Acquired Immunodeficiency Syndrome: Kaizu M

Wilson NA, Keele BF, Reed JS, Piaskowski SM, MacNair CE, Bett AJ, Liang X, Wang F, Thoryk E, Heidecker GJ, Citron MP, Huang L, Lin J, Vitelli S, Ahn CD, Kaizu M, Maness NJ, Reynolds MR, Friedrich TC, Loffredo JT, Rakasz EG, Erickson S, Allison DB, Piatak M, Lifson JD, Shiver JW, Casimiro DR, Shaw GM, Hahn BH, Watkins DI. · Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA. · J Virol. · Pubmed #19403685 No free full text.

Abstract: All human immunodeficiency virus (HIV) vaccine efficacy trials to date have ended in failure. Structural features of the Env glycoprotein and its enormous variability have frustrated efforts to induce broadly reactive neutralizing antibodies. To explore the extent to which vaccine-induced cellular immune responses, in the absence of neutralizing antibodies, can control replication of a heterologous, mucosal viral challenge, we vaccinated eight macaques with a DNA/Ad5 regimen expressing all of the proteins of SIVmac239 except Env. Vaccinees mounted high-frequency T-cell responses against 11 to 34 epitopes. We challenged the vaccinees and eight naïve animals with the heterologous biological isolate SIVsmE660, using a regimen intended to mimic typical HIV exposures resulting in infection. Viral loads in the vaccinees were significantly less at both the peak (1.9-log reduction; P < 0.03) and at the set point (2.6-log reduction; P < 0.006) than those in control naïve animals. Five of eight vaccinated macaques controlled acute peak viral replication to less than 80,000 viral RNA (vRNA) copy eq/ml and to less than 100 vRNA copy eq/ml in the chronic phase. Our results demonstrate that broad vaccine-induced cellular immune responses can effectively control replication of a pathogenic, heterologous AIDS virus, suggesting that T-cell-based vaccines may have greater potential than previously appreciated.

Reynolds MR, Weiler AM, Weisgrau KL, Piaskowski SM, Furlott JR, Weinfurter JT, Kaizu M, Soma T, León EJ, MacNair C, Leaman DP, Zwick MB, Gostick E, Musani SK, Price DA, Friedrich TC, Rakasz EG, Wilson NA, McDermott AB, Boyle R, Allison DB, Burton DR, Koff WC, Watkins DI. · AIDS Vaccine Research Laboratory, Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715, USA. · J Exp Med. · Pubmed #18838548 links to  free full text

Abstract: An effective AIDS vaccine will need to protect against globally diverse isolates of HIV. To address this issue in macaques, we administered a live-attenuated simian immunodeficiency virus (SIV) vaccine and challenged with a highly pathogenic heterologous isolate. Vaccinees reduced viral replication by approximately 2 logs between weeks 2-32 (P < or = 0.049) postchallenge. Remarkably, vaccinees expressing MHC-I (MHC class I) alleles previously associated with viral control completely suppressed acute phase replication of the challenge virus, implicating CD8(+) T cells in this control. Furthermore, transient depletion of peripheral CD8(+) lymphocytes in four vaccinees during the chronic phase resulted in an increase in virus replication. In two of these animals, the recrudescent virus population contained only the vaccine strain and not the challenge virus. Alarmingly, however, we found evidence of recombinant viruses emerging in some of the vaccinated animals. This finding argues strongly against an attenuated virus vaccine as a solution to the AIDS epidemic. On a more positive note, our results suggest that MHC-I-restricted CD8(+) T cells contribute to the protection induced by the live-attenuated SIV vaccine and demonstrate that vaccine-induced CD8(+) T cell responses can control replication of heterologous challenge viruses.

Weiler AM, Li Q, Duan L, Kaizu M, Weisgrau KL, Friedrich TC, Reynolds MR, Haase AT, Rakasz EG. · AIDS Vaccine Laboratory, WNPRC, 555 Science Dr., Madison, WI 53711, USA. · J Virol. · Pubmed #18272571 links to  free full text

Abstract: Here we report the results of studies in the simian immunodeficiency virus (SIV)-rhesus macaque model of intravaginal transmission of human immunodeficiency virus type 1 in the setting of genital ulcerative diseases. We document preferential association of vRNA with induced ulcers during the first days of infection and show that allogeneic cells of the inoculum traffic from the vaginal lumen to lymphatic tissues. This surprisingly rapid systemic dissemination in this cell-associated SIV challenge model thus reveals the challenges of preventing transmission in the setting of genital ulcerative diseases and illustrates the utility of this animal model in tests of strategies aimed at reducing transmission under these conditions.

Kaizu M, Weiler AM, Weisgrau KL, Vielhuber KA, May G, Piaskowski SM, Furlott J, Maness NJ, Friedrich TC, Loffredo JT, Usborne A, Rakasz EG. · Immunogenetics and Virology Unit, Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53711, USA. · J Infect Dis. · Pubmed #16960778 No free full text.

Abstract: The goal of the present study was to develop a nonhuman primate model of intravaginal human immunodeficiency virus (HIV) transmission with cell-associated virus. Reproductively mature, cycling cynomolgus macaques with or without chemically induced, transient ulcers of the lower female reproductive tract repeatedly received challenge with a variable amount of in vitro simian immunodeficiency virus mac239-infected peripheral blood mononuclear cells. Persistent viremia was established with surprisingly few infectious lymphocytes containing physiologically relevant quantities of cell-associated virus. This model will be indispensable for the testing of vaccines and topical agents that are aimed toward the prevention of heterosexual transmission of HIV.

Eda Y, Murakami T, Ami Y, Nakasone T, Takizawa M, Someya K, Kaizu M, Izumi Y, Yoshino N, Matsushita S, Higuchi H, Matsui H, Shinohara K, Takeuchi H, Koyanagi Y, Yamamoto N, Honda M. · AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan. · J Virol. · Pubmed #16699037 links to  free full text

Abstract: In an accompanying report (Y. Eda, M. Takizawa, T. Murakami, H. Maeda, K. Kimachi, H. Yonemura, S. Koyanagi, K. Shiosaki, H. Higuchi, K. Makizumi, T. Nakashima, K. Osatomi, S. Tokiyoshi, S. Matsushita, N. Yamamoto, and M. Honda, J. Virol. 80:5552-5562, 2006), we discuss our production of a high-affinity humanized monoclonal antibody, KD-247, by sequential immunization with V3 peptides derived from human immunodeficiency virus type 1 (HIV-1) clade B primary isolates. Epitope mapping revealed that KD-247 recognized the Pro-Gly-Arg V3 tip sequence conserved in HIV-1 clade B isolates. In this study, we further demonstrate that in vitro, KD-247 efficiently neutralizes CXCR4- and CCR5-tropic primary HIV-1 clade B and clade B' with matching neutralization sequence motifs but does not neutralize sequence-mismatched clade B and clade E isolates. Monkeys were provided sterile protection against heterologous simian/human immunodeficiency virus challenge by the passive transfer of a single high dose (45 mg per kg of body weight) of KD-247 and afforded partial protection by lower antibody doses (30 and 15 mg per kg). Protective neutralization endpoint titers in plasma at the time of virus challenge were 1:160 in animals passively transferred with a high dose of the antibody. The antiviral efficacy of the antibody was further confirmed by its suppression of the ex vivo generation of primary HIV-1 quasispecies in peripheral blood mononuclear cell cultures from HIV-infected individuals. Therefore, KD-247 promises to be a valuable tool not only as a passive immunization antibody for the prevention of HIV infection but also as an immunotherapy for the suppression of HIV in phenotype-matched HIV-infected individuals.

Someya K, Cecilia D, Ami Y, Nakasone T, Matsuo K, Burda S, Yamamoto H, Yoshino N, Kaizu M, Ando S, Okuda K, Zolla-Pazner S, Yamazaki S, Yamamoto N, Honda M. · AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan. · J Virol. · Pubmed #15650171 links to  free full text

Abstract: Although the correlates of vaccine-induced protection against human immunodeficiency virus type 1 (HIV-1) are not fully known, it is presumed that neutralizing antibodies (NAb) play a role in controlling virus infection. In this study, we examined immune responses elicited in rhesus macaques following vaccination with recombinant Mycobacterium bovis bacillus Calmette-Guérin expressing an HIV-1 Env V3 antigen (rBCG Env V3). We also determined the effect of vaccination on protection against challenge with either a simian-human immunodeficiency virus (SHIV-MN) or a highly pathogenic SHIV strain (SHIV-89.6PD). Immunization with rBCG Env V3 elicited significant levels of NAb for the 24 weeks tested that were predominantly HIV-1 type specific. Sera from the immunized macaques neutralized primary HIV-1 isolates in vitro, including HIV-1BZ167/X4, HIV-1SF2/X4, HIV-1CI2/X4, and, to a lesser extent, HIV-1MNp/X4, all of which contain a V3 sequence homologous to that of rBCG Env V3. In contrast, neutralization was not observed against HIV-1SF33/X4, which has a heterologous V3 sequence, nor was it found against primary HIV-1 R5 isolates from either clade A or B. Furthermore, the viral load in the vaccinated macaques was significantly reduced following low-dose challenge with SHIV-MN, and early plasma viremia was markedly decreased after high-dose SHIV-MN challenge. In contrast, replication of pathogenic SHIV-89.6PD was not affected by vaccination in any of the macaques. Thus, we have shown that immunization with an rBCG Env V3 vaccine elicits a strong, type-specific V3 NAb response in rhesus macaques. While this response was not sufficient to provide protection against a pathogenic SHIV challenge, it was able to significantly reduce the viral load in macaques following challenge with a nonpathogenic SHIV. These observations suggest that rBCG vectors have the potential to deliver an appropriate virus immunogen for desirable immune elicitations.

Kaizu M, Ami Y, Nakasone T, Sasaki Y, Izumi Y, Sato H, Takahashi E, Sakai K, Shinohara K, Nakanishi K, Honda M. · AIDS Research Center, National Institute of Infectious Diseases, Shinjuku, Tokyo 162-8640, Japan. · Virology. · Pubmed #12951016 No free full text.

Abstract: We have monitored kinetics of peripheral blood Interleukin (IL)-18 level, viral RNA load, and CD4(+) T cell counts in cynomolgus and rhesus macaques following infections of various simian/human immunodeficiency viruses (SHIVs) causing differential pathogenicity. Infections of cynomolgus and rhesus macaques with pathogenic SHIVs-C2/1 and -89.6PD, respectively, induced high levels of plasma IL-18 (0.1-1 ng/ml) and enhanced apoptosis of peripheral blood T cells during primary viremia, along with a rapid decline of CD4(+) T cells and a high level of set point viral load after primary viremia (six of six cases). In contrast, infections of cynomolgus macaques with nonpathogenic SHIVs-TH09V3 and -MD14 did not cause such IL-18 elevation, showing no decline of CD4(+) T cells and no or low viral set point level following primary viremia (three of three cases). Thus, the elevation of circulating IL-18 level during primary viral infection can be a good indicator of an active pathogenic viral infection. However, the role of increased IL-18 remains to be elucidated and needs further investigation.

Shinohara K, Sakai K, Ando S, Ami Y, Yoshino N, Takahashi E, Someya K, Suzaki Y, Nakasone T, Sasaki Y, Kaizu M, Lu Y, Honda M. · Division of Biosafety Control and Research, National Institute of Infectious Diseases, Tokyo, Japan. · J Gen Virol. · Pubmed #10355770 links to  free full text

Abstract: A highly pathogenic simian/human immunodeficiency virus (SHIV), designated C2/1, was obtained by serum passages in cynomolgus monkeys of p-SHIV, an SHIV strain that contains the env gene of pathogenic human immunodeficiency virus type 1 89.6. CD4+ lymphocyte depletion was induced within 1 week of the SHIV-C2/1 infection in peripheral blood as well as in various lymphoid organs in all the animals tested, with symptoms of diarrhoea and no increase in body weight, followed by intense viraemia. Serum antibody against Env protein was detected from 4 weeks after the virus infection, while the anti-Gag antibody response was absent in the SHIV-C2/1-infected animals. In contrast, both anti-Gag and anti-Env antibody responses were present in animals infected with p-SHIV or the non-pathogenic SHIV-MN. Sequencing of the env gene of isolates of SHIV-C strains showed conserved amino acid changes in the Env C2 and V3 regions that included changes to negatively charged amino acids, in the cytoplasmic region of gp41 that included a 42 amino acid deletion, and in the Nef protein. The pathogenic SHIV-C2/1-monkey model suggests that virus-specific pathogenicity in SHIV infection may be associated with the absence of anti-Gag antibody responses in animals and may be caused by genetic changes during serum passage in vivo.