Early interactions of DNA viruses and host

Wistar Institute, Philadelphia PA

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Abstract

Project Description Human cytomegalovirus (HCMV) infection has serious consequences for immunocompromised individuals, such as AIDS and organ transplant patients and congenitally infected newborns. Of symptomatic newborns, 12% die and many of the survivors suffer mental retardation, vision loss, and sensorineural deafness. Current HCMV interference strategies targeting early events in viral DNA replication are neither permissible nor feasible for treating the infected fetus, and may lead to drug resistance. We propose to investigate the immediate-early stage of the CMV infectious cycle to identify new potential targets of therapy. The immediateearly proteins 1 and 2 (IE1, IE2) are essential for the replicative success and reactivation of HCMV from latency. We hypothesize that: 1. Regulated alternative splicing determines the second step in the multi-step process of reactivation from latency, and 2. IE1 counteracts intrinsic nuclear defenses such as gene silencing and induction of apoptosis, so that a block in IE protein function will greatly reduce or totally abrogate viral replication. To test these hypotheses, we will investigate the major IE proteins of both human and mouse CMV in parallel to establish functional homology. Specifically, we will determine: 1. How splicing determines the amount and timing of the major immediate early transcription unit, 2. Whether a mouse model inducibly expressing the immediate early proteins can elucidate the early steps in the multi-step reactivation sequence and cell-specific expression of IE1 and IE2, and 3. How IE1 counters the gene silencing-based antiviral defenses of the host cell with the goal of deciding whether it is a reasonable target to block the lytic and reactivation cascade. Information from these analyses will shift the paradigm for CMV interference options away from replicative events and toward earlier events in the infection.