Control of Viremia and Prevention of AIDS following Immunotherapy of SIV-Infected Macaques with Peptide-Pulsed Blood

Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
PLoS Pathogens (Impact Factor: 7.56). 06/2008; 4(5):e1000055. DOI: 10.1371/journal.ppat.1000055
Source: PubMed


Effective immunotherapies for HIV are needed. Drug therapies are life-long with significant toxicities. Dendritic-cell based immunotherapy approaches are promising but impractical for widespread use. A simple immunotherapy, reinfusing fresh autologous blood cells exposed to overlapping SIV peptides for 1 hour ex vivo, was assessed for the control of SIV(mac251) replication in 36 pigtail macaques. An initial set of four immunizations was administered under antiretroviral cover and a booster set of three immunizations administered 6 months later. Vaccinated animals were randomized to receive Gag peptides alone or peptides spanning all nine SIV proteins. High-level, SIV-specific CD4 and CD8 T-cell immunity was induced following immunization, both during antiretroviral cover and without. Virus levels were durably approximately 10-fold lower for 1 year in immunized animals compared to controls, and a significant delay in AIDS-related mortality resulted. Broader immunity resulted following immunizations with peptides spanning all nine SIV proteins, but the responses to Gag were weaker in comparison to animals only immunized with Gag. No difference in viral outcome occurred in animals immunized with all SIV proteins compared to animals immunized against Gag alone. Peptide-pulsed blood cells are an immunogenic and effective immunotherapy in SIV-infected macaques. Our results suggest Gag alone is an effective antigen for T-cell immunotherapy. Fresh blood cells pulsed with overlapping Gag peptides is proceeding into trials in HIV-infected humans.

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Available from: Kim Wilson, Oct 02, 2015
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    • "The translation from animal models to humans remains problematic in HIV vaccinology with this study non-predictive for immunogenicity, safety and efficacy between non-human primates and humans [21], [22]. The absence of a clear immunogenic signal in this study is in marked contrast to the significant T-cell immunogenicity observed in studies in Macaca nemestrina with the Opal vaccination methodology [1], [10]. A GLP, repeat dose, non-human primate (Macaca mulatta) toxicology study was conducted to evaluate the safety and immunotoxicity of Opal HIV Gag(c). "
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    ABSTRACT: Preclinical studies of overlapping 15mer peptides, spanning SIV, SHIV or HIV, pulsed on autologous PBMC ex vivo have demonstrated high level, virus-specific T cell responses and viral suppression in non-human primates (NHP). Opal-HIV-Gag(c) consists of 120 synthetic 15mer peptides spanning Clade C, consensus Gag, manufactured to current good manufacturing practice; having been evaluated in a good laboratory practice toxicology study in Macaca mulatta. We evaluated the safety and preliminary immunogenicity of such peptides administered intravenously after short-duration ex vivo incubation, to HIV-positive adults on suppressive antiretroviral therapy. A first-in-human, placebo-controlled, double-blind, dose escalation study was conducted. Twenty-three patients with virus suppressed by antiretroviral therapy were enrolled in four groups 12 mg (n = 6), 24 mg (n = 6), 48 mg (n = 2) or matching placebo (n = 8). Treatment was administered intravenously after bedside enrichment of 120 mL whole blood for white cells using a closed system (Sepax S-100 device), with ex vivo peptide admixture (or diluent alone) and 37°C incubation for one hour prior to reinfusion. Patients received 4 administrations at monthly intervals followed by a 12-week observation post-treatment. Opal-HIV-Gag(c) was reasonably tolerated at doses of 12 and 24 mg. There was an increased incidence of temporally associated pyrexia, chills, and transient/self-limiting lymphopenia in Opal-HIV-Gag(c) recipients compared to placebo. The study was terminated early, after two patients were recruited to the 48 mg cohort; a serious adverse event of hypotension, tachycardia secondary to diarrhoea occurred following a single product administration. An infectious cause for the event could not be identified, leaving the possibility of immunologically mediated product reaction. A serious, potentially life-threatening event of hypotension led to early, precautionary termination of the study. In the absence of a clearly defined mechanism or ability to predict such occurrence, further development of Opal-HIV-Gag(c) will not be undertaken in the current form. NCT01123915; EudraCT: 2008-005142-23.
    PLoS ONE 09/2013; 8(9):e73765. DOI:10.1371/journal.pone.0073765 · 3.23 Impact Factor
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    • "Despite these efforts, standard vaccine delivery of peptides appears to have limited utility in stimulating CD8 T-cell responses, with the exception of one approach. Intravenous infusion of peripheral blood mononuclear cells coated ex vivo with peptides has shown great potency in preclinical animal studies (De Rose et al. 2008). Whether this approach will prove useful in human testing, especially considering the impracticality of such an approach for mass vaccination efforts, remains to be seen. "
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    ABSTRACT: Vaccines are arguably the most powerful medical intervention in the fight against infectious diseases. The enormity of the global human immunodeficiency virus type 1 (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic makes the development of an AIDS vaccine a scientific and humanitarian priority. Research on vaccines that induce T-cell immunity has dominated much of the recent development effort, mostly because of disappointing efforts to induce neutralizing antibodies through vaccination. Whereas T cells are known to limit HIV and other virus infections after infection, their role in protection against initial infection is much less clear. In this article, we will review the rationale behind a T-cell-based vaccine approach, provide an overview of the methods and platforms that are being applied, and discuss the impact of recent vaccine trial results on the future direction of T-cell vaccine research.
    Cold Spring Harbor Perspectives in Medicine 09/2011; 1(1):a007252. DOI:10.1101/cshperspect.a007252 · 9.47 Impact Factor
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    • "Therapeutic immunization for HIV infection during ART has been studied in SIV-infected rhesus macaques and the immunological and virologic consequences have been investigated in peripheral blood using DNA immunization [39-42], as well as other systems [43-45]. After release from ART, variable immunologic and virologic benefits were reported from no control [42], temporal control [43], to long-lasting virologic control [44]. "
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    ABSTRACT: HIV infection causes a qualitative and quantitative loss of CD4+ T cell immunity. The institution of anti-retroviral therapy (ART) restores CD4+ T cell responses to many pathogens, but HIV-specific responses remain deficient. Similarly, therapeutic immunization with HIV antigens of chronically infected, ART treated subjects results in poor induction of HIV-specific CD4 responses. In this study, we used a macaque model of ART treatment during chronic infection to study the virologic consequences of SIV antigen stimulation in lymph nodes early after immunization. Rhesus CMV (RhCMV) seropositive, Mamu A*01 positive rhesus macaques were chronically infected with SIVmac251 and treated with ART. The immune and viral responses to SIV gag and RhCMV pp65 antigen immunization in draining lymph nodes and peripheral blood were analyzed. Animals were immunized on contralateral sides with SIV gag and RhCMV pp65 encoding plasmids, which allowed lymph nodes draining each antigen to be obtained at the same time from the same animal for direct comparison. We observed that both SIV and RhCMV immunizations stimulated transient antigen-specific T cell responses in draining lymph nodes. The RhCMV-specific responses were potent and sustained (50 days post-immunization) in the periphery, while the SIV-specific responses were transient and extinguished quickly. The SIV antigen stimulation selectively induced transient SIV replication in draining lymph nodes. The data are consistent with a model whereby viral replication in response to SIV antigen stimulation limits the generation of SIV antigen-specific responses and suggests a potential mechanism for the early loss and poor HIV-specific CD4+ T cell response observed in HIV-infected individuals.
    Retrovirology 07/2011; 8:57. DOI:10.1186/1742-4690-8-57 · 4.19 Impact Factor
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