{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:29:29Z","timestamp":1790267369563,"version":"4.1.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2009,12,1]],"date-time":"2009-12-01T00:00:00Z","timestamp":1259625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Following the priming and contraction phases of the T cell response, latent persistent herpesviruses lead to an accumulation of large pools of virus-specific CD8 T cells, also known as memory inflation (MI). The mechanism of this inflation is incompletely understood, largely because the molecular reactivation of these viruses in vivo and its impact upon T cell biology have not been resolved in mice, and because the relevant observations in humans remain, by necessity, correlative. Understanding these processes is essential from the standpoint of the proposed critical role for latent herpesviruses in aging of the immune system. We studied the causes of memory CD8 T cell accumulation following systemic HSV-1 administration as a model of widespread latent viral infection in humans. A direct role of viral latency and Ag-specific restimulation in driving the accumulation and maintenance of inflated CD8 T cells and a strongly suggested role of viral reactivation in that process were shown by the following: 1) lack of MI in the absence of established latency; 2) prevention or delay of MI with drugs that curtail viral replication; and 3) abrogation of MI by the transfer of inflated T cells into a virus-free environment. These results strongly suggest that periodic, subclinical reactivations of a latent persistent virus cause dysregulation of memory CD8 T cell homeostasis, similar to the one in humans. Moreover, results with antiviral drugs suggest that this approach could be considered as a treatment modality for maintaining T cell diversity and\/or function in old age.<\/jats:p>","DOI":"10.4049\/jimmunol.0801117","type":"journal-article","created":{"date-parts":[[2009,12,9]],"date-time":"2009-12-09T21:00:25Z","timestamp":1260392425000},"page":"8077-8087","source":"Crossref","is-referenced-by-count":46,"title":["Inflation and Long-Term Maintenance of CD8 T Cells Responding to a Latent Herpesvirus Depend upon Establishment of Latency and Presence of Viral Antigens"],"prefix":"10.1093","volume":"183","author":[{"given":"Anna","family":"Lang","sequence":"first","affiliation":[{"name":"Department of Immunobiology and Arizona Center on Aging, University of Arizona College of Medicine , Tucson, AZ 85724"},{"name":"Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health and Science University , Beaverton, OR 97006"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D","family":"Brien","sequence":"additional","affiliation":[{"name":"Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health and Science University , Beaverton, OR 97006"},{"name":"Department of Microbiology, Washington University School of Medicine , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janko","family":"Nikolich-\u017dugich","sequence":"additional","affiliation":[{"name":"Department of Immunobiology and Arizona Center on Aging, University of Arizona College of Medicine , Tucson, AZ 85724"},{"name":"Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health and Science University , Beaverton, OR 97006"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,15]]},"reference":[{"key":"2026012811223159800_R1","first-page":"406","article-title":"Is immunosenescence infectious?.","volume-title":"Trends Immunol.","year":"2004"},{"key":"2026012811223159800_R2","first-page":"673","article-title":"Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects.","volume-title":"J. Exp. Med.","year":"2005"},{"key":"2026012811223159800_R3","first-page":"3760","article-title":"Genome-wide analysis reveals a highly diverse CD8 T cell response to murine cytomegalovirus.","volume-title":"J. Immunol.","year":"2006"},{"key":"2026012811223159800_R4","first-page":"556","article-title":"An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans.","volume-title":"J. Gerontol. A Biol. Sci. Med. Sci.","year":"2005"},{"key":"2026012811223159800_R5","first-page":"2629","article-title":"Cytomegaloviruses and their replication. D. M. Knipe, and P. M. Howley, eds.","volume-title":"Fields Virology","year":"2001"},{"key":"2026012811223159800_R6","first-page":"403","article-title":"Human cytomegalovirus persistence and latency in endothelial cells and macrophages","year":"2002"},{"key":"2026012811223159800_R7","first-page":"1762","article-title":"Latency, without persistence, of murine cytomegalovirus in the spleen and kidney.","volume-title":"J. Virol.","year":"1995"},{"key":"2026012811223159800_R8","first-page":"S23","article-title":"Mouse models of cytomegalovirus latency: overview.","volume-title":"J. Clin. Virol.","year":"2002"},{"key":"2026012811223159800_R9","first-page":"397","article-title":"Reactivation of latent infection and induction of recurrent herpetic eye disease in mice.","volume-title":"J. Gen. Virol.","year":"1990"},{"key":"2026012811223159800_R10","first-page":"945","article-title":"Reactivation of murine latent HSV infection by epinephrine iontophoresis.","volume-title":"Invest. Ophthalmol. Vis. Sci.","year":"1984"},{"key":"2026012811223159800_R11","first-page":"593","article-title":"Herpes simplex virus-specific memory CD8+ T cells Are selectively activated and retained in latently infected sensory ganglia.","volume-title":"Immunity","year":"2003"},{"key":"2026012811223159800_R12","first-page":"8356","article-title":"Latent virus influences the generation and maintenance of CD8+ T cell memory.","volume-title":"J. Immunol.","year":"2006"},{"key":"2026012811223159800_R13","first-page":"1703","article-title":"Qa-1b and CD94-NKG2a interaction regulate cytolytic activity of herpes simplex virus-specific memory CD8+ T cells in the latently infected trigeminal ganglia.","volume-title":"J. Immunol.","year":"2006"},{"key":"2026012811223159800_R14","first-page":"1177","article-title":"Identification of an immunodominant cytotoxic T-lymphocyte recognition site in glycoprotein B of herpes simplex virus by using recombinant adenovirus vectors and synthetic peptides.","volume-title":"J. Virol.","year":"1991"},{"key":"2026012811223159800_R15","first-page":"2346","article-title":"Herpes simplex virus class I-restricted peptide induces cytotoxic T lymphocytes in vivo independent of CD4+ T cells.","volume-title":"J. Immunol.","year":"1993"},{"key":"2026012811223159800_R16","first-page":"62","article-title":"Epitope specificity of H-2Kb-restricted, HSV-1-, and HSV-2-cross-reactive cytotoxic T lymphocyte clones.","volume-title":"Virology","year":"1993"},{"key":"2026012811223159800_R17","first-page":"4848","article-title":"Age-related dysregulation of CD8+ T cell memory specific for a persistent virus is independent of viral replication.","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012811223159800_R18","first-page":"512","article-title":"Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections.","volume-title":"Nat. Rev. Immunol.","year":"2008"},{"key":"2026012811223159800_R19","first-page":"11495","article-title":"Enrichment of immediate-early 1 (m123\/pp89) peptide-specific CD8 T cells in a pulmonary CD62Llo memory-effector cell pool during latent murine cytomegalovirus infection of the lungs.","volume-title":"J. Virol.","year":"2000"},{"key":"2026012811223159800_R20","first-page":"7496","article-title":"Murine model of interstitial cytomegalovirus pneumonia in syngeneic bone marrow transplantation: persistence of protective pulmonary CD8-T-cell infiltrates after clearance of acute infection.","volume-title":"J. Virol.","year":"2000"},{"key":"2026012811223159800_R21","first-page":"2022","article-title":"Memory inflation: continuous accumulation of antiviral CD8+ T cells over time.","volume-title":"J. Immunol.","year":"2003"},{"key":"2026012811223159800_R22","first-page":"156","article-title":"Characterization of two TCR transgenic mouse lines specific for herpes simplex virus.","volume-title":"Immunol. Cell Biol.","year":"2002"},{"key":"2026012811223159800_R23","first-page":"2919","article-title":"Development and migration of protective CD8+ T cells into the nervous system following ocular herpes simplex virus-1 infection.","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012811223159800_R24","first-page":"1127","article-title":"Turnover of naive- and memory-phenotype T cells.","volume-title":"J. Exp. Med.","year":"1994"},{"key":"2026012811223159800_R25","first-page":"301","article-title":"Molecular, cellular, and antigen requirements for development of age-associated T cell clonal expansions in vivo.","volume-title":"J. Immunol.","year":"2006"},{"key":"2026012811223159800_R26","first-page":"6888","article-title":"The probability of in vivo reactivation of herpes simplex virus type 1 increases with the number of latently infected neurons in the ganglia.","volume-title":"J. Virol.","year":"1998"},{"key":"2026012811223159800_R27","first-page":"5343","article-title":"The latent herpes simplex virus type 1 genome copy number in individual neurons is virus strain specific and correlates with reactivation.","volume-title":"J. Virol.","year":"1998"},{"key":"2026012811223159800_R28","first-page":"56","article-title":"The number of herpes simplex virus-infected neurons and the number of viral genome copies per neuron correlate with the latent viral load in ganglia.","volume-title":"Virology","year":"2007"},{"key":"2026012811223159800_R29","first-page":"3535","article-title":"Antigen-specific CD8+ T cell clonal expansions develop from memory T cell pools established by acute respiratory virus infections.","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012811223159800_R30","first-page":"6657","article-title":"Unexpected expansions of CD8-bearing cells in old mice.","volume-title":"J. Immunol.","year":"1993"},{"key":"2026012811223159800_R31","first-page":"2784","article-title":"Age-related CD8+ T cell clonal expansions express elevated levels of CD122 and CD127 and display defects in perceiving homeostatic signals.","volume-title":"J. Immunol.","year":"2006"},{"key":"2026012811223159800_R32","first-page":"650","article-title":"Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells.","volume-title":"Immunity.","year":"2008"},{"key":"2026012811223159800_R33","first-page":"2645","article-title":"Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly.","volume-title":"J. Immunol.","year":"2006"},{"key":"2026012811223159800_R34","first-page":"247","article-title":"Large numbers of dysfunctional CD8+ T lymphocytes bearing receptors for a single dominant CMV epitope in the very old.","volume-title":"J. Clin. Immunol.","year":"2003"},{"key":"2026012811223159800_R35","first-page":"607","article-title":"Dysfunctional CMV-specific CD8+ T cells accumulate in the elderly.","volume-title":"Exp. Gerontol.","year":"2004"},{"key":"2026012811223159800_R36","first-page":"3131","article-title":"Properties of murine (CD8+)CD27\u2212 T cells.","volume-title":"Eur. J. Immunol.","year":"2005"},{"key":"2026012811223159800_R37","first-page":"1113","article-title":"Evolution of diverse antiviral CD8+ T cell populations after murine cytomegalovirus infection.","volume-title":"Eur. J. Immunol.","year":"2005"},{"key":"2026012811223159800_R38","first-page":"2397","article-title":"Famciclovir: a review of its use in herpes zoster and genital and orolabial herpes.","volume-title":"Drugs","year":"2006"},{"key":"2026012811223159800_R39","first-page":"81","article-title":"Altered substrate specificity of herpes simplex virus thymidine kinase confers acyclovir-resistance.","volume-title":"Nature","year":"1981"},{"key":"2026012811223159800_R40","first-page":"594","article-title":"The comparative effects of famciclovir and valacyclovir on herpes simplex virus type 1 infection, latency, and reactivation in mice.","volume-title":"J. Infect. Dis.","year":"1999"},{"key":"2026012811223159800_R41","first-page":"3534","article-title":"Immunization with a replication-deficient mutant of herpes simplex virus type 1 (HSV-1) induces a CD8+ cytotoxic T-lymphocyte response and confers a level of protection comparable to that of wild-type HSV-1.","volume-title":"J. Virol.","year":"1997"},{"key":"2026012811223159800_R42","first-page":"3675","article-title":"Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8 T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons.","volume-title":"J. Virol.","year":"2005"},{"key":"2026012811223159800_R43","first-page":"7201","article-title":"Control of murine cytomegalovirus in the lungs: relative but not absolute immunodominance of the immediate-early 1 nonapeptide during the antiviral cytolytic T-lymphocyte response in pulmonary infiltrates.","volume-title":"J. Virol.","year":"1998"},{"key":"2026012811223159800_R44","first-page":"2255","article-title":"Expansion of protective CD8+ T-cell responses driven by recombinant cytomegaloviruses.","volume-title":"J. Virol.","year":"2004"},{"key":"2026012811223159800_R45","first-page":"427","article-title":"Aging and CD8+ T cell immunity to respiratory virus infections.","volume-title":"Exp. Gerontol.","year":"2006"},{"key":"2026012811223159800_R46","first-page":"264","article-title":"Inflammatory infiltration of the trigeminal ganglion after herpes simplex virus type 1 corneal infection.","volume-title":"J. Virol.","year":"1996"},{"key":"2026012811223159800_R47","first-page":"4898","article-title":"Gamma interferon expression during acute and latent nervous system infection by herpes simplex virus type 1.","volume-title":"J. Virol.","year":"1995"},{"key":"2026012811223159800_R48","first-page":"3542","article-title":"Persistent cytokine expression in trigeminal ganglion latently infected with herpes simplex virus type 1.","volume-title":"J. Immunol.","year":"1996"},{"key":"2026012811223159800_R49","first-page":"53","article-title":"Acyclovir blocks cytokine gene expression in trigeminal ganglia latently infected with herpes simplex virus type 1.","volume-title":"Virology","year":"1997"},{"key":"2026012811223159800_R50","first-page":"392","article-title":"Herpes simplex virus-specific CD8+ T cells can clear established lytic infections from skin and nerves and can partially limit the early spread of virus after cutaneous inoculation.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012811223159800_R51","first-page":"911","article-title":"Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1).","volume-title":"Exp. Gerontol.","year":"2003"},{"key":"2026012811223159800_R52","first-page":"1347","article-title":"Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense.","volume-title":"J. Exp. Med.","year":"2004"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/12\/8077\/62691861\/0098.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/12\/8077\/62691861\/0098.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T16:23:19Z","timestamp":1769617399000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/183\/12\/8077\/8053106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,12]]},"references-count":52,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2009,12,15]]},"published-print":{"date-parts":[[2009,12,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0801117","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,12]]},"published":{"date-parts":[[2009,12]]}}}