Acquired Immunodeficiency Syndrome: Akari H

Kawada M, Tsukamoto T, Yamamoto H, Iwamoto N, Kurihara K, Takeda A, Moriya C, Takeuchi H, Akari H, Matano T. · International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. · J Virol. · Pubmed #18667518 links to  free full text

Abstract: Gag-specific cytotoxic T lymphocytes (CTLs) exert strong suppressive pressure on human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. However, it has remained unclear whether they can actually contain primary viral replication. Recent trials of prophylactic vaccines inducing virus-specific T-cell responses have indicated their potential to confer resistance against primary SIV replication in rhesus macaques, while the immunological determinant for this vaccine-based viral control has not been elucidated thus far. Here we present evidence implicating Gag-specific CTLs as responsible for the vaccine-based primary SIV control. Prophylactic vaccination using a Gag-expressing Sendai virus vector resulted in containment of SIVmac239 challenge in all rhesus macaques possessing the major histocompatibility complex (MHC) haplotype 90-120-Ia. In contrast, 90-120-Ia-positive vaccinees failed to contain SIVs carrying multiple gag CTL escape mutations that had been selected, at the cost of viral fitness, in SIVmac239-infected 90-120-Ia-positive macaques. These results show that Gag-specific CTL responses do play a crucial role in the control of wild-type SIVmac239 replication in vaccinees. This study implies the possibility of Gag-specific CTL-based primary HIV containment by prophylactic vaccination, although it also suggests that CTL-based AIDS vaccine efficacy may be abrogated in viral transmission between MHC-matched individuals.

Fujita M, Yoshida A, Sakurai A, Tatsuki J, Ueno F, Akari H, Adachi A. · Department of Virology, University of Tokushima Graduate School of Medicine, Japan. · Int J Mol Med. · Pubmed #12684704 No free full text.

Abstract: Susceptibility of HSC-F, a cynomolgus macaque cell line immortalized by Herpesvirus saimiri, to infection with various primate immunodeficiency viruses were monitored. While NL432 clone of human immunodeficiency virus type 1 (HIV-1) did not grow at all in HSC-F cells, GH123 and GL-AN clones of HIV-2, and MA239 clone of simian immunodeficiency virus isolated from macaque monkeys (SIVMAC) did grow in these cells. In addition, NM-3 clone of a chimeric simian and human immunodeficiency virus (SHIV) grew fairly well in HSC-F cells. Mutational analyses of accessory genes of GL-AN were successfully performed in the HSC-F cells. These results have thus demonstrated the importance of this cell line for molecular biological studies on HIV/SIV.

Sugimoto C, Tadakuma K, Otani I, Moritoyo T, Akari H, Ono F, Yoshikawa Y, Sata T, Izumo S, Mori K. · Tsukuba Primate Center for Medical Sciences, National Institute of Infectious Diseases, Tsukuba, Japan. · J Virol. · Pubmed #12634375 links to  free full text

Abstract: 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.

Otani I, Mori K, Sata T, Terao K, Doi K, Akari H, Yoshikawa Y. · Tsukuba Primate Center, National Institute of Infectious Diseases, 1 Hachimandai, Tsukuba, Ibaraki 305-0843, Japan. · Microbes Infect. · Pubmed #10617929 No free full text.

Abstract: We investigated the histological features of lymph nodes, focusing on monocytes/macrophages, in rhesus monkeys (Macaca mulatta) acutely infected with simian immunodeficiency virus (SIV). In monkeys infected with a pathogenic SIV, SIVmac239, MAC387(+) newly blood-derived macrophages markedly increased in number at paracortical areas at 11 to 14 days postinoculation, concomitant with the peak of the primary SIV antigenemia. The MAC387(+) macrophages densely gathered around high endothelial venules and formed cell clusters with CD3(+) T lymphocytes, tingible body macrophages, and plasmacytoid monocytes. In the cell clusters, CD3(+) T lymphocytes which closely adhered to the MAC387(+) macrophages enlarged in size, suggesting a histological manifestation of T-lymphocyte activation by macrophages. By 54 days postinoculation, when SIV antigenemia became undetectable, the MAC387(+) macrophages decreased in number and the cell cluster disappeared from paracortical areas. In contrast, the monkeys infected with a nef-deleted mutant of SIVmac239 showed lower levels of SIV antigenemia and lower numbers of MAC387(+) macrophages in paracortical areas than those infected with SIVmac239. These results indicate that MAC387(+) macrophages accumulate in paracortical areas for the period of the intense primary SIV antigenemia and may play an important role in activating naive T lymphocytes.

Akari H, Nam KH, Mori K, Otani I, Shibata H, Adachi A, Terao K, Yoshikawa Y. · Tsukuba Primate Center, National Institute of Infectious Diseases, Ibaraki, Japan. · Clin Immunol. · Pubmed #10370378 No free full text.

Abstract: We have previously reported that CD4+CD8+ double-positive (DP) T cells with a resting memory phenotype exist in a substantial proportion of peripheral blood lymphocytes of adult cynomolgus macaques. In this study, we examined the effects of simian immunodeficiency virus of macaque (SIVmac) infection on DP T cells. In vitro, SIVmac239 nef-open (239) and its nef-deletion mutant replicated well in both CD4+CD8- and DP T cells. However, when the macaques were infected with 239, DP, but not CD4+CD8-, T cells were transiently increased in parallel with cell activation and viral replication, followed by depletion within 1 month postinfection. Interestingly, the nef gene was required for depletion but not for the increase and activation of DP T cells. These data suggest that the pathogenic SIV infection may downmodulate production and/or blood circulation of DP T cells by a Nef function-related mechanism(s) different from that for the depletion of CD4+CD8- T cells.