A prophylactic and therapeutic AIDS vaccine containing as a component the innocuous Tat Toxoid

doi:10.1016/S0753-3322(99)80020-1

Biomedicine & Pharmacotherapy

Volume 52, Issue 10, December 1998, Pages 431-435

https://doi.org/10.1016/S0753-3322(99)80020-1 Get rights and content

Summary

Extracellular Tat can act as a viral toxin on uninfected cells of different tissues, including the CNS and the immune system, thus in order to immunize humans against Tat we have prepared a biologically inactivated but immunogenic Tat (Tat Toxoid). Tat Toxoid is not toxic in mice even at high doses. It triggers high levels of specific Tat Abs in the mouse and rabbit. Furthermore, in humans Tat Toxoid immunization was safe and induced in seronegatives persistent high levels of Tat Abs and in immunodeficient patients a significant rise of these specific Abs. Facing acute HIV-1 infection, the presence of high level of circulating Tat Abs promoted by Tat Toxoid vaccine should prevent Tatinduced immunosuppression and allow anti-HIV-1 cellular response to develop. As a consequence, early release of β-chemokines could enhance host resistance towards HIV-1, and, in infected people, inhibit viral replication and evolution towards AIDS.

References (26)

MitolaS et al.
Tat-human immunodeficiency virus-1 induces human monocyte chemotaxis by activation of vascular endothelial growth factor receptor-1
Blood
(1997)
StrijbosPJ et al.
Neurotoxic mechanisms of transactivating protein Tat of Maedi-Visna virus
Neurosci Lett
(1995)
HendelH et al.
Contribution of cohort studies in understanding HIV pathogenesis: introduction of the GRIV cohort and preliminary results
Biomed Pharmacother
(1996)
AryaSK et al.
New human and simian HIV-related retro-viruses possess functional transactivator (tat) gene
Nature
(1987)
RubenS et al.
Structural and functional characterization of human immunodeficiency virus Tat protein
J Virol
(1989)
EnsoliB et al.
Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients
Nature
(1990)
MannDA et al.
Endocytosis and targeting of exogenous HIV-1 Tat protein
EMBO J
(1991)
soliB et al.
Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma
Nature
(1994)
JonesM et al.
Intraventricular injection of human immunodeficiency virus type 1 (HIV-1) Tat protein causes inflammation, gliosis, apoptosis and ventricular enlargement
J Neuropathol Exp Neurol
(1998)
SabatierJM et al.
Evidence for neurotoxic activity of Tat from human immunodeficiency virus type 1
J Virol
(1991)

GourdouI et al.

Neurotoxicity in mice due to cysteinerich parts of visna virus and HIV-1 Tat proteins

C R Acad Sci III

(1990)

ChengJ et al.

Neuronal excitatory properties of human immunodeficiency virus type. 1 Tat protein

Neuroscience

(1998)

ShiB et al.

Neuronal apoptosis induced by HIV-1 Tat protein and TNF-alpha: potentiation of neurotoxicity mediated by oxidative stress and implications for HIV-1 dementia

J Neurovirol

(1998)

Cited by (16)

Increasing the humoral immunogenic properties of the HIV-1 Tat protein using a ligand-stabilizing strategy
2008, Vaccine
Citation Excerpt :
Therefore, we postulate that most of the Tat proteins can be made more resistant to proteolysis and more immunogenic if they are previously associated with appropriate sulfated sugars. It is interesting to note that Tat86/PPS raised antibody titers roughly 40 times higher than those raised by Tat86Scam, because Tat86Scam is a Tat86 protein previously inactivated by alkylation of its seven cysteines according to a protocol similar to that used to prepare a toxoid of Tat86 [51] that could only attenuate the clinical signs of the disease in macaques challenged with SHIV89.6PD [24]. We therefore postulate that such a toxoid might raise a stronger immune response following its stabilization using appropriate sulfated polysaccharides.
Tat is regarded as an attractive target for the development of an AIDS vaccine. However, works suggest that Tat is a poorly immunogenic protein and therefore we attempted to increase its immunogenic potency. As we observed that Tat is highly sensitive to enzymatic degradation in vitro we tried to make it less susceptible to proteolysis using ligands. We complexed Tat101 with various sulfated sugars and observed that some of these ligands made the protein more resistant to proteolysis and more immunogenic. In a more thorough study, we observed that a low-molecular-weight heparin fragment, called Hep6000, altered both the cell-binding capacity and transactivating activity of Tat101, suggesting that this sulfated polysaccharide can make the protein less toxic. Sera raised against Tat101 and Tat101/Hep6000 similarly bound mainly to the N-terminal region of the protein, indicating that formation of the complex does not alter the B-cell immunodominant region. Anti-Tat101/Hep6000 antisera neutralized the transactivating activity of Tat101 more efficiently than anti-Tat101 antisera. Altogether, these results indicate that stabilization of Tat101 using sulfated sugars increases its immunogenicity and might be of value in increasing its vaccine efficacy.
Nonstructural HIV proteins as targets for prophylactic or therapeutic vaccines
2004, Current Opinion in Biotechnology
By the end of 2004, more than 20 HIV-1 vaccine candidates will have entered clinical testing in at least 30 trials worldwide. Almost half of these vaccines include nonstructural HIV-1 gene products. This represents an important innovation in the HIV vaccine field, because until 9 years ago not even preclinical testing in small animal models had been carried out with such immunogens. This review briefly discusses the experimental evidence that provides the rationale for the use of nonstructural HIV-1 gene products as vaccine antigens, and summarizes the current status and the future development of these novel vaccines.
The basis for HIV immunotherapeutic vaccines
2001, Vaccine
The drug treatments introduced in recent years for HIV infection have enabled a marked reduction in morbidity and prolongation of life. These treatments, however, are often associated with acute and chronic toxicities, the development of resistant virus can limit their effectiveness, and they are too expensive and difficult to administer in most third world settings. A successful HIV immunotherapeutic vaccine has the potential to overcome these problems, and would be a valuable advance. The most promising approaches have induced the type of immune response found to correlate with reduced activity of HIV in man, especially cytotoxic T-cell responses, or have led to reduced HIV or SIV viral load and increased CD4 counts in non-human primates or man.
The agents that have led to one or both of these effects have been selected for review, and include inactivated envelope depleted virus, recombinant envelope glycoprotein, DNA vaccines utilising HIV peptides or gene products, viral vectors, such as canarypox or attenuated vaccinia, with HIV core proteins. There are other approaches, such as alloimmunity, for which no candidate products yet exist, but which conceptually appear promising. Currently, however, only a few phase III studies of HIV therapeutic vaccines have been completed in man, and there has been a modest therapeutic effect. Further development of both existing and new candidates remains one of the key priorities in our fight against HIV.
Antibodies against full-length Tat protein and some low-molecular-weight Tat-peptides correlate with low or undetectable viral load in HIV-1 seropositive patients
2001, Journal of Clinical Virology
Background: The efficacy of a specific humoral response to transactivating Tat protein was studied in a group of HIV-1 seropositive drug addicts, who had previously received a similar course of anti-retroviral treatment with two reverse transcriptase inhibitors. Objectives: The aim of the study was to evaluate the meaning of an immune response to Tat protein in HIV-1 seropositive patients with different levels of HIV-1 RNA viremia. Study design: The study analyzed the presence of anti-Tat antibody reacting either with full-length Tat or with individual overlapping Tat-peptides (Tat_6–14, Tat_11–24, Tat_36–50, Tat_46–60, Tat_56–70 and Tat_65–80), in a group of HIV-1 seropositive subjects with different peripheral blood viral loads. Plasma samples were examined by immunoenzymatic assay for the presence of anti-Tat IgG antibody and for the quantification of peripheral blood (plasma) viral load by branched DNA assay. Results: The large majority of HIV-1 patients showed detectable levels of serum IgG to full-length-Tat, and the anti-Tat antibody level presented an inverse correlation with viral load magnitude. The analysis of antibody levels against individual overlapping Tat-peptides clearly showed that an undetectable viral load was significantly associated with the presence of a high antibody concentration against Tat_6–14, Tat_36–50 and Tat_46–60 (P=0.002, P=0.027 and P<0.001, respectively). Conclusion: In HIV-1-infected patients, a strong humoral immune response against HIV-1 Tat protein is inversely correlated to peripheral blood viral load and, in particular, a high level of antibody against Tat peptides containing amino acid residues 6–14 (Tat_6–14), 36–50 (Tat_36–50) and 46–60 (Tat_46–60) is associated with an undetectable plasma viral load. These findings may help to tailor anti-HIV-1 Tat-containing vaccines.
Immunization with a novel HIV-1-Tat multiple-peptide conjugate induces effective immune response in mice
2000, Peptides
We report here a novel, highly immunogenic synthetic, multiple-peptide conjugate comprising functional domains Tat_21–40 and Tat_53–68 from HIV-1 group M plus Tat_9–20 from HIV-1 group O of the HIV-Tat protein (HIV-1-Tat-MPC). Vaccination of mice with HIV-1-Tat-MPC induced an effective immune response to all three functional domains. The anti-HIV-1-Tat-MPC antibodies efficiently inhibited Tat-induced viral activation in monocytes infected with HIV_Ba-L as well as with various clinical HIV-1 isolates, and reduced Tat-mediated cytopathicity in infected cells by 60–75%. Our results indicate that anti-HIV-1-Tat-MPC antibodies inhibit viral pathogenesis, possibly by blocking functional determinants of Tat and disrupting autocrine and paracrine actions of secreted Tat protein. This epitope-specific, synthetic Tat construct may, therefore, provide a subunit AIDS vaccine candidate for inducing an effective immunoprophylaxis response to reduce progression of HIV infection.
Induction of cellular immunosuppression by the human papillomavirus type 16 E7 oncogenic protein
1999, Biomedicine and Pharmacotherapy
The human papillomavirus type 16 (HPV-16) E7 oncogenic protein is found in the culture supernatant of SiHa cells, a cervical carcinoma cell line. Extracellular E7 protein, acting as a viral toxin in human immune cells, induces the overproduction of the immune suppressive IFNα cytokine by APCs, and inhibits the T-cell response to recall and allogenic antigens. These effects should be taken into account for the design of anti-human cervical carcinoma vaccines.

View all citing articles on Scopus

View full text

A prophylactic and therapeutic AIDS vaccine containing as a component the innocuous Tat Toxoid

Summary

Blood

Neurosci Lett

Biomed Pharmacother

New human and simian HIV-related retro-viruses possess functional transactivator (tat) gene

Nature

Structural and functional characterization of human immunodeficiency virus Tat protein

J Virol

Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients

Nature

Endocytosis and targeting of exogenous HIV-1 Tat protein

EMBO J

Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma

Nature

Intraventricular injection of human immunodeficiency virus type 1 (HIV-1) Tat protein causes inflammation, gliosis, apoptosis and ventricular enlargement

J Neuropathol Exp Neurol

Evidence for neurotoxic activity of Tat from human immunodeficiency virus type 1

J Virol

Neurotoxicity in mice due to cysteinerich parts of visna virus and HIV-1 Tat proteins

C R Acad Sci III

Neuronal excitatory properties of human immunodeficiency virus type. 1 Tat protein

Neuroscience

Neuronal apoptosis induced by HIV-1 Tat protein and TNF-alpha: potentiation of neurotoxicity mediated by oxidative stress and implications for HIV-1 dementia

J Neurovirol