Cytomegalovirus pp65 limits dissemination but is dispensable for persistence

Daniel Malouli, Scott Hansen, Ernesto S. Nakayasu, Emily Marshall, Colette M. Hughes, Abigail B. Ventura, Roxanne M. Gilbride, Matthew S. Lewis, Guangwu Xu, Craig Kreklywich, Nathan Whizin, Miranda Fischer, Alfred W. Legasse, Kasinath Viswanathan, Don Siess, David G. Camp, Michael Axthelm, Christoph Kahl, Victor De Filippis, Richard D. Smith & 3 others Daniel Streblow, Louis Picker, Klaus Frueh

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17 Citations (Scopus)

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 (RhCMV pp65ab). 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.

Original languageEnglish (US)
Pages (from-to)1928-1944
Number of pages17
JournalJournal of Clinical Investigation
Volume124
Issue number5
DOIs
StatePublished - 2014

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Phosphoproteins
Infection
T-Lymphocytes
Virion
Immunity
Vaccines
cytomegalovirus matrix protein 65kDa
Antigen Presentation
Growth
Cytomegalovirus
Proteins
Genome
Antigens

ASJC Scopus subject areas

  • Medicine(all)

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Cytomegalovirus pp65 limits dissemination but is dispensable for persistence. / Malouli, Daniel; Hansen, Scott; Nakayasu, Ernesto S.; Marshall, Emily; Hughes, Colette M.; Ventura, Abigail B.; Gilbride, Roxanne M.; Lewis, Matthew S.; Xu, Guangwu; Kreklywich, Craig; Whizin, Nathan; Fischer, Miranda; Legasse, Alfred W.; Viswanathan, Kasinath; Siess, Don; Camp, David G.; Axthelm, Michael; Kahl, Christoph; De Filippis, Victor; Smith, Richard D.; Streblow, Daniel; Picker, Louis; Frueh, Klaus.

In: Journal of Clinical Investigation, Vol. 124, No. 5, 2014, p. 1928-1944.

Research output: Contribution to journalArticle

Malouli, D, Hansen, S, Nakayasu, ES, Marshall, E, Hughes, CM, Ventura, AB, Gilbride, RM, Lewis, MS, Xu, G, Kreklywich, C, Whizin, N, Fischer, M, Legasse, AW, Viswanathan, K, Siess, D, Camp, DG, Axthelm, M, Kahl, C, De Filippis, V, Smith, RD, Streblow, D, Picker, L & Frueh, K 2014, 'Cytomegalovirus pp65 limits dissemination but is dispensable for persistence', Journal of Clinical Investigation, vol. 124, no. 5, pp. 1928-1944. https://doi.org/10.1172/JCI67420
Malouli, Daniel ; Hansen, Scott ; Nakayasu, Ernesto S. ; Marshall, Emily ; Hughes, Colette M. ; Ventura, Abigail B. ; Gilbride, Roxanne M. ; Lewis, Matthew S. ; Xu, Guangwu ; Kreklywich, Craig ; Whizin, Nathan ; Fischer, Miranda ; Legasse, Alfred W. ; Viswanathan, Kasinath ; Siess, Don ; Camp, David G. ; Axthelm, Michael ; Kahl, Christoph ; De Filippis, Victor ; Smith, Richard D. ; Streblow, Daniel ; Picker, Louis ; Frueh, Klaus. / Cytomegalovirus pp65 limits dissemination but is dispensable for persistence. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 5. pp. 1928-1944.
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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 (RhCMV pp65ab). 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.",
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AU - Malouli, Daniel

AU - Hansen, Scott

AU - Nakayasu, Ernesto S.

AU - Marshall, Emily

AU - Hughes, Colette M.

AU - Ventura, Abigail B.

AU - Gilbride, Roxanne M.

AU - Lewis, Matthew S.

AU - Xu, Guangwu

AU - Kreklywich, Craig

AU - Whizin, Nathan

AU - Fischer, Miranda

AU - Legasse, Alfred W.

AU - Viswanathan, Kasinath

AU - Siess, Don

AU - Camp, David G.

AU - Axthelm, Michael

AU - Kahl, Christoph

AU - De Filippis, Victor

AU - Smith, Richard D.

AU - Streblow, Daniel

AU - Picker, Louis

AU - Frueh, Klaus

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N2 - 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 (RhCMV pp65ab). 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.

AB - 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 (RhCMV pp65ab). 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.

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