Expansion of activated memory CD4+ T cells affects infectivity of CCR5-tropic HIV-1 in humanized NOD/SCID/JAK3null mice

• Published in: PloS one Vol. 8; no. 1; p. e53495
• Main Authors: Terahara, Kazutaka, Ishige, Masayuki, Ikeno, Shota, Mitsuki, Yu-ya, Okada, Seiji, Kobayashi, Kazuo, Tsunetsugu-Yokota, Yasuko
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2013; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Animals; Biology; Blood banks; Bone marrow; CCR5 protein; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - virology; Cell Culture Techniques; Chimerism; Cytokines - metabolism; Dendritic cells; Effector cells; Fetal Blood - cytology; Genotype & phenotype; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; HIV; HIV-1 - metabolism; Homeostasis; Human immunodeficiency virus; Humans; Immunologic Memory; Immunological memory; Immunology; Infections; Infectious diseases; Infectivity; Irradiation; Janus Kinase 3 - genetics; Ki-67 Antigen - metabolism; Lymphocytes; Lymphocytes T; Lymphopenia; Medicine; Memory cells; Mice; Mice, Inbred NOD; Mice, SCID; Pathogenesis; Phenotype; Receptors, CCR5 - metabolism; Rodents; Stem cell transplantation; Stem cells; Transplantation; Umbilical cord; Viral infections; Virology; Viruses; Japan
• DOI: 10.1371/journal.pone.0053495
• ISSN: 1932-6203

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.