title: Expansion of activated memory CD4+ T cells affects infectivity of CCR5-tropic HIV-1 in humanized NOD/SCID/JAK3null mice.
abstract: Humanized mice reconstituted with human hematopoietic cells have been developed as an experimental animal model for human immunodeficiency virus type 1 (HIV-1) infection. Myeloablative irradiation is usually performed to augment the engraftment of donor hematopoietic stem cells (HSCs) in recipient mice; however, some mouse strains are susceptible to irradiation, making longitudinal analysis difficult. We previously attempted to construct humanized NOD/SCID/JAK3(null) (hNOJ) mice, which were not irradiated prior to human HSC transplantation. We found that, over time, many of the reconstituted CD4(+) T cells expanded with an activated effector memory phenotype. Therefore, the present study used hNOJ mice that were irradiated (hNOJ (IR+)) or not (hNOJ (IR-)) prior to human HSC transplantation to examine whether the development and cellularity of the reconstituted CD4(+) T cells were influenced by the degree of chimerism, and whether they affected HIV-1 infectivity. Indeed, hNOJ (IR+) mice showed a greater degree of chimerism than hNOJ (IR-) mice. However, the conversion of CD4(+) T cells to an activated effector memory phenotype, with a high percentage of cells showing Ki-67 expression, occurred in both hNOJ (IR+) and hNOJ (IR-) mice, probably as a result of lymphopenia-induced homeostatic expansion. Furthermore, when hNOJ (IR+) and hNOJ (IR-) mice, which were selected as naïve- and memory CD4(+) T cell subset-rich groups, respectively, were infected with CCR5-tropic HIV-1 in vivo, virus replication (as assessed by the plasma viral load) was delayed; however, the titer subsequently reached a 1-log higher level in memory-rich hNOJ (IR-) mice than in naïve-rich hNOJ (IR+) mice, indicating that virus infectivity in hNOJ mice was affected by the different status of the reconstituted CD4(+) T cells. Therefore, the hNOJ mouse model should be used selectively, i.e., according to the specific experimental objectives, to gain an appropriate understanding of HIV-1 infection/pathogenesis.
authors.affiliation: Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Terahara
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ishige
authors.forename: Shota
authors.initials: S
authors.lastname: Ikeno
authors.forename: Yu-ya
authors.initials: YY
authors.lastname: Mitsuki
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Tsunetsugu-Yokota
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000821:virology*; D018929:Cell Culture Techniques; D016207:Cytokines / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology; D015497:HIV-1 / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006706:Homeostasis; D006801:Humans; D007156:Immunologic Memory; D053616:Janus Kinase 3 / Q000235:genetics*; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010641:Phenotype; D019713:Receptors, CCR5 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D019394:Ki-67 Antigen; D019713:Receptors, CCR5; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3