Candidate HIV-1 Tat vaccine development: from basic science to clinical trials

Ensoli, Barbara; Fiorelli, Valeria; Ensoli, Fabrizio; Cafaro, Aurelio; Titti, Fausto; Buttò, Stefano; Monini, Paolo; Magnani, Mauro; Caputo, Antonella; Garaci, Enrico

doi:10.1097/qad.0b013e3280112cd1

Cited by 66 publications

(59 citation statements)

References 125 publications

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“…It is a relatively conserved protein among all of the viral isolates, and the status of Abs against Tat protein has been shown to be directly proportional to the progression of the disease in several clinical studies (43). The hypothesis that Tat plays an important role in the immunopathogenesis of HIV-1 has led to several studies using Tat as a candidate protein for HIV vaccine as both individual and multicomponent vaccine candidates (44). Several studies indicate that Abs to Tat play a host-protective role in HIV-1 infection and thus have been also considered as a target for the development of novel AIDS therapy (45).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Tat Suppresses gp120-Specific T Cell Response in IL-10-Dependent Manner

Gupta

Boppana

Mishra

et al. 2008

The Journal of Immunology

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A large number of multicomponent vaccine candidates are currently in clinical evaluation, many of which also include the HIV-1 Tat protein, an important regulatory protein of the virus. However, whether Tat, a known immune effector molecule with a well-conserved sequence among different HIV subtypes, affects the immune response to a coimmunogen is not well understood. In this study, using a bicistronic vector expressing both gp120 and Tat, we have analyzed the role of Tat in elicitation of the gp120-specific immune response. The T cell responses to gp120 were greatly diminished in mice coimmunized with Tat as compared with mice immunized with gp120 alone. This immunosuppressive activity of Tat was not confined to viral Ag only because it also suppressed the immune response of unrelated Ag. Analysis of the cytokine profile suggests that Tat induces IL-10 and since IL-10 has been demonstrated to have appreciable T cell inhibitory activity, it is plausible that IL-10 could be responsible for Tat-mediated immunosuppression. Finally, the immunosuppressive effect of Tat was not observed in IL-10-deficient mice, confirming the role of IL-10 in Tat-mediated immunosuppression. Thus, our results demonstrate for the first time that the immunosuppressive effect of Tat is mediated through IL-10 and suggests that Tat-induced IL-10-mediated immune suppression seems to cripple immune surveillance during HIV-1 infection.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Tat Suppresses gp120-Specific T Cell Response in IL-10-Dependent Manner

Gupta

Boppana

Mishra

et al. 2008

The Journal of Immunology

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“…In addition, evidence exists that natural IgM antibodies reacting with Tat may provide an early initial defense against the pathological effects of Tat after HIV infection and influence the course of AIDS progression [131,132]. Similarly, immunization with Tat elicits antibody responses in rodents, monkeys, and humans able to block the activity of extracellular Tat on cellular entry, gene expression, and replication [4,84,[133][134][135][136][137][138][139][140][141][142]. Moreover, strong anti-Tat antibody responses correlated with an efficient reduction in plasma viremia and long-term protection in Tat protein-vaccinated monkeys challenged intrarectally with an heterologous SHIV virus [143].…”

Section: The Choice Of Tat As Vaccine Relevant Antigenmentioning

confidence: 99%

“…4,63,67,84,85] and 46% of anti-Tat seropositive individuals were reported when anti-Tat ELISA were carried out with Tat variants specific for the subtype infecting patients [119]. High antibody titers directed against a broad spectrum of Tat functional domains neutralize the effects of extracellular Tat on virus replication and cell functions and play an important role in the control of the HIV infection and disease progression [105,[119][120][121][122][123][124][125][126][127][128][129][130].…”

Section: The Choice Of Tat As Vaccine Relevant Antigenmentioning

confidence: 99%

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HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

Caputo

Gavioli

Bellino

et al. 2009

International Reviews of Immunology

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“…Extracellular Tat can exert different effects on cell functions and generate a wide array of cell responses ranging from cell activation (T-cells and endothelial cells) to stimulation of cytokine secretion (T-cells and monocytes) and cell death (neurons and endothelial and T-cells) (1, 4 -7). Accumulating evidence suggests that extracellular Tat is involved in the evolution to AIDS (1, 4 -6), and Tat is considered as an important component in developing anti-HIV-1 vaccines (13).…”

mentioning

confidence: 99%

Mechanism for HIV-1 Tat Insertion into the Endosome Membrane

Yezid¹,

Konate²,

Debaisieux³

et al. 2009

Journal of Biological Chemistry

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The human immunodeficiency virus, type 1, transactivating protein Tat is a small protein that is strictly required for viral transcription and multiplication within infected cells. The infected cells actively secrete Tat using an unconventional secretion pathway. Extracellular Tat can affect different cell types and induce severe cell dysfunctions ranging from cell activation to cell death. To elicit most cell responses, Tat needs to reach the cell cytosol. To this end, Tat is endocytosed, and low endosomal pH will then trigger Tat translocation to the cytosol. Although this translocation step is critical for Tat cytosolic delivery, how Tat could interact with the endosome membrane is unknown, and the key residues involved in this interaction require identification. We found that, upon acidification below pH 6.0 (i.e. within the endosomal pH range), Tat inserts into model membranes such as monolayers or lipid vesicles. This insertion process relies on Tat single Trp, Trp-11, which is not needed for transactivation and could be replaced by another aromatic residue for membrane insertion. Nevertheless, Trp-11 is strictly required for translocation. Tat conformational changes induced by low pH involve a sensor made of its first acidic residue (Glu/Asp-2) and the end of its basic domain (residues 55-57). Mutation of one of these elements results in membrane insertion above pH 6.5. Tat basic domain is also required for efficient Tat endocytosis and membrane insertion. Together with the strict conservation of Tat Trp among different virus isolates, our results point to an important role for Tat-membrane interaction in the multiplication of human immunodeficiency virus type 1.

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Candidate HIV-1 Tat vaccine development: from basic science to clinical trials

Cited by 66 publications

References 125 publications

HIV-1 Tat Suppresses gp120-Specific T Cell Response in IL-10-Dependent Manner

HIV-1 Tat Suppresses gp120-Specific T Cell Response in IL-10-Dependent Manner

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

Mechanism for HIV-1 Tat Insertion into the Endosome Membrane

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