Epidemiologic data indicate that increased age is associated with increased incidences of various bacterial and viral infections, as well as increased morbidity and mortality subsequent to these infections. Few studies have directly assessed the role of the decreased immune response in diminished control of infections in the aged. The applicants have observed a significant age-associated decrease in the ability of aged mice to control retrovirus infection. Thus, young mice of certain inbred strains demonstrate resistance to the E55+ murine leukemic virus (MuLV). Both susceptible and resistant young mice mount an early response that results in a dramatic decrease in the number of virus-infected cells within 4-8 weeks after infection, while immunosuppression of mice prior to inoculation of virus prevents this decrease. Subsequently, susceptible mice develop an increase in virus-infected cells and progress to virus-induced disease. Resistant mice generate an effective anti-virus T cell response that appears to keep infected cells at low levels. Aged mice demonstrate an infection profile with E55+ virus similar to immunosuppressed mice: the level of virus production remains constant at 2, 8, and 12 weeks of infection. Since: 1) the control of virus production in resistant mice appears to be due to an effective immune response; 2) the level of virus in aged mice is comparable to immunosuppressed mice; and 3) the level of immune response declines with increasing age, the applicants hypothesize that maintenance of persistent E55+ MuLV infection at high levels in aged mice is due to the failure of aged mice to generate an effective immune response to the virus. The proposed studies will assess the age-associated differences in humoral (Aim 1) and cellular (Aim 2) immune responses which may result in the observed differences in regulation of virus production. In addition, the applicants will determine whether the pattern of E55+ infection in aged mice can be altered by immunotherapy, including adoptive transfer of cells from young mice and immunization (Aim 3). The proposed studies with the E55+ virus infection model provides an opportunity to examine directly the hypothesis that the age-associated alterations in immune response are causally related to the reduced ability of the aged to control a persistent virus infection.
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