Human cytomegalovirus (HCMV)‐specific T cell but not neutralizing or IgG binding antibody responses to glycoprotein complexes gB, gHgLgO, and pUL128L correlate with protection against high HCMV viral load reactivation in solid‐organ transplant recipients

Abstract

Immune correlates of protection against human cytomegalovirus (HCMV) infection are still debated. This study aimed to investigate which arm of the immune response plays a major role in protection against HCMV infection in kidney transplant recipients (n = 40) and heart transplant recipients (n = 12). Overall, patients were divided into 2 groups: one including 37 patients with low viral load (LVL), and the other including 15 patients with high viral load (HVL). All LVL patients resolved the infection spontaneously, whereas HVL patients were all treated with one or more courses of antivirals. In HVL patients, viral DNAemia, which was more than 100 times higher than LVL, appeared and peaked at significantly earlier times, but disappeared much later than in LVL patients. During a 1-year follow-up, all LVL patients had levels of HCMV-specific CD4 (and CD8 ) T cells significantly higher than HVL patients. On the contrary, titers of neutralizing antibodies and enzyme-linked immunosorbent assay-IgG antibodies to gB, gHgLgO, and pentamer gHgLpUL128L were overlapping in the 2 patient groups. In conclusion, while a valid HCMV-specific T-cell response was detected in more than 90% of LVL patients, >90% of HVL patients lacked an adequate T-cell response. Antibody responses did not appear to be associated directly or indirectly with protection.

Cell-to-Cell Spread Blocking Activity Is Extremely Limited in the Sera of Herpes Simplex Virus 1 (HSV-1)- and HSV-2-Infected Subjects

“…After washing with 0.1% Tween 20 in PBS solution, serum IgGs were detected with goat anti-human IgG (Fab specific)-peroxidase antibody and a Pierce TMB substrate kit, measuring the OD 450 . Titers of specific IgGs were calculated by interpolating from the sigmoidal standard curves obtained with human monoclonal antibodies (37).…”

Human Cytomegalovirus Congenital (cCMV) Infection Following Primary and Nonprimary Maternal Infection: Perspectives of Prevention through Vaccine Development

“…In recent years, reports have been published that have claimed that protection from infection might be conferred by extraneutralizing antibody functions, such as AD-cellular cytotoxicity (ADCC) [108], AD-cellular phagocytosis (ADCP), [109], AD-complement deposition (ADCD) [107], and AD-NK cell activation [7]. In transplanted patient sera, we repeatedly observed the presence of very high NAb titers as well as ELISA IgG antibody response to PC, in the absence of protection against HCMV infection [110]. These results were recently confirmed by an ADCC-assay, which showed that the protective effect elicited by the gB vaccine cannot be explained either by NAb or ADCC in PI of transplanted patients [111].…”

“…Similar to the pregnant women population, the HCMV-specific CD4 + and CD8 + T cell responses were also repeatedly investigated in both solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients [110,[113][114][115], confirming the primary role of the CD4 + T cell response in association with the complementary and supporting role of CD8 + T cells. A major breakthrough in the study of the mechanism of protection against HCMV infection might have been brought about by the development of antibody-dependent cellular assays, in which a cooperation of cellular and humoral arms of the immune response appears to be a potential major tool of defense against HCMV infections.…”

Virus-Like Particles and Nanoparticles for Vaccine Development against HCMV

“…Although the HCMV-specific T cell response is very broad, the vast majority of the results points toward antigens that are highly conserved among different HCMV strains, such as the 65 kDa phosphoprotein (pp65) and the immediate early 1 (IE1) proteins, which are recognized by more than 50% of seropositive individuals [28]. CD8 + T cells were proven to have a protective role in both HSCT and SOT recipients [33][34][35] and a function in preventing congenital HCMV infection [36]. However, one of the paradoxes of the cellular immunity against HCMV comes from the observation that HCMV does induce a very large T cell response, meanwhile the virus also possesses sophisticated and numerous immune evasion mechanisms [37].…”