Research Group of M. Mach

Virology

Head of Institute:
Prof. Dr. med. Klaus Überla

Protective Immune Response against Cytomegalovirus

Human cytomegalovirus (HCMV) is an important, ubiquitously occurring, human pathogen in immunocompromised hosts.

The virus can cause severe disease in transplant recipients. In large parts of the world HCMV is also the most common viral infection acquired in utero. In the USA and Europe an estimated 0.2% -1.2% of all live born infants are infected with HCMV and 5-15% of these babies develop long term sequelae resulting from congenital infection. As a consequence of the importance of congenital HCMV infection for public health, the Institute of Medicine at the National Institutes of Health (NIH), USA, has ranked the development of a HCMV vaccine as a top priority.

A major obstacle for the development of a vaccine is a lack of knowledge of the nature and specificities of protective responses that should be induced by the vaccine. HCMV is a complex virus containing numerous antigens within the viral envelope that could be targets for protective antibodies. Glycoprotein B (gB) is an important target for neutralizing antibodies and hence an interesting molecule for intervention strategies such as vaccination or passive immunotherapy. We have used the murine model system of CMV (MCMV) to explore the potential of gB-specific antibodies in immunotherapy or prophylaxis. Our results show that anti-gB antibodies can protect immunodeficient hosts from the lethal course of the infection. During therapy, both neutralizing as well as non-neutralizing antibodies showed significant protection with neutralizing antibodies being superior. Among the neutralizing antibodies protection correlated with in vivo half-life rather than with in vitro neutralizing titer. Interestingly, both neutralizing and non-neutralizing antibodies showed comparable protection when given prophylactically i.e. one day before infection with MCMV. Thus, our data indicate that in vitro neutralizing capacity of CMV-specific antibodies may not necessarily correlate directly with in vivo protection.

During our work on the antibody mediated protection against MCMV we serendipitously stumbled across a cell type which seems to be a potent player in the defense against CMV: γδ T cells.

We were able show for murine CMV infections that mice that lack CD8 and CD4 αβ T cells as well as B lymphocytes can control a MCMV infection that is lethal in RAG-1-/- mice lacking any T- and B-cells (Figure 1). γδ T cells, isolated from infected mice can kill MCMV infected target cells in vitro and, importantly, provide long-term protection in infected RAG-1-/- mice after adoptive transfer. γδ T cells in MCMV infected hosts undergo a prominent and long-lasting phenotypic change most compatible with the view that the majority of the γδ T cell population persists in an effector/memory state even after resolution of the acute phase of the infection. A clonotypically focused Vγ1 and Vγ2 repertoire was observed at later stages of the infection in the organs where MCMV persists. These findings add γδ T cells as yet another protective component to the anti-CMV immune response. Our data provide clear evidence that γδ T cells can provide an effective control mechanism of acute CMV infections, particularly when conventional adaptive immune mechanisms are insufficient or absent, like in transplant patients or in the developing immune system in utero.

Based on their properties, γδ T cells represent promising candidates for a cellular therapy against CMV infection and reactivation for example after organ or hematopoietic stem cell transplantation.

Figure 1. CD3+ T cells control MCMV infection in mice depleted of CD4+ and CD8+ T-lymphocytes and B cells.
(A) In two separate experiments CD8-/-JHT mice, which lack both CD8+ T cells and B cells, either untreated or treated with antibodies against CD4 or CD3 were infected with 105 pfu MCMV. In vivo imaging was performed on the days indicated. Images were obtained from a 120 sec acquisition. The pseudocolor scale shows relative photon flux for each image.
(B) RAG-/- mice were transferred 3 days after infection with 800,000 γδ T cells from infected CD8-/- JHT donor mice.
(C) Survival of RAG-/- mice adoptively transferred with 200,000 γδ T cells from naive (black) or infected (red) donors or PBS treated (grey) (P < 0.005; Mantel-Cox Test).
 
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Summary