HIV-1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycans through its basic region

Chang, Hsiao C.; Samaniego, Felipe; Nair, Bindukumar; Buonaguro, Luigi; Ensoli, Barbara

doi:10.1097/00002030-199712000-00006

Cited by 410 publications

(372 citation statements)

References 54 publications

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“…Tat, another HIV1 protein that has been found to either induce 21,56,57 or repress 58 cell death in vitro, is not present in the viral particles, but is released by HIV1-producing cells. 59 Therefore, it is possible that Tat was present in the 100-450 nm fractions purified from supernatants of living, HIV1-transfected HeLa cells that we used as a source of virus. However, because both the wild type and Denv HIV1 plasmids that we used encoded tat, and because the Denv HIV1 particles did not affect CD4 þ T-cell survival in the presence of cellular factors released by dying cells, our data suggest that Tat does not play a significant role in CD4 þ T-cell killing in our model.…”

Section: Discussionmentioning

confidence: 99%

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

et al. 2004

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CD4 þ T-cell death is a crucial feature of AIDS pathogenesis, but the mechanisms involved remain unclear. Here, we present in vitro findings that identify a novel process of HIV1 mediated killing of bystander CD4 þ T cells, which does not require productive infection of these cells but depends on the presence of neighboring dying cells. X4-tropic HIV1 strains, which use CD4 and CXCR4 as receptors for cell entry, caused death of unstimulated noncycling primary CD4 þ T cells only if the viruses were produced by dying, productively infected T cells, but not by living, chronically infected T cells or by living HIV1-transfected HeLa cells. Inducing cell death in HIV1-transfected HeLa cells was sufficient to obtain viruses that caused CD4 þ T-cell death. The addition of supernatants from dying control cells, including primary T cells, allowed viruses produced by living HIV1-transfected cells to cause CD4 þ Tcell death. CD4 þ T-cell killing required HIV1 fusion and/or entry into these cells, but neither HIV1 envelope-mediated CD4 or CXCR4 signaling nor the presence of the HIV1 Nef protein in the viral particles. Supernatants from dying control cells contained CD95 ligand (CD95L), and antibody-mediated neutralization of CD95L prevented these supernatants from complementing HIV1 in inducing CD4 þ T-cell death. Our in vitro findings suggest that the very extent of cell death induced in vivo during HIV1 infection by either virus cytopathic effects or immune activation may by itself provide an amplification loop in AIDS pathogenesis. More generally, they provide a paradigm for pathogen-mediated killing processes in which the extent of cell death occurring in the microenvironment might drive the capacity of the pathogen to induce further cell death.

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Section: Discussionmentioning

confidence: 99%

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

et al. 2004

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“…The Tat protein (1-86 aa) from the HTLV-IIIB isolate, BH-10 clone (clade B), was expressed in E. coli, purified and stored as described earlier [9,32,34]. The purified Tat protein was fully monomeric and had full biological activity as assessed by virus transactivation assays and by uptake studies in monocyte-derived dendritic cells [6,9,32,34].…”

Section: Recombinant Proteinsmentioning

confidence: 99%

“…The purified Tat protein was fully monomeric and had full biological activity as assessed by virus transactivation assays and by uptake studies in monocyte-derived dendritic cells [6,9,32,34]. Tat used for in vitro studies was resuspended in degassed buffer before use as described [6,28,34].…”

Section: Recombinant Proteinsmentioning

confidence: 99%

“…Tat is essential for viral replication, transmission and disease progression [1,[4][5][6][7]. In addition, Tat can modulate the expression of cytokines and cellular genes [6][7][8][9][10][11], and chemokine receptors [12][13][14][15], which are responsible for the transmission of macrophageand T-cell-tropic HIV-1 strains, respectively. In addition, the Tat protein also plays key roles in viral pathogenesis and in the pathogenesis of acquired immune deficiency syndrome (AIDS)-associated Kaposi's sarcoma [8,[16][17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

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Long-term protection against SHIV89.6P replication in HIV-1 Tat vaccinated cynomolgus monkeys

Maggiorella

Baroncelli

Michelini

et al. 2004

Vaccine

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Vaccination with a biologically active Tat protein or tat DNA contained infection with the highly pathogenic SHIV89.6P virus, preventing CD4 T-cell decline and disease onset. Here we show that protection was prolonged, since neither CD4 T-cell decline nor active virus replication was observed in all vaccinated animals that controlled virus replication up to week 104 after the challenge. In contrast, virus persisted and replicated in peripheral blood mononuclear cells and lymph nodes of infected animals, two of which died. Tat-specific antibody, CD4 and CD8 T-cell responses were high and stable only in the animals controlling the infection. In contrast, Gag-specific antibody production and CD4 and CD8 T-cell responses were consistently and persistently positive only in the monkeys that did not control primary virus replication. These results indicate that vaccination with Tat protein or DNA induced long-term memory Tat-specific immune responses and controlled primary infection at its early stages allowing a long-term containment of virus replication and spread in blood and tissues.

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“…Tat is produced early after infection [1,2] and is indispensable for viral replication, transmission, and AIDS pathogenesis [3][4][5][6]. Release of Tat from infected cells and its uptake by infected and uninfected cells is critical to the biology of the virus [5,[7][8][9][10]. In infected cells, Tat promotes viral replication or transactivates the replication of tat-defective or latent proviruses [11].…”

Section: Introductionmentioning

confidence: 99%

Comparative study of Tat vaccine regimens in Mauritian cynomolgus and Indian rhesus macaques: Influence of Mauritian MHC haplotypes on susceptibility/resistance to SHIV89.6P infection

Florese

Wiseman

Venzon

et al. 2008

Vaccine

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Protection afforded by HIV Tat-based vaccines has differed in Indian rhesus and Mauritian cynomolgus macaques. We evaluated native Tat and Ad-HIVtat priming/Tat-boosting regimens in both species. Both vaccines were immunogenic. Only the Ad-tat regimen modestly reduced acute viremia in rhesus macaques after SHIV 89.6P challenge. Confounding variables uncovered in Mauritian macaques included significant associations of susceptibility to infection with MHC class IB and class II H2 and H5 haplotypes, and resistance to infection with class IB haplotypes H3 and H6. Although protection here was limited, Tat-based vaccines incorporating other HIV components have shown greater efficacy. Combination strategies should be further explored.

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HIV-1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycans through its basic region

Abstract: These results demonstrate that Tat exits from intact cells through a leaderless secretion pathway which shares several features with that of acid FGF or bFGF. The released Tat binds to HSPG through its basic region and this determines its storage into the ECM, as occurs for bFGF.

Cited by 410 publications

References 54 publications

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

Long-term protection against SHIV89.6P replication in HIV-1 Tat vaccinated cynomolgus monkeys

Comparative study of Tat vaccine regimens in Mauritian cynomolgus and Indian rhesus macaques: Influence of Mauritian MHC haplotypes on susceptibility/resistance to SHIV89.6P infection

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