Assessing And Restoring Adaptive Immunity To HSV, VZV, And HHV-6 in Solid Organ And Hematopoietic Cell Transplant Recipients

abstract

Background: Herpes simplex virus (HSV) 1 and 2, varicella-zoster virus (VZV), and human herpesvirus 6 (HHV-6) cause severe infections in immunocompromised hosts. Interventions to optimize virus-specific adaptive immunity may have advantages over antivirals in the prophylaxis and treatment of these infections.

Objectives: We sought to review adaptive immune responses and methods for assessing and replenishing cellular and humoral immunity to HSV, VZV, and HHV-6 in solid organ transplant and hematopoietic cell transplant recipients.

Sources: We searched PubMed for relevant studies on immune responses to HSV, VZV, and HHV-6 as well as studies describing methods for evaluating and restoring cell-mediated immunity to other double-stranded DNA viruses in transplant recipients. Recent studies, randomized controlled trials, and investigations highlighting key concepts in clinical virology were prioritized for inclusion. 

Content: We describe the mechanisms of adaptive immunity to HSV, VZV, and HHV-6 and the limitations of antivirals as prophylaxis and treatment for these infections in solid organ transplant and hematopoietic cell transplant recipients. We review methods for measuring and restoring cellular immunity to double-stranded DNA viruses; their potential applications to the management of HSV, VZV, and HHV-6 in immunocompromised hosts; and barriers to clinical use. Vaccination and virus-specific T-cell therapies are discussed in detail.

Implications: The growing repertoire of diagnostic and therapeutic techniques focused on virus-specific adaptive immunity provides a novel approach to the management of viral infections in transplant recipients. Investigations to optimize such interventions specifically in HSV, VZV, and HHV-6 are needed. Madeleine R. Heldman, Clin Microbiol Infect 2022.

Virus-specific adaptive immunity is closely related to immunity. Virus-specific adaptive immunity can greatly improve the body's immunity to viruses because, after the training of immune memory, the body can produce specific immune responses more quickly and strengthen its resistance to virus invasion. In addition, virus-specific adaptive immunity can also produce long-term immune protection and further improve the body's immunity. Therefore, virus-specific adaptive immunity and immunity are interdependent and mutually reinforcing. Therefore, we need to pay attention to the improvement of our immunity in our daily life. Cistanche has the effect of enhancing immunity. Meat ash contains a variety of biologically active components, such as polysaccharides, two mushrooms, Huang Li, etc. These ingredients Can stimulate various cells of the immune system and increase their immune activity.

Click cistanche tubulosa benefits

Introduction

The human herpesviruses are a group of eight double-stranded DNA viruses that establish lifelong latency in human cells after primary infection [1]. Reactivation of latent herpesviruses is facilitated by loss of regulatory cellular immunity and may occur any time after primary infection. The immunocompromised state associated with solid organ transplant (SOT), and hematopoietic cell transplant (HCT) increases the risk for severe disease during both primary infection and viral reactivation, and transplant recipients are prone to frequent episodes of the latter [1].

 Decades of research have centered on immune responses to cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in transplant recipients, whereas adaptive immunity to non-EBV, and non-CMV herpesviruses are seldom the focus of large investigations. The majority of adults worldwide are infected with herpes simplex virus (HSV) 1 and 2, varicella-zoster virus (VZV), and/or human herpesvirus 6 (HHV-6), and these infections may cause significant morbidity and occasional mortality after SOT or HCT [2e4]. Severe sequelae from human herpesvirus 7 and human herpesvirus 8 are rare in transplant recipients [3]. In this review, we describe adaptive immunity to HSV, VZV, and HHV-6; discuss methods for evaluating virus-specific cellular responses; highlight limitations of available antiviral therapies; and explore novel mechanisms for restoring humoral in SOT and HCT recipients.

Overview of adaptive immunity in HSV, VZV, and HHV-6 infections

Herpes simplex viruses

The herpes simplex viruses are a-herpesviruses that most commonly infect the oral or genital mucosa during primary infection and establish latency in the trigeminal nerve (oral HSV) or sacral dorsal root ganglia (genital HSV). HSV-1 and HSV-2 infect approximately 60% and 15%e20% of adults by age 50, respectively [5,6]. Most clinical HSV infections in human immunodeficiency virus-negative immunocompromised adults are due to HSV-1 and are characterized by mucocutaneous disease in the orofacial region [6,7]. Immunocompromised hosts are predisposed to more severe manifestations of HSV, including dissemination with visceral organ involvement [6,8].

Cell-mediated immunity (CMI) has a key role in maintaining HSV latency [9,10]. In both SOT and HCT recipients, the risk of HSV-1 reactivation is highest in the early post-transplant period when cellular immunity is most impaired [6,7]. Before routine antiviral prophylaxis, HSV-1 mucocutaneous disease occurred in up to 80% of seropositive HCT recipients and 15% of seropositive SOT recipients in the first several months after transplant [6,11e13]. Impaired T-cell immunity also facilitates the emergence of acyclovir-resistant HSV during appropriately dosed prophylaxis, reflecting opportunities for viral mutants to arise during unchecked viral replication and the persistence of less fit variants that would otherwise be eliminated in immunocompetent hosts [14,15]. Cross-placental transfer of maternal HSV antibodies is a major mechanism of protection against neonatal HSV among infants born to seropositive mothers, suggesting that humoral immunity (HI) plays a key role during primary infection (Fig. 1) [16,17]. HI likely has a lesser role in the maintenance of HSV latency, and isolated hypogammaglobinemia has not been associated with an increased risk of HSV reactivation [8,18].

Varicella zoster virus

VZV is a ubiquitous a-herpesvirus that infected nearly all children before the advent of childhood varicella vaccination (VARIVAX, Merck) in 1995 [19]. Primary infection (varicella) manifests as a characteristic chickenpox rash, after which VZV establishes latency in ganglionic neurons. Thirty percent of VZV-infected individuals experience viral reactivation, manifested as herpes zoster (HZ; shingles) [20]. The incidence of HZ is up to 10 times higher in immunocompromised patients [21]. Approximately 15% of HZ cases result in post-herpetic neuralgia, which carries significant morbidity and is more common among immunocompromised persons [22].

CMI has a central role in maintaining VZV latency. The first investigation of VZV-specific donor T-cell infusion for seropositive allogeneic HCT recipients demonstrated limited viral reactivation during the post-transplant period, supporting a model of HZ pathogenesis in which cyclical viral reactivation is subclinical when CMI is intact [23]. VZV-specific CMI has been inversely correlated with HZ incidence and related complications, including postherpetic neuralgia [24]. The role of HI in the prevention of HZ is less clear and likely less critical. In a study of 12 522 adults, of whom 401 developed HZ over 3 years, VZV-specific CMIdbut not VZV-specific antibody titers correlated with protection against HZ [24].

Human herpesvirus 6

HHV-6 (roseola virus) is a b-herpesvirus that consists of two subspecies, HHV-6A and HHV-6B. Nearly all clinical manifestations of HHV-6 are due to HHV-6B, which infects >95% of people during early childhood [25]. Primary HHV-6B infection may be asymptomatic or present with a mild, rash-associated febrile illness known as exanthema subitem or roseola [26]. HHV-6B reactivation occurs in 30%e50% of allogeneic HCT recipients, often during the pre-engraftment and early post-engraftment periods [3]. HHV-6B in HCT recipients is associated with a variety of complications, including limbic encephalitis (1%e8% of HCT recipients), which, when not fatal, frequently leads to severe and prolonged disability [3]. HHV-6B reactivation occurs in up to one-third of patients in the first 12 weeks after liver transplantation, but HHV-6B encephalitis in SOT recipients is rare [3,27].

As with HSV and VZV, CMI plays a greater role in controlling HHV-6 reactivation compared to HI. CD8 knockout, but not B-cell deficiency, causes rapidly fatal infection in mice infected with murine roseola virus, a b-herpesvirus related to HHV-6 [28]. In HCT recipients, post-transplant HHV-6B viral loads are inversely correlated with the absolute number of HHV6B-specific CD4 T cells contained in the graft, and higher proportions of perforin-expressing CD8 T cells are associated with HHV-6B clearance in viremic patients [28e30].

Limitations of antivirals

In SOT recipients, prophylaxis with acyclovir, valacyclovir, or famciclovir is recommended in HSV and/or VZV seropositive patients for 1 month post-transplant and during treatment for rejection [6]. HCT recipients remain at risk for VZV reactivation for months to years after transplant, and antiviral prophylaxis is extended for at least 1 year after HCT [7]. HHV-6 prophylaxis is not recommended in SOT or HCT recipients [25]. Plasma surveillance and/or pre-emptive therapy is not recommended for HSV, VZV, or HHV-6, although antivirals should be given when there is high suspicion for disease [6,7,25].

Antivirals are not universally successful in preventing or treating herpesvirus infections. Breakthrough HSV infections occur in up to 10% of SOT and HCT recipients receiving prophylaxis, particularly if antivirals are underdosed for renal function or when absorption of oral agents is inadequate [6,7]. The emergence of HSV antiviral resistance while on adequately dosed prophylaxis may render pharmacotherapy ineffective, and HHV-6 encephalitis is associated with prolonged morbidity even in patients who receive targeted antiviral therapy [2,4,31]. HZ after discontinuation of routine prophylaxis is common late after HCT and occurs in 26% of umbilical cord blood transplant recipients within 5 years of transplant [4]. Although acyclovir and valacyclovir are relatively safe and inexpensive, high pill burden, medication fatigue, and transitions between healthcare teams limit long-term adherence [4].

Antiviral prophylaxis may have other unintended consequences that result in poor immune reconstitution. For example, CMV prevention with prophylactic letermovir (HCT) or valganciclovir (SOT) is associated with reduced CMV-specific polyfunctional T-cell responses beyond day 100 compared to pre-emptive treatment approaches, potentially leaving patients vulnerable to higher incidence of late CMV reactivation and disease [32e34]. Clinically, such rebound effects have not been demonstrated after prolonged antiviral prophylaxis for VZV or HSV despite reduced VZV-specific lymphocyte proliferation among HCT recipients exposed to acyclovir [35,36]. Diagnostic tools that assess virus-specific immunity could identify patients at the highest risk for viral infections and guide the necessary duration of prophylaxis, and therapies that restore immune function offer an alternative to antivirals for both prophylaxis and treatment of herpesviruses (Table 1).

Assessing humoral and cellular immune responses

Assessing humoral immunity

Measurement of virus-specific immunoglobulins in clinical practice is rarely performed to evaluate humoral immunity. Instead, HSV- and VZV-specific immunoglobulins are used to detect latent infection and identify patients at risk of reactivation after HCT and SOT [6]. Antibody tests for HHV-6 are not readily available and not recommended in transplant recipients [25]. Furthermore, titers of HSV-, VZV-, or HHV-6-specific immunoglobulins measured by enzyme-linked immunoassay (ELISA) do not necessarily correlate with neutralizing activity [16,37,38]. Some experts use total IgG levels as a marker of global infection risk, but hypogammaglobulinemia without concurrent lymphopenia does not correlate with the risk of VZV, HSV, or HHV-6B reactivation or disease [39,40].

Assessing cellular immunity

Absolute CD4 T cell count is often measured as a global assessment of immune reconstitution in transplant recipients but may not accurately reflect virus-specific CMI [4,41]. Cytokine release assays that measure virus-specific CMI have the potential to predict the risk of herpesvirus infections. Commercial and in-house enzyme-linked immunospot (ELISPOT) assays, which detect interferon-g release by purified peripheral blood mononuclear cells after incubation with virus-specific peptides or antigen lysates, have been developed to assess CMV-CMI but are unable to differentiate CD4 and CD8 responses [42,43]. The ratio of IFN- g-producing cells to peripheral blood mononuclear cells are measured, but thresholds for positivity vary among individual assays [42]. Prospective studies of CMV-ELISPOT assays in HCT and kidney transplant recipients have demonstrated that positive results, indicative of in vitro CMV-CMI, have high negative predictive values (>93%) but low positive predictive values (<30%) for clinically significant CMV infection (CSCMVi) [43,44]. Among 241 CMV seropositive allogeneic HCT recipients, CMV-CMI was low in 94% of patients who experienced CSCMVi in the first 6 months after transplant [43].

Such CMI assays for HSV, VZV, and HHV-6 are not clinically available but could help providers understand an individual's risk for viral infections and guide the duration of HSV and VZV pharmacologic prophylaxis after transplant or after immunization, particularly among HCT recipients with profound T-cell dysfunction. VZV-CMI has been correlated with protection against HZ in vaccine clinical trials, suggesting that VZV-CMI assays may predict the safe termination of VZV prophylaxis after HCT [24]. Specific thresholds associated with protection need to be established before CMI assays for non-CMV herpesviruses can be integrated into clinical practice.

Restoring humoral and cellular immunity

Active immunization (vaccination)

Vaccination to promote endogenous humoral and cellular immunity is one approach to restoring virus-specific immune responses. VZV is the only herpes virus for which licensed vaccines are currently available. Vaccines for the prevention of HSV and HHV-6 primary infection have been developed, but efforts have not focused on immunocompromised populations [16,38]. In addition to the live attenuated vaccine given to children to prevent varicella, two vaccines have been developed for the prevention of HZ in adults: a live attenuated vaccine (zoster vaccine live [ZVL], ZOSTAVAX, Merck) and an adjuvanted recombinant glycoprotein E subunit vaccine (recombinant zoster vaccine [RZV], SHINGRIX, GlaxoSmithKline). RZV has greater vaccine efficacy than ZVL for the prevention of HZ and is the only zoster vaccine available in the United States [45,46]. Unlike ZVL, RZV does not carry the risk of disseminated VZV infection and is, therefore, safer in immunocompromised populations. The United States Food and Drug Administration has approved RZV for immunocompromised adults aged 18 and older [47].

SOT and autologous HCT recipients receiving RZV in clinical trials demonstrated similar or slightly reduced humoral and cellular immune responses compared to immunocompetent adults [20,45,48e52]. In a placebo-controlled clinical trial of RZV in autologous HCT recipients, vaccine efficacy was ~70% and RZV elicited humoral and cellular responses in 67% and 93% of vaccinees, respectively [48]. RZV may be less immunogenic and less effective in allogeneic HCT recipients. In an observational series of allogeneic HCT recipients who received RZV at a median of 7 months posttransplant, humoral response occurred in only 3 of 18 (18%) patients [53]. In a separate cohort of allogeneic HCT recipients who received two doses of RZV and subsequently discontinued antiviral prophylaxis, three (2%) developed HZ within 6 months of the second dose [53]. Notably, data on the safety, immunogenicity, and efficacy of RZV in the first 6e12 months after allogeneic HCT or SOT are limited, and RZV has not eliminated the need for antiviral prophylaxis in the early post-transplant periods. Passive immunization strategies may be more effective in the early periods after HCT and SOT until adequate immune reconstitution is achieved and documented with virus-specific assays.

Immune globulins

Passive immunization with pooled intravenous (or subcutaneous) immune globulin replenishes humoral immunity and is used to prevent bacterial and sinopulmonary infections in patients with a variety of immunocompromising conditions but does not have a major role in the management of HSV, VZV, or HHV-6 [6,7,25,39]. Immune globulin preparations containing high titers of anti-VZV IgG are recommended to reduce the attack rate and prevent complications of varicella in VZV-seronegative immunocompromised patients after VZV exposure but are not routinely used to prevent reactivation of or treat infections due to HSV, VZV, or HHV-6 in seropositive immunocompromised populations [6,7,25,54].

Virus-specific T cells

Single or repeated virus-specific T cell (VST) infusions are a promising passive immunization strategy to replenish cellular immunity in immunocompromised patients. In HCT recipients, donor lymphocyte infusions are limited by graft versus host reactions due to the population of donor T cells recognizing recipient antigens. Selected infusion of CD4 and CD8 VSTs, or other approaches such as virus-specific NK cells or T cells with engineered receptors, may provide CMI while avoiding off-target T cell alloreactivity [55,56]. VST products were first designed to target individual viruses, including CMV, EBV, BK virus, and adenovirus [57]. More recently, multi-virus VST products that recognize a collection of double-stranded DNA viruses, including HHV-6B, are being studied for prophylaxis and treatment of viral infections in high-risk HCT recipients and have been administered for drug-refractory HHV-6B encephalitis in a limited number of patients [56,58,59]. HSV1-specific VSTs have been generated in vitro, but there are no reports of HSV- or VZV-specific T-cell use in humans to date [56,60].

No serious adverse events have been causally linked to VST infusion, though graft versus host disease and cytokine release syndrome are theoretical risks [56]. Despite VST's potential to revolutionize the management of viral infections in immunocompromised populations, evidence from placebo-controlled trials is not yet available, and there are several challenges to VST implementation in clinical practice (Table 2).

Conclusions

HSV, VZV, and HHV-6 continue to cause severe disease in patients with impaired cellular immunity. Although antiviral prophylaxis has reduced the incidence of VZV and HSV infections after HCT and SOT, there are several limitations of antivirals in terms of safety, efficacy, and implementation. Laboratory methods assessing virus-specific CMI immunity have the potential to guide the duration of VZV prophylaxis after HCT, but clinical correlates of protection need to be established before routine use. Interventions focusing on measuring and optimizing an individual's cellular immunity offer a precision medicine approach to infection prevention and management. Highly immunogenic vaccines may be valuable in some immunocompromised patients, and initiatives to develop vaccines that prevent HSV and HHV-6B reactivation are needed. However, in patients with the most profound deficits in CMI, active immunization is unlikely to induce protective immunity. VSTs are a promising tool to reduce viral reactivation and replication in highly immunocompromised patients awaiting CMI recovery. Overcoming the impact of immunosuppressants on VST expansion and function should be a focus of future investigations.

Transparency declaration

MRH received speaking honoraria from Cigna LifeSource and Thermo Fisher Scientific. JAH received consulting fees from Gilead Sciences, Allovir, and Takeda and research support from Takeda, Allovir, Deverra Therapeutics, and Gilead. KMA has no relevant interests to disclose.

This work was supported by the National Institute of Allergy and Infectious Diseases (T32AI118690 to MRH) and the National Cancer Institute (U01CA247548 to JAH) of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author contributions

MRH and JAH identified relevant content and designed the manuscript. MRH and KMA wrote the initial manuscript. JAH provided supervision and assistance with editing.

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