Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL

Elizabeth Connick, Joy M. Folkvord, Katherine T. Lind, Eva G. Rakasz, Brodie Miles, Nancy A. Wilson, Mario L. Santiago, Kimberly Schmitt, Edward B. Stephens, Hyeon O. Kim, Reece Wagstaff, Shengbin Li, Hadia M. Abdelaal, Nathan Kemp, David Watkins, Samantha MaWhinney, Pamela J. Skinner

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Abstract

We previously demonstrated that HIV replication is concentrated in lymph node B cell follicles during chronic infection and that HIV-specific CTL fail to accumulate in large numbers at those sites. It is unknown whether these observations can be generalized to other secondary lymphoid tissues or whether virus compartmentalization occurs in the absence of CTL. We evaluated these questions in SIVmac239-infected rhesus macaques by quantifying SIV RNA+ cells and SIV-specific CTL in situ in spleen, lymph nodes, and intestinal tissues obtained at several stages of infection. During chronic asymptomatic infection prior to simian AIDS, SIVproducing cells were more concentrated in follicular (F) compared with extrafollicular (EF) regions of secondary lymphoid tissues. At day 14 of infection, when CTL have minimal impact on virus replication, there was no compartmentalization of SIV-producing cells. Virus compartmentalization was diminished in animals with simian AIDS, which often have low-frequency CTL responses. SIV-specific CTL were consistently more concentrated within EF regions of lymph node and spleen in chronically infected animals regardless of epitope specificity. Frequencies of SIV-specific CTL within F and EF compartments predicted SIV RNA+ cells within these compartments in a mixed model. Few SIV-specific CTL expressed the F homing molecule CXCR5 in the absence of the EF retention molecule CCR7, possibly accounting for the paucity of F CTL. These findings bolster the hypothesis that B cell follicles are immune privileged sites and suggest that strategies to augment CTL in B cell follicles could lead to improved viral control and possibly a functional cure for HIV infection.

Original languageEnglish
Pages (from-to)5613-5625
Number of pages13
JournalJournal of Immunology
Volume193
Issue number11
DOIs
StatePublished - Jan 1 2014

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Simian Immunodeficiency Virus
Lymphoid Tissue
Virus Replication
Macaca mulatta
Simian Acquired Immunodeficiency Syndrome
Viruses
B-Lymphocytes
Lymph Nodes
HIV Infections
Spleen
RNA
Asymptomatic Infections
Infection
Epitopes
HIV

ASJC Scopus subject areas

  • Immunology

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Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL. / Connick, Elizabeth; Folkvord, Joy M.; Lind, Katherine T.; Rakasz, Eva G.; Miles, Brodie; Wilson, Nancy A.; Santiago, Mario L.; Schmitt, Kimberly; Stephens, Edward B.; Kim, Hyeon O.; Wagstaff, Reece; Li, Shengbin; Abdelaal, Hadia M.; Kemp, Nathan; Watkins, David; MaWhinney, Samantha; Skinner, Pamela J.

In: Journal of Immunology, Vol. 193, No. 11, 01.01.2014, p. 5613-5625.

Research output: Contribution to journalArticle

Connick, E, Folkvord, JM, Lind, KT, Rakasz, EG, Miles, B, Wilson, NA, Santiago, ML, Schmitt, K, Stephens, EB, Kim, HO, Wagstaff, R, Li, S, Abdelaal, HM, Kemp, N, Watkins, D, MaWhinney, S & Skinner, PJ 2014, 'Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL', Journal of Immunology, vol. 193, no. 11, pp. 5613-5625. https://doi.org/10.4049/jimmunol.1401161
Connick, Elizabeth ; Folkvord, Joy M. ; Lind, Katherine T. ; Rakasz, Eva G. ; Miles, Brodie ; Wilson, Nancy A. ; Santiago, Mario L. ; Schmitt, Kimberly ; Stephens, Edward B. ; Kim, Hyeon O. ; Wagstaff, Reece ; Li, Shengbin ; Abdelaal, Hadia M. ; Kemp, Nathan ; Watkins, David ; MaWhinney, Samantha ; Skinner, Pamela J. / Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL. In: Journal of Immunology. 2014 ; Vol. 193, No. 11. pp. 5613-5625.
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T1 - Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL

AU - Connick, Elizabeth

AU - Folkvord, Joy M.

AU - Lind, Katherine T.

AU - Rakasz, Eva G.

AU - Miles, Brodie

AU - Wilson, Nancy A.

AU - Santiago, Mario L.

AU - Schmitt, Kimberly

AU - Stephens, Edward B.

AU - Kim, Hyeon O.

AU - Wagstaff, Reece

AU - Li, Shengbin

AU - Abdelaal, Hadia M.

AU - Kemp, Nathan

AU - Watkins, David

AU - MaWhinney, Samantha

AU - Skinner, Pamela J.

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N2 - We previously demonstrated that HIV replication is concentrated in lymph node B cell follicles during chronic infection and that HIV-specific CTL fail to accumulate in large numbers at those sites. It is unknown whether these observations can be generalized to other secondary lymphoid tissues or whether virus compartmentalization occurs in the absence of CTL. We evaluated these questions in SIVmac239-infected rhesus macaques by quantifying SIV RNA+ cells and SIV-specific CTL in situ in spleen, lymph nodes, and intestinal tissues obtained at several stages of infection. During chronic asymptomatic infection prior to simian AIDS, SIVproducing cells were more concentrated in follicular (F) compared with extrafollicular (EF) regions of secondary lymphoid tissues. At day 14 of infection, when CTL have minimal impact on virus replication, there was no compartmentalization of SIV-producing cells. Virus compartmentalization was diminished in animals with simian AIDS, which often have low-frequency CTL responses. SIV-specific CTL were consistently more concentrated within EF regions of lymph node and spleen in chronically infected animals regardless of epitope specificity. Frequencies of SIV-specific CTL within F and EF compartments predicted SIV RNA+ cells within these compartments in a mixed model. Few SIV-specific CTL expressed the F homing molecule CXCR5 in the absence of the EF retention molecule CCR7, possibly accounting for the paucity of F CTL. These findings bolster the hypothesis that B cell follicles are immune privileged sites and suggest that strategies to augment CTL in B cell follicles could lead to improved viral control and possibly a functional cure for HIV infection.

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