Two-Drug Combinations of Zidovudine, Didanosine, and Recombinant Interferon-  A Inhibit Replication of Zidovudine-Resistant Human Immunodeficiency Virus Type 1 Synergistically In Vitro

Johnson, Victoria A.; Merrill, Debra P.; Videler, Joseph A.; Chou, Ting‐Chao; Byington, Roy E.; Eron, Joseph J.; D’Aquila, Richard T.; Hirsch, Martin S.

doi:10.1093/infdis/164.4.646

Cited by 126 publications

(58 citation statements)

References 45 publications

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“…After 48 h of incubation, 100 l of cells/well was transferred to a 96-well black solid plate (Costar), and the luminescence was measured using a Britelite Plus luminescence reporter gene assay system (Perkin-Elmer Life Sciences). Wells producing relative luminescence units of Ͼ3ϫ the background were scored as positive, and the 50% tissue culture infective dose (TCID 50 ) was calculated by the method of Reed and Muench, as previously described (19,31,35). The concentration of the pseudoviruses was measured using a commercial p24 enzymelinked immunosorbent assay (ELISA) (Perkin-Elmer Life Sciences) per its protocol.…”

Section: Methodsmentioning

confidence: 99%

Origin and Evolution of HIV-1 in Breast Milk Determined by Single-Genome Amplification and Sequencing

Salazar-Gonzalez

Salazar

Learn

et al. 2011

J Virol

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HIV transmission via breastfeeding accounts for a considerable proportion of infant HIV acquisition. However, the origin and evolution of the virus population in breast milk, the likely reservoir of transmitted virus variants, are not well characterized. In this study, HIV envelope (env) genes were sequenced from virus variants amplified by single-genome amplification from plasmas and milk of 12 chronically HIV-infected, lactating Malawian women. Maximum likelihood trees and statistical tests of compartmentalization revealed interspersion of plasma and milk HIV env sequences in the majority of subjects, indicating limited or no compartmentalization of milk virus variants. However, phylogenetic tree analysis further revealed monotypic virus variants that were significantly more frequent in milk (median proportion of identical viruses, 29.5%; range, 0 to 61%) than in plasma (median proportion of identical viruses, 0%; range, 0 to 26%) (P ‫؍‬ 0.002), suggesting local virus replication in the breast milk compartment. Moreover, clonally amplified virus env genes in milk produced functional virus Envs that were all CCR5 tropic. Milk and plasma virus Envs had similar predicted phenotypes and neutralization sensitivities to broadly neutralizing antibodies in both transmitting and nontransmitting mothers. Finally, phylogenetic comparison of longitudinal milk and plasma virus env sequences revealed synchronous virus evolution and new clonal amplification of evolved virus env genes in milk. The limited compartmentalization and the clonal amplification of evolving, functional viruses in milk indicate continual seeding of the mammary gland by blood virus variants, followed by transient local replication of these variants in the breast milk compartment.

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Section: Methodsmentioning

confidence: 99%

Origin and Evolution of HIV-1 in Breast Milk Determined by Single-Genome Amplification and Sequencing

Salazar-Gonzalez

Salazar

Learn

et al. 2011

J Virol

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“…HIV's effect on KS development and progression is indirect; it may contribute to the severity of the tumor by reducing the immune response to HHV-8, by stimulating the production of inflammatory cytokines, and by the release of its transactivator protein Tat, which acts synergistically with other angiogenic cytokines to stimulate spindle cell proliferation, adhesion and migration in vitro [49]. Although multiple studies attest to the inhibitory effect of IFNα on HIV replication and its synergistic inhibitory activity in combination with other antiretroviral agents in vitro [12,[50][51][52], it is not known to what extent (if any) inhibition of HIV contributes to IFN-induced KS regression.…”

Section: Antiviral Activitiesmentioning

confidence: 99%

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Krown

2007

Cytokine & Growth Factor Reviews

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Interferon alfa (IFNA) was one of the first agents to be used therapeutically in AIDS-associated Kaposi's sarcoma (KS) more than 25 years ago, and induces tumor regression in a subset of patients. Although much has been learned about the clinical role of IFNα in KS treatment, little is currently known about the mechanism(s) by which IFNA causes KS regression. This is despite a growing understanding of both KS pathogenesis and relevant IFNA activities. To a large extent other agents have supplanted IFNA as treatments for KS, but there may still remain a therapeutic role for IFNA, possibly in combination with other agents targeting angiogenesis and/or HHV-8-encoded human gene homologs that encode proteins involved in cell cycle regulation and signaling. KeywordsInterferon; Kaposi's sarcoma In 1995, when I was honored as a recipient of the ISICR Milstein Award, the AIDS epidemic had recently begun its 15 th year and the human immunodeficiency virus (HIV-1) had been isolated some 12 years previously [1]. However, the virus associated with Kaposi's sarcoma (KS), the most common AIDS-associated malignancy, had been described less than a year earlier [2], its significance was still in some question and its role in KS development had not been characterized, and the active combination drug regimens with which we now treat HIV infection had not yet become widely available. Recombinant interferon alfa preparations (IFNα2a and IFNα2b), which had received approval from the U.S. Food and Drug Administration (FDA) for treatment of AIDS-associated KS in 1988, were still the only approved drugs for systemic treatment of KS (the chemotherapeutic agent, liposomal doxorubicin, would receive FDA approval later in 1995, as did liposomal daunorubicin in 1996 and paclitaxel in 1997). Now, more than a quarter century after the first published reports describing AIDS and its association with KS [3-6] and our first modestly successful attempts to treat KS with IFNα [7], this agent is used infrequently to treat KS, although it still finds use in HIV-infected individuals co-infected with hepatitis C. In this brief review, I will summarize some of the history of IFNα in the treatment of AIDS-associated KS, concentrating on examples of clinical trials in which I have personally been involved, and consider whether there remains a potentially valuable role for this agent in KS treatment.

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“…For example, combinations of efavirenz (EFV)-TFV, EFV-FTC, rilpivirine (RPV)-TFV, and RPV-FTC have shown moderate to strong antiviral synergy against HIV-1 in cell culture (3,10). Studies have also shown that some combinations within a drug class, such as two or more NRTIs, can act synergistically in vitro (11)(12)(13)(14)(15)(16)(17). In-depth studies have been performed on the combination of FTC and TFV, and these two drugs show synergy (by median-effect analysis, combination index range of 0.52 to 0.56) to strong synergy (by MacSynergy analysis, synergy volumes of 153 to 181 nM 2 %) against HIV-1 in cell culture (3,10).…”

mentioning

confidence: 99%

The Combined Anti-HIV-1 Activities of Emtricitabine and Tenofovir plus the Integrase Inhibitor Elvitegravir or Raltegravir Show High Levels of SynergyIn Vitro

Kulkarni

Hluhanich

McColl

et al. 2014

Antimicrob Agents Chemother

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Highly active antiretroviral therapy (HAART) is the current standard of care for HIV infection and involves treatment with a combination of three or more antiretroviral agents. Generally, these are combinations of two or more drug classes which target different steps of the HIV-1 replication cycle. The most extensively studied anti-HIV-1 drug combinations are those of nucleoside/nucleotide reverse transcriptase (RT) inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs). NRTIs are competitive inhibitors of HIV-1 RT that cause chain termination of viral DNA polymerization and form the two-drug backbone of most regimens. The third agents are chosen from the different drug classes, consisting of NNRTIs (noncompetitive inhibitors of HIV-1 RT), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). The first single-tablet regimen containing an INSTI was recently approved and consists of the two NRTIs emtricitabine (FTC) and tenofovir (TFV) disoproxil fumarate (TDF), an oral prodrug of TFV; the INSTI elvitegravir (EVG); and the pharmacoenhancer cobicistat (COBI), which increases EVG concentrations (1).Combinations of antiviral inhibitors can directly affect the antiviral potency of their counterparts in an additive, antagonistic, or synergistic manner. Determination of the in vitro antiviral interactions between inhibitors used together in patients is an important component of the drug development process. Combinations that show antagonism should be avoided, and combinations that show synergy may have added benefit in vivo. There have been a number of studies showing that combinations of NRTIs plus NNRTIs inhibit HIV-1 infection more efficiently than the additive effect expected for the individual drugs studied alone, thus demonstrating synergy in vitro (2-9). For example, combinations of efavirenz (EFV)-TFV, EFV-FTC, rilpivirine (RPV)-TFV, and RPV-FTC have shown moderate to strong antiviral synergy against HIV-1 in cell culture (3,10). Studies have also shown that some combinations within a drug class, such as two or more NRTIs, can act synergistically in vitro (11)(12)(13)(14)(15)(16)(17). In-depth studies have been performed on the combination of FTC and TFV, and these two drugs show synergy (by median-effect analysis, combination index range of 0.52 to 0.56) to strong synergy (by MacSynergy analysis, synergy volumes of 153 to 181 nM 2 %) against HIV-1 in cell culture (3, 10). This has been partially explained by a positive metabolic interaction between FTC and TFV that leads to higher levels of phosphorylation to the active metabolites when dosed in combination and more efficient trapping of TFV in a dead-end chainterminated complex (3, 10, 17). Combinations of NRTIs or NNRTIs with INSTIs have also shown additive to synergistic effects in vitro (18,19). As combination therapies are the standard of care in HIV treatment, it is important to understand how newer inhibitors in different classes work in combination with existing therapies. This study evaluates the in vitro anti-HIV activity ...

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Two-Drug Combinations of Zidovudine, Didanosine, and Recombinant Interferon- A Inhibit Replication of Zidovudine-Resistant Human Immunodeficiency Virus Type 1 Synergistically In Vitro

Cited by 126 publications

References 45 publications

Origin and Evolution of HIV-1 in Breast Milk Determined by Single-Genome Amplification and Sequencing

Origin and Evolution of HIV-1 in Breast Milk Determined by Single-Genome Amplification and Sequencing

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

The Combined Anti-HIV-1 Activities of Emtricitabine and Tenofovir plus the Integrase Inhibitor Elvitegravir or Raltegravir Show High Levels of SynergyIn Vitro

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