Neutralizing activity and cellular immune responses induced in mice after immunization with apoptotic HIV-1/murine leukemia virus infected cells

Hinkula, Jorma; Walther‐Jallow, Lilian; Laurén, Anna; Mäkitalo, Barbro; Öberg, Monica; Wahrén, Britta; Fenyõ, Éva Mária; Spetz, Anna-Lena

doi:10.1016/j.vaccine.2009.06.016

Cited by 4 publications

(2 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5– 7), we anticipate that such medicines may also display immunogenic activity in vivo. When introduced into a host with a functioning immune system, HIV-infected PBMCs rendered apoptotic ex vivo induce HIV-1 specific cellular and humoral responses that effectively protect against challenge with live HIV-infected cells [196]–[198]. Similarly, infected cells rendered apoptotic in situ by medicines like CPX or DEF, might serve as vehicles that deliver retroviral immunogens to an immune system that has, at least temporarily, been de-paralyzed by the same drugs via their ability to inhibit HIV-1 gene expression.…”

Section: Discussionmentioning

confidence: 99%

Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection

et al. 2013

View full text Add to dashboard Cite

HIV-1 blocks apoptosis, programmed cell death, an innate defense of cells against viral invasion. However, apoptosis can be selectively reactivated in HIV-infected cells by chemical agents that interfere with HIV-1 gene expression. We studied two globally used medicines, the topical antifungal ciclopirox and the iron chelator deferiprone, for their effect on apoptosis in HIV-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Both medicines activated apoptosis preferentially in HIV-infected cells, suggesting that the drugs mediate escape from the viral suppression of defensive apoptosis. In infected H9 cells, ciclopirox and deferiprone enhanced mitochondrial membrane depolarization, initiating the intrinsic pathway of apoptosis to execution, as evidenced by caspase-3 activation, poly(ADP-ribose) polymerase proteolysis, DNA degradation, and apoptotic cell morphology. In isolate-infected peripheral blood mononuclear cells, ciclopirox collapsed HIV-1 production to the limit of viral protein and RNA detection. Despite prolonged monotherapy, ciclopirox did not elicit breakthrough. No viral re-emergence was observed even 12 weeks after drug cessation, suggesting elimination of the proviral reservoir. Tests in mice predictive for cytotoxicity to human epithelia did not detect tissue damage or activation of apoptosis at a ciclopirox concentration that exceeded by orders of magnitude the concentration causing death of infected cells. We infer that ciclopirox and deferiprone act via therapeutic reclamation of apoptotic proficiency (TRAP) in HIV-infected cells and trigger their preferential elimination. Perturbations in viral protein expression suggest that the antiretroviral activity of both drugs stems from their ability to inhibit hydroxylation of cellular proteins essential for apoptosis and for viral infection, exemplified by eIF5A. Our findings identify ciclopirox and deferiprone as prototypes of selectively cytocidal antivirals that eliminate viral infection by destroying infected cells. A drug-based drug discovery program, based on these compounds, is warranted to determine the potential of such agents in clinical trials of HIV-infected patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection

et al. 2013

View full text Add to dashboard Cite

show abstract

“…For instance, subcutaneous immunisation is routinely applied commercially to produce hyperimmune ovine sera [22], [23] and facilitates antigen interaction with skin-associated DCs, including Langerhans cells, conventional DCs and macrophage-derived DCs [30]. Alternatively, intraperitoneal immunisation promotes antigen interaction with conventional DCs macrophages and plasmacytoid DCs, which may be beneficial depending on the antigen type [31], [32]. The functionality of site-specific DC subsets in sheep has not been well studied and thus empirical assessment is required to determine an optimal immunisation route.…”

Section: Introductionmentioning

confidence: 99%

An Empirical Approach towards the Efficient and Optimal Production of Influenza-Neutralizing Ovine Polyclonal Antibodies Demonstrates That the Novel Adjuvant CoVaccine HT™ Is Functionally Superior to Freund's Adjuvant

et al. 2013

View full text Add to dashboard Cite

Passive immunotherapies utilising polyclonal antibodies could have a valuable role in preventing and treating infectious diseases such as influenza, particularly in pandemic situations but also in immunocompromised populations such as the elderly, the chronically immunosuppressed, pregnant women, infants and those with chronic diseases. The aim of this study was to optimise current methods used to generate ovine polyclonal antibodies. Polyclonal antibodies to baculovirus-expressed recombinant influenza haemagglutinin from A/Puerto Rico/8/1934 H1N1 (PR8) were elicited in sheep using various immunisation regimens designed to investigate the priming immunisation route, adjuvant formulation, sheep age, and antigen dose, and to empirically ascertain which combination maximised antibody output. The novel adjuvant CoVaccine HT™ was compared to Freund’s adjuvant which is currently the adjuvant of choice for commercial production of ovine polyclonal Fab therapies. CoVaccine HT™ induced significantly higher titres of functional ovine anti-haemagglutinin IgG than Freund’s adjuvant but with fewer side effects, including reduced site reactions. Polyclonal hyperimmune sheep sera effectively neutralised influenza virus in vitro and, when given before or after influenza virus challenge, prevented the death of infected mice. Neither the age of the sheep nor the route of antigen administration appeared to influence antibody titre. Moreover, reducing the administrated dose of haemagglutinin antigen minimally affected antibody titre. Together, these results suggest a cost effective way of producing high and sustained yields of functional ovine polyclonal antibodies specifically for the prevention and treatment of globally significant diseases.

show abstract