Postexposure vaccination massively increases the prevalence of γ-herpesvirus-specific CD8⁺T cells but confers minimal survival advantage on CD4-deficient mice

Abstract

Mice that lack CD4 ؉ T cells remain clinically normal for more than 60 days after respiratory challenge with the murine ␥-herpesvirus 68 (␥HV-68), then develop symptoms of a progressive wasting disease. The ␥HV-68-specific CD8 ؉ T cells that persist in these I-A b؊/؊ mice are unable to prevent continued, but relatively low level, virus replication. Postexposure challenge with recombinant vaccinia viruses expressing ␥HV-68 lytic cycle epitopes massively increased the magnitude of the ␥HV-68-specific CD8 ؉ population detectable by staining with tetrameric complexes of MHC class I glycoprotein ؉ peptide, or by interferon-␥ production subsequent to in vitro restimulation with peptide. The boosting effect was comparable for ␥HV-68-infected I-A b؊/؊ and I-A b؉/؉ mice within 7 days of challenge, and took more than 110 days to return to prevaccination levels in the I-A b؉/؉ controls. Although the life-span of the I-A b؊/؊ mice was significantly increased, there was no effect on long-term survival. A further boost with a recombinant influenza A virus failed to improve the situation. Onset of weight loss was associated with a decline in ␥HV-68-specific CD8 ؉ T cell numbers, though it is not clear whether this was a cause or an effect of the underlying pathology. Even very high levels of virus-specific CD8 ؉ T cells thus provide only transient protection against the uniformly lethal consequences of ␥HV-68 infection under conditions of CD4 ؉ T cell deficiency.T he murine ␥-herpesvirus 68 (␥HV-68) is related (1, 2) both to Epstein-Barr virus (EBV) and to human herpesvirus 8 (HHV-8). These three ␥HVs are characterized by the establishment of life-long latency in B lymphocytes, subsequent to (at least for ␥HV-68 and EBV) a transient phase of lytic infection in the oropharynx and respiratory epithelium. Increased levels of ␥HV replication and tumorigenesis (EBV and HHV-8) are common consequences (3) of AIDS induced by HIV. It is far from clear whether the escape of these persistent ␥HVs from immune control in AIDS patients is a direct reflection of the compromised CD4 ϩ T cell response (4-6), or is because of the subsequent decline in virus-specific CD8 ϩ T cell numbers.Mice that lack CD4 ϩ T cells as a consequence of homozygous disruption of the H2-IA b gene (I-A bϪ/Ϫ ) remain healthy for 2-3 mo after respiratory challenge with ␥HV-68, then develop symptoms of chronic wasting disease (7-9). Unlike the situation for congenic I-A bϩ/ϩ mice, the ␥HV-68 lytic phase in lung epithelium is never completely controlled. Apparently, both CD4 ϩ and CD8 ϩ effectors are important, with the CD4 ϩ set operating by means of ␥-interferon (IFN-␥) production (9) and the CD8 ϩ

Dendritic Cells Present Lytic Antigens and Maintain Function throughout Persistent γ-Herpesvirus Infection

“…Similarly, adoptive transfer of T cells educated in chronically infected hosts into naive mice is poorly maintained and fails to undergo homeostatic proliferation (60). Interestingly, some persistent infections, such as murine ␥-HV infection, generate CD8 ϩ T cells that appear to be completely functional throughout viral persistence (22,61,62). These Ag-specific CD8 ϩ T cells frequently persist for prolonged periods at high levels and are maintained by increased division compared with rapidly cleared virus infections such as influenza (23).…”

Inhibition of MHC class I-restricted antigen presentation by γ2-herpesviruses

“…In contrast, a lack of CD4 ϩ T cells leads to a lethal wasting disease associated with chronic lytic viral replication (16). This does not reflect CTL exhaustion in CD4 ϩ T cell-deficient mice (17); indeed, there is some increase in their virus-specific CD8 ϩ T cell numbers as the antigen load rises (17), and even massively boosting the CD8 response by postexposure, epitope-specific vaccination does not improve survival (18). Clearly CTLs can respond to some ␥HV-68-infected cells but cannot fully control lytic cycle replication.…”

Maintenance of Gammaherpesvirus Latency Requires Viral Cyclin in the Absence of B Lymphocytes

“…Vaccination against gammaherpesviruses has been a major goal in preventing gammaherpesvirus-associated morbidity and mortality (22,28,29); however, it has not yet proven efficient in preventing chronic disease (4). Recent studies have demonstrated effective protection from wt ␥HV68 latency (35) by vaccination with a v-cyclin-deficient live attenuated virus; this promising strategy has been predicted to result in prevention of chronic disease.…”