title: Cytomegalovirus pp65 limits dissemination but is dispensable for persistence.
abstract: The most abundantly produced virion protein in human cytomegalovirus (HCMV) is the immunodominant phosphoprotein 65 (pp65), which is frequently included in CMV vaccines. Although it is nonessential for in vitro CMV growth, pp65 displays immunomodulatory functions that support a potential role in primary and/or persistent infection. To determine the contribution of pp65 to CMV infection and immunity, we generated a rhesus CMV lacking both pp65 orthologs (RhCMVΔpp65ab). While deletion of pp65ab slightly reduced growth in vitro and increased defective particle formation, the protein composition of secreted virions was largely unchanged. Interestingly, pp65 was not required for primary and persistent infection in animals. Immune responses induced by RhCMVΔpp65ab did not prevent reinfection with rhesus CMV; however, reinfection with RhCMVΔUS2-11, which lacks viral-encoded MHC-I antigen presentation inhibitors, was prevented. Unexpectedly, induction of pp65b-specific T cells alone did not protect against RhCMVΔUS2-11 challenge, suggesting that T cells targeting multiple CMV antigens are required for protection. However, pp65-specific immunity was crucial for controlling viral dissemination during primary infection, as indicated by the marked increase of RhCMVΔpp65ab genome copies in CMV-naive, but not CMV-immune, animals. Our data provide rationale for inclusion of pp65 into CMV vaccines but also demonstrate that pp65-induced T cell responses alone do not recapitulate the protective effect of natural infection.
authors.forename: Daniel
authors.initials: D
authors.lastname: Malouli
authors.forename: Scott G
authors.initials: SG
authors.lastname: Hansen
authors.forename: Ernesto S
authors.initials: ES
authors.lastname: Nakayasu
authors.forename: Emily E
authors.initials: EE
authors.lastname: Marshall
authors.forename: Colette M
authors.initials: CM
authors.lastname: Hughes
authors.forename: Abigail B
authors.initials: AB
authors.lastname: Ventura
authors.forename: Roxanne M
authors.initials: RM
authors.lastname: Gilbride
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Lewis
authors.forename: Guangwu
authors.initials: G
authors.lastname: Xu
authors.forename: Craig
authors.initials: C
authors.lastname: Kreklywich
authors.forename: Nathan
authors.initials: N
authors.lastname: Whizin
authors.forename: Miranda
authors.initials: M
authors.lastname: Fischer
authors.forename: Alfred W
authors.initials: AW
authors.lastname: Legasse
authors.forename: Kasinath
authors.initials: K
authors.lastname: Viswanathan
authors.forename: Don
authors.initials: D
authors.lastname: Siess
authors.forename: David G
authors.initials: DG
authors.lastname: Camp
authors.forename: Michael K
authors.initials: MK
authors.lastname: Axthelm
authors.forename: Christoph
authors.initials: C
authors.lastname: Kahl
authors.forename: Victor R
authors.initials: VR
authors.lastname: DeFilippis
authors.forename: Richard D
authors.initials: RD
authors.lastname: Smith
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Streblow
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Picker
authors.forename: Klaus
authors.initials: K
authors.lastname: Früh
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D022482:Cytomegalovirus Vaccines / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D022482:Cytomegalovirus Vaccines; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa