In Vitro and In Vivo Transactivation of HIV-1 by Human Herpesvirus 6

Abstract

1.1 Latency and reactivation of HIV-1 Since the discovery of human immunodeficiency virus type 1 (HIV-1), there has been a great deal of interest in identifying cofactors that might accelerate the stages of development associated with acquired immunodeficiency syndrome (AIDS). Many environmental agents, namely inherent factors such as ethnicity and geographical location, were first implicated as risk factors in the study of HIV infection. However, speculation that infectious diseases may act as cofactors in HIV infection began to be studied soon thereafter. These speculations led to one of the early opinions that HIV plays a correlary role in AIDS, but not a causative role (Duesberg, 1989). AIDS patients have a history of both circumstantial serological and microbial evidence of increased exposure to a number of common and opportunistic infectious agents. It is difficult to ascertain, however, whether these various coinfections contribute anything to the progressive decline of the immune system (Pedersen et al., 1990). In vivo, infection with HIV-1 is followed by a long disease-free period, during which a low number of CD4+ mononuclear leukocytes (CCR5 coreceptor positive monocytes and CXCR4 coreceptor positive lymphocytes) containing transcriptionally silent integrated provirus can be found. HIV-1 replication can be demonstrated in only a small population of T cells without inducing clinical manifestations. This state of latency is partly due to low transcriptional activity of the integrated provirus in resting cells. Activation of CD4+ cells by antigens, mitogens (Tobiume et al., 1998) or superinfection by other viruses interacting with HIV-1 via viral and/or cellular transacting factors may terminate HIV-1 latency, leading to a productive HIV-1 infection. Transactivation of the HIV-1 long terminal repeat (LTR) in turn will induce gene expression, including the synthesis of the HIV-1 transactivator protein (TAT) (Arya et al., 1985). TAT will then independently amplify HIV-1 gene expression, ultimately leading to a high level of virus replication and death of infected cells. Onset and progression of AIDS correlates with augmented production of infectious virions parallel to a