to do in life. Will return all e-mails within 24 hr period! 41 , https://xkcd.com/2557/ fi