Infection of lymphocytes by a virus that aborts cytotoxic T lymphocyte activity and establishes persistent infection.

For viruses to establish persistent infections in their hosts, they must possess some mechanism for evading clearance by the immune system. When inoculated into adult immunocompetent mice, wild-type lymphocytic choriomeningitis virus (LCMV ARM) induces a CD8(+)-mediated cytotoxic T lymphocyte (CTL) response that clears the infection within 7-14 d (CTL+ [P-]). By contrast, variant viruses isolated from lymphoid tissues of persistently infected mice fail to induce a CTL response and are thus able to establish a persistent infection in adult mice (CTL- [P+]). This report compares the interaction of CTL+ (P-) and CTL- (P+) viruses with cells of the immune system. Both types of virus initially bind to 2-4% of CD4+ and CD8+ T lymphocytes and replicate within cells of both subsets. The replication of CTL- (P+) and CTL+ (P-) viruses in lymphocytes in vivo is similar for the first 5 d after initiating infection. Thereafter, in mice infected with CTL- (P+) variants, lymphocytes retain viral genetic information, and infectious virus can be recovered throughout the animals' lives. In contrast, when adult mice are infected with wild-type CTL+ (P-) LCMV ARM, virus is not recovered from lymphocytes for greater than 7 d after infection. A CD8(+)-mediated anti-LCMV CTL response is induced in such mice. Clearance of infected lymphocytes is produced by these LCMV-specific CTLs, as shown by their ability to lyse lymphocytes expressing LCMV determinants in vitro and the fact that depletion of CD8+ lymphocytes before infection with CTL+ (P-) viruses results in levels of infected lymphocytes similar to those found in undepleted CTL- (P+)-infected mice. Hence, CTL-mediated lysis of T lymphocytes carrying infectious virus is a critical factor determining whether virus persists or the infection is terminated

Virus-induced immunosuppression. 1. Age at infection relates to a selective or generalized defect.

Viruses that persist must develop strategies to escape immunologic surveillance in order to survive. Investigation of lymphocytic choriomeningitis virus (LCMV)-induced persistence has indicated that this virus avoids immune clearance mainly by aborting the viral specific cytotoxic T lymphocyte (CTL) response, a response that is necessary for terminating viral infection. This study demonstrates that persistence established in immunologically immature newborns selectively depletes the LCMV-specific CTL response but does not hinder CTL responses to the RNA and DNA viruses influenza, vaccinia, or herpes simplex. In contrast, persistence established in immunologically mature adults leads not to selective but rather to generalized immunosuppression during which CTL responses to LCMV, influenza, vaccinia, and herpes simplex viruses are all ablated or down-regulated. These results indicate that the state of maturity of the immune system at the time of virus-induced immunosuppression can result in two distinct phenotypes. These observations may account for the differing patterns of infection caused by hepatitis B virus or human immunodeficiency virus initiated in the neonatal period compared to that initiated in adulthood