New Class of HIV Integrase Inhibitors that Block Viral Replication in Cell Culture

Pannecouque, Christophe; Pluymers, W; Maele, Bénédicte Van; Tetz, Victor; Cherepanov, Peter; Clercq, Erik De; Witvrouw, Myriam; Debyser, Zeger

doi:10.1016/s0960-9822(02)00952-1

Cited by 95 publications

(84 citation statements)

References 48 publications

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“…It was well established that integration of wt HIV cDNA should be completed between 16 and 20 h p.i. (Levin et al, 2009b;Pannecouque et al, 2002). Interestingly, the level of integration observed from 16 to 288 h after the 1st-INF was very close or identical to that observed following a single infection [compare Fig.…”

Section: Promotion Of Sir By Double Infection With Wt Hiv-1supporting

confidence: 69%

“…This is not necessarily surprising since in a certain respect, the single infection process may present the same features that characterize double infection. It has been well established that the same cell can interact with more than one virus particle and that the course of virus-cell adsorption may extend over a period of about 4 h (Levin et al, 2009b;Pannecouque et al, 2002). Thus, the possibility of the first round of infection conferring, on a cellular level and due to de novo Rev synthesis, immunity to the second round of infection cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

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A novel role for the viral Rev protein in promoting resistance to superinfection by human immunodeficiency virus type 1

Levin

Hayouka

Friedler

et al. 2010

Journal of General Virology

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At the cellular level, cells infected with human immunodeficiency virus type 1 (HIV-1) exhibit immunity to a second infection by the virus that initiated the first infection or by related viruses [superinfection resistance (SIR)]. In the case of HIV infection, SIR was basically attributed to downregulation of the CD4 receptors. We have recently reported on an interaction between HIV-1 Rev and integrase (IN) proteins, which results in inhibition of IN activity in vitro and integration of cDNA in HIV-1-infected cells. A novel function for the viral Rev protein in controlling integration of HIV cDNAs was thus proposed. The results of the present work suggest involvement of the inhibitory Rev in sustaining SIR. A single exposure to wild-type HIV-1 resulted in one to two integrations per cell. The number of integrated proviral cDNA copies remained at this low level even after double infection or superinfection. SIR was dependent on Rev expression by the strain used for the first infection and was eliminated by peptides that disrupt intracellular complex formation between IN and Rev. The same lack of resistance was observed in the absence of Rev, namely following first infection with a DRev HIV strain. The involvement of Rev, expressed from either unintegrated or integrated viral cDNA, in promoting SIR was clearly demonstrated. We conclude that SIR involves Rev-dependent control of HIV cDNA integration.

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Section: Promotion Of Sir By Double Infection With Wt Hiv-1supporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

A novel role for the viral Rev protein in promoting resistance to superinfection by human immunodeficiency virus type 1

Levin

Hayouka

Friedler

et al. 2010

Journal of General Virology

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“…For at least two classes of compounds, inhibition of HIV-1 integration in cell culture has been clearly demonstrated (14,25). DKA were the first class of IN inhibitors discovered.…”

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confidence: 99%

“…The results of this study support clinical studies with S-1360 in HIV seropositive subjects (2). Recently, a series of 5H-pyrano[2,3-d:-6,5-dЈ] dipyrimidines (PDPs) has been identified as the second class of inhibitors that interfere with HIV-1, HIV-2, and SIV integration in cell culture (25). The most potent congener of this class, V-165, inhibited HIV-1 replication in cell culture and IN activity in an oligonucleotide-based enzymatic assay at micromolar concentrations.…”

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confidence: 99%

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Development of Resistance against Diketo Derivatives of Human Immunodeficiency Virus Type 1 by Progressive Accumulation of Integrase Mutations

Fikkert

Maele

Vercammen³

et al. 2003

J Virol

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108

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. Antiviral resistance was also studied at the level of recombinant integrase. Single mutations did not appear to impair specific enzymatic activity. However, 3 processing and strand transfer activities of the recombinant integrases with two (T66I L74M) and three (T66I L74M S230R) mutations were notably lower than those of the wild-type integrase. Although the virus with three mutations was resistant to inhibition by diketo acids, the sensitivity of the corresponding enzyme to L-708,906 or S-1360 was reduced only two-to threefold. As to the replication kinetics of the selected strains, the replication fitness for all strains was lower than that of the wild-type HIV-1 strain.

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Strategies in the Design of Antiviral Drugs

Clercq

Herdewijn

2010

Pharmaceutical Sciences Encyclopedia

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Effective vaccines have led to the eradication of important viral pathogens such as smallpox, polio, measles, mumps, and rubella. The strategies for interfering with the key events in the viral replicative cycle have the potential to target virtually all important human viral pathogens. This article focuses on approaches targeted at specific processes in viral infection, including virus adsorption, virus‐cell fusion, viral DNA or RNA synthesis, and viral enzymes.

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New Class of HIV Integrase Inhibitors that Block Viral Replication in Cell Culture

Abstract: Based on their mode of action, which is different from that of clinically approved anti-HIV drugs, PDPs are good candidates for further development into new drugs and to be included in future combination regimens.

Cited by 95 publications

References 48 publications

A novel role for the viral Rev protein in promoting resistance to superinfection by human immunodeficiency virus type 1

A novel role for the viral Rev protein in promoting resistance to superinfection by human immunodeficiency virus type 1

Development of Resistance against Diketo Derivatives of Human Immunodeficiency Virus Type 1 by Progressive Accumulation of Integrase Mutations

Strategies in the Design of Antiviral Drugs

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