Ocular myositis as first presenting symptom of human immunodeficiency virus (HIV-1) infection and its response to high-dose cortisone treatment.

To evaluate the safety and efficacy of didanosine (ddl) monotherapy and three different combinations of zidovudine (ZDV) and ddl in asymptomatic human immunodeficiency virus-1 (HIV-1) infection, we conducted an open-label, phase I/II study in 126 asymptomatic HIV-1-infected hemophilic and nonhemophilic subjects with a CD4 count of 200 to 500/mm3 stratified for prior zidovudine treatment and baseline CD4 count. Study arms included arm A, low-dose combination (ZDV 150 mg and ddl 134 mg, daily); arm B, moderate-dose combination (ZDV 300 mg and ddI 334 mg, daily); arm C, high-dose combination (ZDV 600 mg and ddl 500 mg, daily), and arm D, ddl monotherapy (ddl 500 mg, daily). Earlier, more frequent hepatotoxicity was experienced by hemophilic subjects (P = .008), but there were no differences in toxicity between treatment arms (P = .51), nor were there any differences in the rate of development of clinical endpoints by treatment (P = .41). Smaller median CD4 increases occurred over the first 12 weeks for arms A and D, 44/mm3 and 42/mm3, than arms B and C, 105/mm3 and 114/mm3, respectively, (P = .015). Hemophilia status (P = .0004) and prior ZDV experience (P = .044) independently predicted weaker CD4 responses during the first 12 weeks of treatment. Using a regression model and adjusting for hemophilia status, prior ZDV treatment, and baseline CD4, there was a significant reduction in quantitative viral load from baseline by week 12 for all treatment arms combined (P = .0001), with significantly lower median percent reduction for arm A (56.3%) than arms B, C, and D (94.6%, 98.5%, and 91.9%, respectively, P = .015). Although greater hepatoxicity and weaker CD4 responses occur in hemophilic subjects, didanosine monotherapy and combination therapy with zidovudine are safe and effective in asymptomatic HIV-1-infected patients.

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Effective Suppression of Human Immunodeficiency Virus Type 1 through a Combination of Short- or Long-Hairpin RNAs Targeting Essential Sequences for Retroviral Integration

Journal of Virology ◽

10.1128/jvi.00078-06 ◽

2006 ◽

Vol 80 (15) ◽

pp. 7658-7666 ◽

Cited By ~ 60

Author(s):

Hironori Nishitsuji ◽

Michinori Kohara ◽

Mari Kannagi ◽

Takao Masuda

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Attachment Site ◽

High Dose ◽

Wild Type ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Small interfering RNA (siRNA) could provide a new therapeutic approach to treating human immunodeficiency virus type 1 (HIV-1) infection. For long-term suppression of HIV-1, emergence of siRNA escape variants must be controlled. Here, we constructed lentiviral vectors encoding short-hairpin RNAs (shRNA) corresponding to conserved target sequences within the integrase (int) and the attachment site (att) genes, both of which are essential for HIV-1 integration. Compared to shRNA targeting of the HIV-1 transcription factor tat (shTat), shRNA against int (shIN) or the U3 region of att (shU3) showed a more potent inhibitory effect on HIV-1 replication in human CD4+ T cells. Infection with a high dose of HIV-1 resulted in the emergence of escape mutants during long-term culture. Of note, limited genetic variation was observed in the viruses resistant to shIN. A combination of shINs against wild-type and escape mutant sequences had a negative effect on their antiviral activities, indicating a potentially detrimental effect when administering multiple shRNA targeting the same region to combat HIV-1 variants. The combination of shIN and shU3 att exhibited the strongest anti-HIV-1 activity, as seen by complete abrogation of viral DNA synthesis and viral integration. In addition, a modified long-hairpin RNA spanning the 50 nucleotides in the shIN target region effectively suppressed wild-type and shIN-resistant mutant HIV-1. These results suggest that targeting of incoming viral RNA before proviral DNA formation occurs through the use of nonoverlapping multiple siRNAs is a potent approach to achieving sustained, efficient suppression of highly mutable viruses, such as HIV-1.

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Induction of Neutralizing Antibodies to T-Cell Line-Adapted and Primary Human Immunodeficiency Virus Type 1 Isolates with a Prime-Boost Vaccine Regimen in Chimpanzees

Journal of Virology ◽

10.1128/jvi.72.2.1052-1059.1998 ◽

1998 ◽

Vol 72 (2) ◽

pp. 1052-1059 ◽

Cited By ~ 56

Author(s):

Susan Zolla-Pazner ◽

Michael Lubeck ◽

Serena Xu ◽

Sherri Burda ◽

Robert J. Natuk ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Cell Line ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

High Dose ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Five chimpanzees were immunized by administration of one or more intranasal priming doses of one to three recombinant adenoviruses containing a gp160 insert from human immunodeficiency virus type 1 (HIV-1) MN (HIV-1MN) followed by one or more boosts of recombinant HIV-1SF2 gp120 delivered intramuscularly with MF59 adjuvant. This regimen resulted in humoral immune responses in three of five animals. Humoral responses included immunochemically active anti-HIV-1 antibodies (Abs) directed to recombinant gp120 and neutralizing Abs reactive with T-cell-line-adapted HIV-1MNand HIV-1SF2. In addition, neutralizing activity was detected to the two homologous primary isolates and to two of three heterologous primary isolates which, like the immunizing strains, can use CXCR4 as a coreceptor for infection. The three animals with detectable neutralizing Abs and a fourth exhibiting the best cytotoxic T-lymphocyte response were protected from a low-dose intravenous challenge with a cell-free HIV-1SF2 primary isolate administered 4 weeks after the last boost. Animals were rested for 46 weeks and then rechallenged, without a boost, with an eightfold-higher challenge dose of HIV-1SF2. The three animals with persistent neutralizing Abs were again protected. These data show that a strong, long-lived protective Ab response can be induced with a prime-boost regimen in chimpanzees. The data suggest that in chimpanzees, the presence of neutralizing Abs correlates with protection for animals challenged intravenously with a high dose of a homologous strain of HIV-1, and they demonstrate for the first time the induction of neutralizing Abs to homologous and heterologous primary isolates.

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Vaccine Protection against a Heterologous, Non-Syncytium-Inducing, Primary Human Immunodeficiency Virus

Journal of Virology ◽

10.1128/jvi.72.12.10275-10280.1998 ◽

1998 ◽

Vol 72 (12) ◽

pp. 10275-10280 ◽

Cited By ~ 53

Author(s):

Marjorie Robert-Guroff ◽

Harvinder Kaur ◽

L. Jean Patterson ◽

Michel Leno ◽

Anthony J. Conley ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Neutralizing Antibody ◽

High Dose ◽

Antibody Activity ◽

Complete Protection ◽

Vaccine Strategy ◽

Vaccine Protection ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Vaccine-induced protection of chimpanzees against laboratory-adapted and syncytium-inducing, multiply passaged primary human immunodeficiency virus type 1 (HIV-1) isolates, but not against non-syncytium-inducing, minimally passaged ones, has been demonstrated. Following challenge with such an isolate, HIV-15016, we obtained complete protection in one of three chimpanzees previously protected against low- and high-dose HIV-1SF2 exposures after immunization with an adenovirus-HIV-1MN gp160 priming–HIV-1SF2gp120 boosting regimen. At challenge, the protected chimpanzee exhibited broad humoral immunity, including neutralizing antibody activity. These results demonstrate the potential of this combination vaccine strategy and suggest that vaccine protection against an HIV isolate relevant to infection of people is feasible.

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Anti-V3 Humanized Antibody KD-247 Effectively Suppresses Ex Vivo Generation of Human Immunodeficiency Virus Type 1 and Affords Sterile Protection of Monkeys against a Heterologous Simian/Human Immunodeficiency Virus Infection

Journal of Virology ◽

10.1128/jvi.02095-05 ◽

2006 ◽

Vol 80 (11) ◽

pp. 5563-5570 ◽

Cited By ~ 35

Author(s):

Yasuyuki Eda ◽

Toshio Murakami ◽

Yasushi Ami ◽

Tadashi Nakasone ◽

Mari Takizawa ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Ex Vivo ◽

High Dose ◽

Virus Challenge ◽

Clade B ◽

Immunodeficiency Virus ◽

Hiv 1

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.

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Vaccination of Rhesus Macaques with Recombinant Mycobacterium bovis Bacillus Calmette-Guérin Env V3 Elicits Neutralizing Antibody-Mediated Protection against Simian-Human Immunodeficiency Virus with a Homologous but Not a Heterologous V3 Motif

Journal of Virology ◽

10.1128/jvi.79.3.1452-1462.2005 ◽

2005 ◽

Vol 79 (3) ◽

pp. 1452-1462 ◽

Cited By ~ 32

Author(s):

Kenji Someya ◽

Dayaraj Cecilia ◽

Yasushi Ami ◽

Tadashi Nakasone ◽

Kazuhiro Matsuo ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Viral Load ◽

Mycobacterium Bovis ◽

Neutralizing Antibodies ◽

Rhesus Macaques ◽

Neutralizing Antibody ◽

High Dose ◽

Immunodeficiency Virus ◽

Hiv 1

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.

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Macrophage Tropism of Human Immunodeficiency Virus Type 1 Facilitates In Vivo Escape from Cytotoxic T-Lymphocyte Pressure

Journal of Virology ◽

10.1128/jvi.75.6.2706-2709.2001 ◽

2001 ◽

Vol 75 (6) ◽

pp. 2706-2709 ◽

Cited By ~ 17

Author(s):

M. Schutten ◽

C. A. van Baalen ◽

C. Guillon ◽

R. C. Huisman ◽

P. H. M. Boers ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

High Dose ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Early after seroconversion, macrophage-tropic human immunodeficiency virus type 1 (HIV-1) variants are predominantly found, even when a mixture of macrophage-tropic and non-macrophage-tropic variants was transmitted. For virus contracted by sexual transmission, this is presently explained by selection at the port of entry, where macrophages are infected and T cells are relatively rare. Here we explore an additional mechanism to explain the selection of macrophage-tropic variants in cases where the mucosa is bypassed during transmission, such as blood transfusion, needle-stick accidents, or intravenous drug abuse. With molecularly cloned primary isolates of HIV-1 in irradiated mice that had been reconstituted with a high dose of human peripheral blood mononuclear cells, we found that a macrophage-tropic HIV-1 clone escaped more efficiently from specific cytotoxic T-lymphocyte (CTL) pressure than its non-macrophage-tropic counterpart. We propose that CTLs favor the selective outgrowth of macrophage-tropic HIV-1 variants because infected macrophages are less susceptible to CTL activity than infected T cells.

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Generation and Evaluation of Clade C Simian-Human Immunodeficiency Virus Challenge Stocks

Journal of Virology ◽

10.1128/jvi.03279-14 ◽

2014 ◽

Vol 89 (4) ◽

pp. 1965-1974 ◽

Cited By ~ 21

Author(s):

Hui-Wen Chang ◽

Lawrence J. Tartaglia ◽

James B. Whitney ◽

So-Yon Lim ◽

Srisowmya Sanisetty ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Rhesus Monkeys ◽

Acute Infection ◽

High Dose ◽

Mucosal Transmission ◽

Preclinical Evaluation ◽

Immunodeficiency Virus ◽

Clade C ◽

Hiv 1

ABSTRACTThe development of a panel of mucosally transmissible simian-human immunodeficiency virus (SHIV) challenge stocks from multiple virus clades would facilitate preclinical evaluation of candidate HIV-1 vaccines and therapeutics. The majority of SHIV stocks that have been generated to date have been derived from clade B HIV-1envsequences from viruses isolated during chronic infection and typically required serial animal-to-animal adaptation for establishing mucosal transmissibility and pathogenicity. To capture essential features of mucosal transmission of clade C viruses, we produced a series of SHIVs with early clade C HIV-1envsequences from acutely HIV-1-infected individuals from South Africa. SHIV-327c and SHIV-327cRM expressedenvsequences that were 99.7 to 100% identical to the original HIV-1 isolate and did not requirein vivopassaging for mucosal infectivity. These challenge stocks infected rhesus monkeys efficiently by both intrarectal and intravaginal routes, replicated to high levels during acute infection, and established chronic setpoint viremia in 13 of 17 (76%) infected animals. The SHIV-327cRM challenge stock was also titrated for both single, high-dose intrarectal challenges and repetitive, low-dose intrarectal challenges in rhesus monkeys. These SHIV challenge stocks should facilitate the preclinical evaluation of vaccines and other interventions aimed at preventing clade C HIV-1 infection.IMPORTANCEWe describe the development of two related clade C SHIV challenge stocks. These challenge stocks should prove useful for preclinical testing of vaccines and other interventions aimed at preventing clade C HIV-1 infection.

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Systemic Immunization with an ALVAC-HIV-1/Protein Boost Vaccine Strategy Protects Rhesus Macaques from CD4+ T-Cell Loss and Reduces both Systemic and Mucosal Simian-Human Immunodeficiency Virus SHIVKU2 RNA Levels

Journal of Virology ◽

10.1128/jvi.80.8.3732-3742.2006 ◽

2006 ◽

Vol 80 (8) ◽

pp. 3732-3742 ◽

Cited By ~ 55

Author(s):

Ranajit Pal ◽

David Venzon ◽

Sampa Santra ◽

Vaniambadi S. Kalyanaraman ◽

David C. Montefiori ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Immune Responses ◽

Cell Loss ◽

High Dose ◽

Relative Efficacy ◽

Vaccine Strategy ◽

Resistant Variant ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Transmission of human immunodeficiency virus type 1 (HIV-1) occurs primarily via the mucosal route, suggesting that HIV-1 vaccines may need to elicit mucosal immune responses. Here, we investigated the immunogenicity and relative efficacy of systemic immunization with two human ALVAC-HIV-1 recombinant vaccines expressing Gag, Pol, and gp120 (vCP250) or Gag, Pol, and gp160 (vCP1420) in a prime-boost protocol with their homologous vaccine native Env proteins. The relative efficacy was measured against a high-dose mucosal exposure to the pathogenic neutralization-resistant variant SHIVKU2 (simian-human immunodeficiency virus). Systemic immunization with both vaccine regimens decreased viral load levels not only in blood but unexpectedly also in mucosal sites and protected macaques from peripheral CD4+ T-cell loss. This protective effect was stronger when the gp120 antigen was included in the vaccine. Inclusion of recombinant Tat protein in the boosting phase along with the Env protein did not contribute further to the preservation of CD4+ T cells. Thus, systemic immunization with ALVAC-HIV-1 vaccine candidates elicits anti-HIV-1 immune responses able to contain virus replication also at mucosal sites in macaques.

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