title: 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.
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, SIV-producing 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.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO 80045; liz.connick@ucdenver.edu.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Connick
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO 80045;
authors.forename: Joy M
authors.initials: JM
authors.lastname: Folkvord
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO 80045;
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Lind
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715;
authors.forename: Eva G
authors.initials: EG
authors.lastname: Rakasz
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO 80045;
authors.forename: Brodie
authors.initials: B
authors.lastname: Miles
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715;
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Wilson
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO 80045;
authors.forename: Mario L
authors.initials: ML
authors.lastname: Santiago
authors.affiliation: Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City, KS 66160;
authors.forename: Kimberly
authors.initials: K
authors.lastname: Schmitt
authors.affiliation: Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City, KS 66160;
authors.forename: Edward B
authors.initials: EB
authors.lastname: Stephens
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN;
authors.forename: Hyeon O
authors.initials: HO
authors.lastname: Kim
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN;
authors.forename: Reece
authors.initials: R
authors.lastname: Wagstaff
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN;
authors.forename: Shengbin
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN; Department of Microbiology and Immunology, Zagazig University, Zagazig, Egypt 44519; and.
authors.forename: Hadia M
authors.initials: HM
authors.lastname: Abdelaal
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN;
authors.forename: Nathan
authors.initials: N
authors.lastname: Kemp
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715;
authors.forename: David I
authors.initials: DI
authors.lastname: Watkins
authors.affiliation: Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Samantha
authors.initials: S
authors.lastname: MaWhinney
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN;
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Skinner
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D002465:Cell Movement; D002478:Cells, Cultured; D018450:Disease Progression; D008198:Lymph Nodes / Q000276:immunology*; D008253:Macaca mulatta; D012367:RNA, Viral / Q000032:analysis; D054400:Receptors, CCR7 / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D013154:Spleen / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D014779:Virus Replication
chemical_list: D000956:Antigens, Viral; D012367:RNA, Viral; D054400:Receptors, CCR7; D054380:Receptors, CXCR5