New treatment options for HIV salvage patients: An overview of second generation PIs, NNRTIs, integrase inhibitors and CCR5 antagonists

Hughes, Amelia; Barber, Tristan; Nelson, Mark

doi:10.1016/j.jinf.2008.05.006

Cited by 49 publications

(37 citation statements)

References 18 publications

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“…They inhibit cleavage of the Gag polyprotein and block formation of the conical capsid of mature virions (15,40). Figure 1 provides a schematic of these and subsequent events.…”

Section: (Rt) Inhibitors (Nrti) Nonnucleoside Reverse Transcriptase mentioning

confidence: 99%

“…Enfuvirtide binds to the exposed transmembrane region of the Env protein (gp41), blocking subsequent conformational changes and disabling the fusogenic process (17). Following formation of triphosphorylated forms of the nucleoside (abacavir) and the nucleotide (tenofovir), reverse transcriptase inhibitors become incorporated into the lengthening HIV DNA chain during reverse transcription but lack a terminal hydroxyl group which is necessary for continuation of this process (15). On the other hand, nonnucleoside reverse transcriptase inhibitors such as rilpivirine interfere with the lengthening HIV DNA chain through binding to the RT enzyme near the catalytic site (3,37).…”

Section: (Rt) Inhibitors (Nrti) Nonnucleoside Reverse Transcriptase mentioning

confidence: 99%

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Timing of the Components of the HIV Life Cycle in Productively Infected CD4 ⁺ T Cells in a Population of HIV-Infected Individuals

Murray

Kelleher

Cooper

2011

J Virol

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We estimate the time required for HIV to complete separate stages of its infection cycle in productively infected CD4؉ T cells in vivo by comparing initial delays after administration of single antiretroviral drugs until HIV RNA reduction in peripheral blood. Data were obtained from monotherapy studies of eight antiretroviral drugs from all currently licensed HIV drug classes: CCR5 blockers (maraviroc), fusion inhibitors (enfuvirtide), nucleoside and nonnucleoside reverse transcriptase inhibitors (abacavir, tenofovir, and rilpivirine), integrase inhibitors (raltegravir), and protease inhibitors (ritonavir and nelfinavir). We find that HIV requires an average of 52 h between export of virions in one generation to export in the next, with most of this (33 h) taken up by reverse transcription. Reverse transcription in vivo was three times longer than in vitro and began soon after virion fusion, as we determined no difference in mean times for commencement of reverse transcription and virion fusion as calculated by timing of the effects for tenofovir and maraviroc. Approximately 7 h is required between HIV integration and virion production. First-phase HIV RNA decay (half-life of 17 h over all drugs) seemed to slow as the stage being inhibited by the drug was further from viral production. The mean estimated half-life of plasma virions was 5 min, significantly shorter than previous estimates.

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“…They inhibit cleavage of the Gag polyprotein and block formation of the conical capsid of mature virions (15,40). Figure 1 provides a schematic of these and subsequent events.…”

Section: (Rt) Inhibitors (Nrti) Nonnucleoside Reverse Transcriptase mentioning

confidence: 99%

Section: (Rt) Inhibitors (Nrti) Nonnucleoside Reverse Transcriptase mentioning

confidence: 99%

Timing of the Components of the HIV Life Cycle in Productively Infected CD4 ⁺ T Cells in a Population of HIV-Infected Individuals

Murray

Kelleher

Cooper

2011

J Virol

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“…Future studies investigating these enzymes may identify the antimalarial target of the PIs and help explain the poor antimalarial activity of darunavir. Interestingly, darunavir has a similar structure to amprenavir, another PI with weak antimalarial activity (5,18).…”

mentioning

confidence: 99%

Antimalarial Asexual Stage-Specific and Gametocytocidal Activities of HIV Protease Inhibitors

Peatey

Andrews

Eickel

et al. 2010

Antimicrob Agents Chemother

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The stage-specific antimalarial activities of a panel of antiretroviral protease inhibitors (PIs), including two nonpeptidic PIs (tipranavir and darunavir), were tested in vitro against Plasmodium falciparum. While darunavir demonstrated limited antimalarial activity (effective concentration [EC 50 ], >50 M), tipranavir was active at clinically relevant concentrations (EC 50 , 12 to 21 M). Saquinavir, lopinavir, and tipranavir preferentially inhibited the growth of mature asexual-stage parasites (24 h postinvasion). While all of the PIs tested inhibited gametocytogenesis, tipranavir was the only one to exhibit gametocytocidal activity.The global distributions of HIV and malaria overlap in many regions of the world (reviewed in reference 17). Although data on the number of individuals with both diseases are unavailable, rates of coinfection are likely to be high (7). Furthermore, coinfection often leads to severe disease (4,12,19,20). While the effects of antiretroviral therapy on the outcome of malaria infection are not understood, defining these interactions is important (11,13,16,18). Understanding the antimalarial activities of the antiretroviral protease inhibitors (PIs) (reviewed in reference 17), for example, may lead to treatment recommendations that improve clinical outcomes and may also result in the identification of a new antimalarial drug target.Current data suggest that PIs kill malaria parasites by inhibiting one or more of the six nondigestive vacuole plasmepsins (reviewed in reference 17). In the present study we investigated the stage-specific effects of the PIs on asexual-and sexual-stage Plasmodium falciparum parasites in order to help define the antimalarial target(s) of these drugs and to help guide partner drug choices in the field. To gain additional structure-activity data and information that may be relevant for coinfected individuals we also examined the activities of the nonpeptidic PIs tipranavir (Aptivus) and darunavir (Prezista), new-generation PIs that are active against HIV-1 strains resistant to first generation PIs (9).The antimalarial activities of saquinavir, lopinavir, ritonavir, tipranavir, darunavir, and chloroquine (diphosphate salt; Sigma) were determined as described previously (18). Concentrations required to achieve 10, 50, and 90% growth inhibition (Ϯ the standard error [SE]) were determined by nonlinear regression curve fitting. Each assay was performed in triplicate on at least two separate occasions. Stage-specific growth inhibition assays were performed on synchronized parasite cultures (8) at 0 (ring), 24 (trophozoite), and 36 h (schizont) postsynchronization. Cultures were washed post-drug exposure, resuspended in drug-free medium, and seeded into tissue culture plates containing 0.5 Ci/well [ 3 H]hypoxanthine for 40 h. Incorporation of [ 3 H]hypoxanthine was compared to that in vehicle controls.Drug-induced effects on gametocytogenesis were examined using Pfs16-GFP parasites (3) as previously described (14). Assays were performed in triplicate on three separat...

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“…Até o momento, dispõe-se das seguintes classes de drogas ARV's para o tratamento do HIV: inibidores da transcriptase reversa análogos de nucleosídeos, inibidores da transcriptase reversa não análogos de nucleosídeos, inibidores da protease, inibidores da integrase, antagonistas de CCR5 e inibidores de fusão [7].…”

Section: O Uso De Medicamentosunclassified

Explorando Longo Período de Interação entre Sistema Imunológico e HIV

Malaquias

Yang

2010

Tend. Mat. Apl. Comput.

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Resumo. O Vírus da Imunodeficiência Humana (HIV), infectando células T-CD4+ , consegue comprometer gravemente o funcionamento do Sistema Imunoló-gico, resultando em AIDS. Formulamos e analisamos três modelos matemáticos para este processo de infecção. Foi possível encontrar um limiar para a permanência do vírus na corrente sanguínea e evidenciar a necessidade da apoptose de células ativadas, após a eliminação do antígeno. Através da introdução de um termo de exaustão cumulativa (resultado da constante tentativa do sistema imunológico responder à infecção pelo HIV) também reproduzimos a diminuição do número de células T-CD4 + ao longo dos anos. Introdução

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New treatment options for HIV salvage patients: An overview of second generation PIs, NNRTIs, integrase inhibitors and CCR5 antagonists

Cited by 49 publications

References 18 publications

Timing of the Components of the HIV Life Cycle in Productively Infected CD4 ⁺ T Cells in a Population of HIV-Infected Individuals

Timing of the Components of the HIV Life Cycle in Productively Infected CD4 ⁺ T Cells in a Population of HIV-Infected Individuals

Antimalarial Asexual Stage-Specific and Gametocytocidal Activities of HIV Protease Inhibitors

Explorando Longo Período de Interação entre Sistema Imunológico e HIV

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New treatment options for HIV salvage patients: An overview of second generation PIs, NNRTIs, integrase inhibitors and CCR5 antagonists

Cited by 49 publications

References 18 publications

Timing of the Components of the HIV Life Cycle in Productively Infected CD4 + T Cells in a Population of HIV-Infected Individuals

Timing of the Components of the HIV Life Cycle in Productively Infected CD4 + T Cells in a Population of HIV-Infected Individuals

Antimalarial Asexual Stage-Specific and Gametocytocidal Activities of HIV Protease Inhibitors

Explorando Longo Período de Interação entre Sistema Imunológico e HIV

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Timing of the Components of the HIV Life Cycle in Productively Infected CD4 ⁺ T Cells in a Population of HIV-Infected Individuals

Timing of the Components of the HIV Life Cycle in Productively Infected CD4 ⁺ T Cells in a Population of HIV-Infected Individuals