Reconsidering targeted toxins to eliminate HIV infection: You gotta have HAART

Berger, Edward A.; Moss, Bernard; Pastan, Ira

doi:10.1073/pnas.95.20.11511

Cited by 47 publications

(36 citation statements)

References 33 publications

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“…It might even be possible to construct a recombinant toxin specific for the latent virus present in a particular infected individual. Such a molecule, administered together with agents that induce the expression of dormant integrated provirus (e.g., cytokines or activators of protein kinase C), might help to reduce or possibly eliminate latent reservoirs of HIV-1 (35). Preliminary ex vivo experiments show that 5-Helix-PE indeed can block the deoxyphorbol ester-mediated induction of latent HIV-1 replication in CD8-depleted peripheral blood mononuclear cells from an HIV-1-infected individual receiving antiretroviral therapy.…”

Section: Discussionmentioning

confidence: 99%

Targeting therapeutics to an exposed and conserved binding element of the HIV-1 fusion protein

Root

Hamer

2003

Proc. Natl. Acad. Sci. U.S.A.

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There is an urgent need for new drugs that can kill HIV type 1 (HIV-1)-infected cells. HIV-1 glycoprotein Env, which promotes viral membrane fusion through receptor-mediated conformational changes, is an attractive target for such agents because it is expressed on the surface of both virions and infected cells. Unfortunately, conserved binding elements on this protein frequently are buried under a canopy of flexible, glycosylated peptide loops or exposed only transiently during the fusion process. Here, we investigate the exposure of the C-terminal region of the Env ectodomain outside the context of membrane fusion. This binding element is the target of the 5-Helix protein, a designed entry inhibitor that disrupts conformational changes in Env subunit gp41, essential for the fusion process. We show that 5-Helix is capable of interacting with HIV-1 Env in a receptor-independent fashion and that a chimeric 5-Helix͞Pseudomonas exotoxin protein recognizes cells expressing Env from a broad spectrum of HIV-1 strains including primary isolates from clades B, D, E, G, and H. This recombinant toxin selectively kills HIV-1-infected cells and blocks spreading infection while still maintaining potent inhibitory activity against membrane fusion. Our results demonstrate that the C-terminal region of the gp41 ectodomain is an accessible target on HIV-1-infected cells for the development of antiviral therapeutics and neutralizing antibodies.

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Section: Discussionmentioning

confidence: 99%

Targeting therapeutics to an exposed and conserved binding element of the HIV-1 fusion protein

Root

Hamer

2003

Proc. Natl. Acad. Sci. U.S.A.

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“…They represent a major obstacle for eradicating HIV-1 infection due to their long lifespan and their relative resistance to cytopathic effects of HIV infection (27,28). AZT is known to block HIV spreading in both macrophages and T lymphocytes (60) but is devoid of antiretroviral activity in cells containing integrated proviruses, such as chronically infected cell lines (61).…”

Section: Discussionmentioning

confidence: 99%

“…Although circulating monocytes are infrequently infected (23), tissue macrophages are reservoirs of both actively replicating as well as latent HIV-1, and play a crucial role in propagating the infection in organs such as the brain and the lungs (24 -26). Infection of tissue macrophages is considered a major obstacle for eradicating HIV-1 infection due to their long lifespan and relative absence of cytopathicity consequent to retroviral infection (27,28). Although expressing both CCR5 and CXC chemokine receptor 4, monocyte-derived macrophages (MDM) sustain efficient replication of R5, but usually not of X4 HIV-1 due to restrictions occurring at a postentry level (29).…”

mentioning

confidence: 99%

The Binding Subunit of Pertussis Toxin Inhibits HIV Replication in Human Macrophages and Virus Expression in Chronically Infected Promonocytic U1 Cells

Alfano¹,

Vallanti²,

Biswas³

et al. 2001

The Journal of Immunology

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We have recently shown that the binding subunit of pertussis toxin (PTX-B) inhibits the entry and replication of macrophage-tropic (R5) HIV-1 strains in activated primary T lymphocytes. Furthermore, PTX-B suppressed the replication of T cell-tropic (X4) viruses at a postentry level in the same cells. In this study we demonstrate that PTX-B profoundly impairs entry and replication of the HIV-1ADA (R5), as well as of HIV pseudotyped with either murine leukemia virus or vesicular stomatitis virus envelopes, in primary monocyte-derived macrophages. In addition, PTX-B strongly inhibited X4 HIV-1 replication in U937 promonocytic cells and virus expression in the U937-derived chronically infected U1 cell line stimulated with cytokines such as TNF-α and IL-6. Of interest, TNF-α-mediated activation of the cellular transcription factor NF-κB was unaffected by PTX-B. Therefore, PTX-B may represent a novel and potent inhibitor of HIV-1 replication to be tested for efficacy in infected individuals. In support of this proposition, a genetically modified mutant of PTX (PT-9K/129G), which is safely administered for prevention of Bordetella pertussis infection, showed an in vitro anti-HIV profile superimposable to that of PTX-B.

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“…Highly active antiretroviral therapy (HAART) with these inhibitors has achieved high-level suppression of viral load in HIV-1-infected patients. The emergence of drug-resistant HIV-1 mutants during long-term HAART may result in the failure of therapy (Berger et al, 1998). However, some patients showed a sign of drug-resistance in the absence of drugresistant viruses (Groschel et al, 1997).…”

mentioning

confidence: 99%

Breast Cancer Resistance Protein (BCRP/ABCG2) Induces Cellular Resistance to HIV-1 Nucleoside Reverse Transcriptase Inhibitors

Wang

Furukawa

Nitanda

et al. 2003

Molecular Pharmacology

127

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Breast cancer resistance protein (BCRP/ABCG2) is a novel member of ATP-binding cassette transporters, which induce multidrug resistance in cancer cells. We found that a high level of BCRP expression in CD4 ϩ T cells conferred cellular resistance to human immunodeficiency virus type-1 (HIV-1) nucleoside reverse transcriptase inhibitors. The cell line MT-4/DOX 500 was established through the long-term culture of MT-4 cells in the presence of doxorubicin (DOX) and had reduced sensitivity to not only DOX but also zidovudine (AZT). MT-4/DOX 500 cells showed reduced intracellular accumulation and retention of DOX and increased ATP-dependent rhodamine 123 efflux. The cells were also resistant to several anticancer agents such as mitoxantrone, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, and 7-ethyl-10-hydroxycamptothecin. AZT was 7.5-fold less inhibitory to HIV-1 replication in MT-4/DOX 500 cells than in MT-4 cells. Furthermore, the anti-HIV-1 activity of lamivudine was severely impaired in MT-4/DOX 500 cells. In contrast, the antiviral activity of non-nucleoside reverse transcriptase inhibitors and protease inhibitors was not affected in the cells. MT-4/DOX 500 cells expressed glycosylated BCRP but not P-glycoprotein (ABCB1), multidrug resistance protein 1, 2, or 4 (ABCC1, -2, or -4), or lung resistance-related protein. In addition, the BCRP-specific inhibitor fumitremorgin C completely abolished the resistance of MT-4/DOX 500 cells to AZT as well as to DOX. An analysis for intracellular metabolism of AZT suggests that the resistance is attributed to the increase of ATP-dependent efflux of its metabolites, presumably AZT 5Ј-monophosphate, in MT-4/DOX 500 cells.

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Reconsidering targeted toxins to eliminate HIV infection: You gotta have HAART

Cited by 47 publications

References 33 publications

Targeting therapeutics to an exposed and conserved binding element of the HIV-1 fusion protein

Targeting therapeutics to an exposed and conserved binding element of the HIV-1 fusion protein

The Binding Subunit of Pertussis Toxin Inhibits HIV Replication in Human Macrophages and Virus Expression in Chronically Infected Promonocytic U1 Cells

Breast Cancer Resistance Protein (BCRP/ABCG2) Induces Cellular Resistance to HIV-1 Nucleoside Reverse Transcriptase Inhibitors

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