Human cytomegalovirus-specific cytotoxic T cells. Relative frequency of stage-specific CTL recognizing the 72-kD immediate early protein and glycoprotein B expressed by recombinant vaccinia viruses.

Abstract

CTL are held to be an important host defense mechanism in persistent herpes-virus infections. We have therefore studied the nature and specificity of human cytomegalovirus (HCMV)-specific CTL in normal persistently infected individuals. This was achieved by using vaccinia recombinants encoding viral genes expressed at different stages of the virus replicative cycle, a structural glycoprotein gB (vac.gB) and the major 72-kD immediate early nonstructural protein (vac.IE) of HCMV, combined with limiting dilution analysis of the CTL response. In two subjects, 43 and 58% of HCMV CTL precursors (CTLp) lysed vac.IE-infected cells, in contrast to less than 6% lysing gB-infected cells. HCMV-specific CTL could also be generated by secondary in vitro stimulation with vac.gB- but not vac.IE-infected autologous fibroblasts. The high frequency of 72-kD IE protein-specific CTL suggests that this is at least a major recognition element for the HCMV-specific CTL response in asymptomatic persistently infected individuals, and CTL with this specificity may be important in maintaining the normal virus/host equilibrium.

Human Cytomegalovirus Proteins pp65 and Immediate Early Protein 1 Are Common Targets for CD8+ T Cell Responses in Children with Congenital or Postnatal Human Cytomegalovirus Infection

“…Our data suggest that infants are capable of generating IE1-specific CD8 ϩ T cell responses, and that IE1 may be more commonly targeted by CD8 ϩ T cells. The apparent prominence of IE1-specific CD8 ϩ T cell responses over time is compatible with the reported immunogenicity of IE1 in mice (58,59) and humans (26). Moreover, culture-based methodologies used in early studies to identify targets of HCMV-specific CD8 ϩ T cell responses may have preferentially expanded pp65-specific CD8 ϩ T cells (55).…”

Enhancement of CD4 and CD8 immunity by anti-CD137 (4-1BB) monoclonal antibodies during hepatitis C vaccination with recombinant adenovirus

“…However, they are weak and inefficient [3][4][5][6][7][8][9][10]14,15,45]. In fact, the frequency of CTL precursors against HCV proteins found in patients with chronic hepatitis C is very low, in comparison to that found in HIV or CMV infections [46][47][48]. It has been described that HCV can infect DC and that expression of HCV proteins inside DC induces an impairment of its stimulatory functions [20] and this impairment might lead an inefficient priming of anti-HCV T cell responses [19,29,49].…”

Presentation of CMV immediate-early antigen to cytolytic T lymphocytes is selectively prevented by viral genes expressed in the early phase

“…For human CMV there is evidence that IE genes, but not late genes, are expressed in latently infected cells (Rice et al , 1984;Schrier et al, 1985). Since in human CMV the gene IE1 corresponding to gene iel of MCMV also codes for an immunodominant antigen for CTLs (Borysiewicz et al, 1988), it remains an unsolved question how latently infected cells expressing a protein of proven antigenicity can survive in the face of a specific CTL response. The kind of negative regulation of antigen presentation documented here for MCMV could provide the solution for this paradox.…”

“…tory phosphoprotein pp89, wh ich is eneoded by MCMV gene iel (Keil et al, 1985Koszinowski et al, 1986), are required tor the subsequent expression of early-phase genes, which, after onset of DNA replieation, are followed by late-phase genes. IE proteins also represent antigens recognized by the majority of antiviral CTLs Koszinowski et aI., 1987;Borysiewicz et al. 1988).…”