nef gene is required for robust productive infection by simian immunodeficiency virus of T-cell-rich paracortex in lymph nodes.
The pathogenesis of AIDS virus infection in a nonhuman primate AIDS model was studied by comparing plasma viral loads, CD4(+) T-cell subpopulations in peripheral blood mononuclear cells, and simian immunodeficiency virus (SIV) infection in lymph nodes for rhesus macaques infected with a pathogenic molecularly cloned SIVmac239 strain and those infected with its nef deletion mutant (Deltanef). In agreement with many reports, whereas SIVmac239 infection induced AIDS and depletion of memory CD4(+) T cells in 2 to 3 years postinfection (p.i.), Deltanef infection did not induce any manifestation associated with AIDS up to 6.5 years p.i. To explore the difference in SIV infection in lymphoid tissues, we biopsied lymph nodes at 2, 8, 72, and 82 weeks p.i. and analyzed them by pathological techniques. Maximal numbers of SIV-infected cells (SIV Gag(+), Env(+), and RNA(+)) were detected at 2 weeks p.i. in both the SIVmac239-infected animals and the Deltanef-infected animals. In the SIVmac239-infected animals, most of the infected cells were localized in the T-cell-rich paracortex, whereas in the Deltanef-infected animals, most were localized in B-cell-rich follicles and in the border region between the paracortex and the follicles. Analyses by double staining of CD68(+) macrophages and SIV Gag(+) cells and by double staining of CD3(+) T cells and SIV Env(+) cells revealed that SIV-infected cells were identified as CD4(+) T cells in either the SIVmac239 or the Deltanef infection. Whereas the many functions of Nef protein were reported from in vitro studies, our finding of SIVmac239 replication in the T-cell-rich paracortex in the lymph nodes supports the reported roles of Nef protein in T-cell activation and enhancement of viral infectivity. Furthermore, the abundance of SIVmac239 infection and the paucity of Deltanef infection in the T-cell-rich paracortex accounted for the differences in viral replication and pathogenicity between SIVmac239 and the Deltanef mutant. Thus, our in vivo study indicated that the nef gene enhances SIV replication by robust productive infection in memory CD4(+) T cells in the T-cell-rich region in lymphoid tissues.
Sugimoto
Chie
C
Tsukuba Primate Center for Medical Sciences, National Institute of Infectious Diseases, Tsukuba, Japan.
Tadakuma
Kei
K
Otani
Isao
I
Moritoyo
Takashi
T
Akari
Hirofumi
H
Ono
Fumiko
F
Yoshikawa
Yasuhiro
Y
Sata
Tetsutaro
T
Izumo
Shuji
S
Mori
Kazuyasu
K
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D017353:Gene Deletion; D015754:Genes, nef; D018858:Germinal Center / Q000276:immunology / Q000473:pathology / Q000821:virology; D007156:Immunologic Memory; D019012:Integrin beta1 / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology / Q000821:virology; D008253:Macaca mulatta; D016097:Simian Acquired Immunodeficiency Syndrome / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000821:virology; D014766:Viremia / Q000209:etiology; D014779:Virus Replication / Q000235:genetics; D000097382:CD68 Molecule
D000914:Antibodies, Viral; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017252:CD3 Complex; D019012:Integrin beta1; C067980:CD68 antigen, human; D000097382:CD68 Molecule