Role of CD8⁺Lymphocytes in Control and Clearance of Measles Virus Infection of Rhesus Monkeys

Abstract

The creation of an improved vaccine for global measles control will require an understanding of the immune mechanisms of measles virus containment. To assess the role of CD8 ؉ cytotoxic T lymphocytes in measles virus clearance, rhesus monkeys were depleted of CD8؉ lymphocytes by monoclonal anti-CD8 antibody infusion and challenged with wild-type measles virus. The CD8 ؉ lymphocyte-depleted animals exhibited a more extensive rash, higher viral loads at the peak of virus replication, and a longer duration of viremia than did the control antibody-treated animals. These findings indicate a central role for CD8؉ lymphocytes in the control of measles virus infections and the importance of eliciting a cell-mediated immune response in new measles vaccine strategies.Measles remains an important cause of morbidity and mortality in young children. Although a preventative live attenuated measles virus (MV) vaccine has long been available, its efficacy is incomplete. The immunogenicity of this vaccine has been limited in young infants by maternal antibody interference and immune system immaturity (6), leaving substantial numbers of vaccinated infants susceptible to disease. In fact, approximately 1 million deaths per year are still attributable to measles, with the majority of these deaths occurring in subSaharan Africa (1).Defining the immune mechanisms critical for the control of MV replication will be important in developing new measles vaccination strategies. It is well established that anti-MV antibodies play a central role in protection against MV infection. However, accruing data have implicated cell-mediated immune responses in the control of MV replication (10,16,17,23,34). MV-specific, CD8 ϩ cytotoxic T lymphocytes are known to be activated and expanded in the peripheral blood in temporal association with the onset of the measles rash (16,17,21,30). Soluble CD8 and ␤ 2 microglobulin are increased in the plasma during acute measles infection in children (12).A number of clinical observations have also implicated MVspecific cellular immune responses in the clearance of this virus. Children with cellular immune deficiencies have more severe clinical disease after MV infection than children who are hypogammaglobulinemic or who are immunologically intact (8,24), and the potency of the cell-mediated immune response has been correlated with the ability of infected individuals to recover from MV infection (3). Human immunodeficiency virus-infected children are more likely to have prolonged shedding of MV than those who are human immunodeficiency virus negative (26), presumably because of impaired MV-specific cellular immune responses. In a transgenic mouse model of MV infection (25), the T-lymphocytemediated immune response is required for clearance of neuronal infection (22). Nevertheless, these observations have all been correlative. The importance of cell-mediated immunity in MV clearance has not been directly demonstrated.Nonhuman primates can be infected with MV experimentally and provide the only available animal mod...

Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics

“…Consistent with a demonstrated role of CD8 + T cells in controlling viral infection (10,34), our model showed that the activation of the MeVspecific T-cell response correlated with the control of infectious virus and the initial decline in levels of MeV RNA (Fig. 3 and Fig.…”

“…Infection is initiated in the respiratory tract, and virus spreads to local lymphoid tissue and then to multiple organs, including the skin (9). In uncomplicated measles, clinical recovery occurs soon after the onset of the rash 10-14 d after infection and coincides with rapid clearance of infectious virus from the blood (10,11). Because of the short period of infectiousness and solid immunity against retransmission after recovery, large populations are required to maintain MeV transmission (12), especially in regions with highly seasonal population aggregation (13).…”

Modulation of disease, T cell responses, and measles virus clearance in monkeys vaccinated with H-encoding alphavirus replicon particles

“…CD8 ϩ T cells are induced by infection (68,69) and infiltrate sites of MV replication (8,70,71). Clearance of infectious virus is delayed in monkeys depleted of CD3 ϩ or CD8 ϩ T cells (72,73). In contrast, monkeys depleted of B cells clear infectious virus normally (74), and children with hypogammaglobulinemia recover from infection (75).…”

Morbilliviruses and human disease

“…The cotton rat model mimics aspects of immunosuppression of MV in the human [176,177]. The most realistic model that mimics MV infection in humans is that of infection in macaques [34,[178][179][180][181][182][183][184], but the cost of these animals is high and small numbers are available. Rash is shown as a reliable indicator of the value of a model.…”