Target cell availability and the successful suppression of HIV by hydroxyurea and didanosine

Boer, Rob J. de; Boucher, Charles A.; Perelson, Alan S.

doi:10.1097/00002030-199813000-00002

Cited by 42 publications

(12 citation statements)

References 48 publications

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“…Although diminished cellular proliferation may not appear advantageous in HIV disease, it is important to underscore that conditions leading to cellular proliferation favor viral replication as well (21). Results from several clinical trials in which HU has been used in combination with anti-HIV drugs have shown an impressive control of the virus (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Induction of G ₁ cycle arrest in T lymphocytes results in increased extracellular levels of β-chemokines: A strategy to inhibit R5 HIV-1

Heredia

Davis

Amoroso

et al. 2003

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

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The ␤-chemokines RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein-1␣ (MIP-1␣), and MIP-1␤ are the natural ligands of the HIV-1 coreceptor CCR5 and compete with the virus for receptor binding. We show that secretion of the ␤-chemokines by activated lymphocytes starts before cellular DNA synthesis is detected and demonstrate that transient prolongation of the G1 phase of the cell cycle by treatment with cytostatic drugs results in increased levels of the three chemokines in culture supernatants. Supernatants collected from peripheral blood mononuclear cells exposed to hydroxyurea, which arrests the cell cycle in late G 1, contained high levels of ␤-chemokines. These supernatants were able to inhibit HIV-1 replication when added to cultures of infected lymphocytes. The observed antiviral effect likely was due to the increased levels of ␤-chemokines RANTES, MIP-1␣, and MIP-1␤ because (i) supernatants greatly inhibited the replication of HIV-1 BaL, whereas they affected HIV-1 IIIb replication only slightly; (ii) neutralizing antibodies against the chemokines abrogated the antiviral effect of the supernatants; and (iii) the hydroxyurea concentrations shown to up-regulate chemokine levels were not sufficient to inhibit virus replication by depletion of intracellular nucleotide pools. Although antiviral properties have been reported previously for the cytostatic agents shown here to up-regulate ␤-chemokine levels, our results provide an additional mechanism by which these drugs may exert antiviral activity. In summary, increased extracellular levels of anti-HIV-1 ␤-chemokines resulting from transient prolongation of the G1 phase of the lymphocyte cell cycle by treatment with cytostatic drugs may help to control the replication of CCR5-using strains of HIV-1.

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Section: Discussionmentioning

confidence: 99%

Induction of G ₁ cycle arrest in T lymphocytes results in increased extracellular levels of β-chemokines: A strategy to inhibit R5 HIV-1

Heredia

Davis

Amoroso

et al. 2003

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

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“…Limiting the activation and available pool of target cells in patients during sustained HIV suppression may be beneficial and may reduce the risk of viral rebound. 18,30 Promising results have been observed in studies of hydroxyurea, a drug known to inhibit cellular activation, and additional candidates are undergoing evaluation. 31,32 …”

Section: Discussionmentioning

confidence: 99%

Maintenance Antiretroviral Therapies in HIV-Infected Subjects with Undetectable Plasma HIV RNA after Triple-Drug Therapy

et al. 1998

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“…Hydroxyurea limits cellular proliferation thereby limiting virus replication in target cells (i.e. CD4 T cells) [16][17][18][19]. Others have described that hydroxyurea also increases the efficacy of pyrimidine analogues, such as zidovudine and zaltacitabine, by enhancing the activity of pyrimidine kinases in the salvage pathway [20,21].…”

Section: Mechanism Of Action Of Hydroxyurea-didanosine Combinationmentioning

confidence: 99%

Virostatics: A New Class of Anti-HIV Drugs

Friedman¹,

Foli²,

Kelly³

et al. 2007

CMC

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In this review we discuss the features of a new class of antiretroviral combinations, namely "Virostatics". Virostatics are characterized by the combination of a drug directly inhibiting virus production (viro), and another drug indirectly inhibiting the virus by reducing cellular proliferation (static). In particular, we will focus on the combination of hydroxyurea and didanosine against HIV-1. Hydroxyurea and didanosine synergize to control viral replication and present with a favorable resistance profile, suppressing several resistant quasi-species. Because virostatics target essential cellular proteins, they exert an immune modulating activity and reduce viral targets (CD4 T cells), possibly with limited immunosuppressive effects. Importantly, a dose-finding clinical study has shown that decreasing the dose of hydroxyurea not only diminishes toxicity but also increases antiviral potency. Therefore, the combination of hydroxyurea and didanosine strikes a balance between viral suppression, drug-related toxicity and viral escape, and could have a role both in induction and maintenance therapy. In this review we would like to appraise what is known about hydroxyurea and didanosine and specifically address the major advantages, i.e. novel mechanism of action leading to a new class of drugs and resistance profile providing durability, as well as the major criticisms of this combination, i.e. toxicity and reasons for prescribing a perceived immune suppressant to immune compromised patients.

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Target cell availability and the successful suppression of HIV by hydroxyurea and didanosine

Cited by 42 publications

References 48 publications

Induction of G ₁ cycle arrest in T lymphocytes results in increased extracellular levels of β-chemokines: A strategy to inhibit R5 HIV-1

Induction of G ₁ cycle arrest in T lymphocytes results in increased extracellular levels of β-chemokines: A strategy to inhibit R5 HIV-1

Maintenance Antiretroviral Therapies in HIV-Infected Subjects with Undetectable Plasma HIV RNA after Triple-Drug Therapy

Virostatics: A New Class of Anti-HIV Drugs

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Target cell availability and the successful suppression of HIV by hydroxyurea and didanosine

Cited by 42 publications

References 48 publications

Induction of G 1 cycle arrest in T lymphocytes results in increased extracellular levels of β-chemokines: A strategy to inhibit R5 HIV-1

Induction of G 1 cycle arrest in T lymphocytes results in increased extracellular levels of β-chemokines: A strategy to inhibit R5 HIV-1

Maintenance Antiretroviral Therapies in HIV-Infected Subjects with Undetectable Plasma HIV RNA after Triple-Drug Therapy

Virostatics: A New Class of Anti-HIV Drugs

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Product

Resources

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Induction of G ₁ cycle arrest in T lymphocytes results in increased extracellular levels of β-chemokines: A strategy to inhibit R5 HIV-1

Induction of G ₁ cycle arrest in T lymphocytes results in increased extracellular levels of β-chemokines: A strategy to inhibit R5 HIV-1