Activity of a ritonavir plus saquinavir-containing regimen in patients with virologic evidence of indinavir or ritonavir failure

Deeks, Steven G.; Grant, Robert M.; Beatty, George; Horton, Christopher; Detmer, Jill; Eastman, Scott W.

doi:10.1097/00002030-199810000-00002

Cited by 95 publications

(45 citation statements)

References 9 publications

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“…All 11 patients had been previously enrolled in clinical studies: 5 in a prospective clinical trial of nelfinavir-saquinavir salvage therapy, 3 in an observational study, and 3 in a clinical trial evaluating indinavir (9,10). For each patient, plasma samples were obtained from the date protease inhibitor therapy was initiated through the date that virologic failure was confirmed.…”

Section: Methodsmentioning

confidence: 99%

Evolution of Phenotypic Drug Susceptibility and Viral Replication Capacity during Long-Term Virologic Failure of Protease Inhibitor Therapy in Human Immunodeficiency Virus-Infected Adults

Barbour

Wrin

Grant

et al. 2002

J Virol

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145

104

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Continued use of antiretroviral therapy despite the emergence of drug-resistant human immunodeficiency virus (HIV) has been associated with the durable maintenance of plasma HIV RNA levels below pretherapy levels. The factors that may account for this partial control of viral replication were assessed in a longitudinal observational study of 20 HIV-infected adults who remained on a stable protease inhibitor-based regimen despite ongoing viral replication (plasma HIV RNA levels consistently >500 copies/ml). Longitudinal plasma samples (n ‫؍‬ 248) were assayed for drug susceptibility and viral replication capacity (measured by using a single-cycle recombinant-virus assay). The initial treatment-mediated decrease in plasma viremia was directly proportional to the reduction in replicative capacity (P ‫؍‬ 0.01). Early virologic rebound was associated the emergence of a virus population exhibiting increased protease inhibitor phenotypic resistance, while replicative capacity remained low. During long-term virologic failure, plasma HIV RNA levels often remained stable or increased slowly, while phenotypic resistance continued to increase and replicative capacity decreased slowly. The emergence of primary genotypic mutations within protease (particularly V82A, I84V, and L90M) was temporally associated with increasing phenotypic resistance and decreasing replicative capacity, while the emergence of secondary mutations within protease was associated with more-gradual changes in both phenotypic resistance and replicative capacity. We conclude that HIV may be constrained in its ability to become both highly resistant and highly fit and that this may contribute to the continued partial suppression of plasma HIV RNA levels that is observed in some patients with drug-resistant viremia.

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Section: Methodsmentioning

confidence: 99%

Evolution of Phenotypic Drug Susceptibility and Viral Replication Capacity during Long-Term Virologic Failure of Protease Inhibitor Therapy in Human Immunodeficiency Virus-Infected Adults

Barbour

Wrin

Grant

et al. 2002

J Virol

Self Cite

145

104

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“…V82A also occurs in isolates from patients receiving prolonged therapy with saquinavir following the development of the mutation G48V (330,409 [70][71]2000) resistance to each PI. I84V tends to develop in isolates that already have the mutation L90M and is rarely the first major mutation to develop in patients receiving a PI (178).…”

Section: Protease Substrate Cleft Mutationsmentioning

confidence: 99%

“…In a study of ritonavir/saquinavir salvage therapy, the number of mutations at positions 46, 48, 54, 82, 84, and 90 predicted the virologic response at 4, 12, and 24 weeks. Patients with three or more of these mutations had no response to [70][71]2000). A decreased response to therapy was observed only in those patients that had Ն6 of the listed mutations.…”

Section: Pi Cross-resistance Patternsmentioning

confidence: 99%

Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance

2002

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There are 16 approved human immunodeficiency virus type 1 (HIV-1) drugs belonging to three mechanistic classes: protease inhibitors, nucleoside and nucleotide reverse transcriptase (RT) inhibitors, and nonnucleoside RT inhibitors. HIV-1 resistance to these drugs is caused by mutations in the protease and RT enzymes, the molecular targets of these drugs. Drug resistance mutations arise most often in treated individuals, resulting from selective drug pressure in the presence of incompletely suppressed virus replication. HIV-1 isolates with drug resistance mutations, however, may also be transmitted to newly infected individuals. Three expert panels have recommended that HIV-1 protease and RT susceptibility testing should be used to help select HIV drug therapy. Although genotypic testing is more complex than typical antimicrobial susceptibility tests, there is a rich literature supporting the prognostic value of HIV-1 protease and RT mutations. This review describes the genetic mechanisms of HIV-1 drug resistance and summarizes published data linking individual RT and protease mutations to in vitro and in vivo resistance to the currently available HIV drugs

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“…The first drug-resistant mutation that often occurs in patients, V82A (47), is frequently associated with indinavir or ritonavir therapy (5,9,11,30). Our previous studies have shown that V82A is a prime site for drug resistance to occur, as the valine at residue 82 is not critical for substrate recognition but does extensively contact many of the commonly used inhibitors (39).…”

mentioning

confidence: 99%

Structural Basis for Coevolution of a Human Immunodeficiency Virus Type 1 Nucleocapsid-p1 Cleavage Site with a V82A Drug-Resistant Mutation in Viral Protease

Prabu-Jeyabalan

Nalivaika

King

et al. 2004

J Virol

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Maturation of human immunodeficiency virus (HIV) depends on the processing of Gag and Pol polyproteinsby the viral protease, making this enzyme a prime target for anti-HIV therapy. Among the protease substrates, the nucleocapsid-p1 (NC-p1) sequence is the least homologous, and its cleavage is the rate-determining step in viral maturation. In the other substrates of HIV-1 protease, P1 is usually either a hydrophobic or an aromatic residue, and P2 is usually a branched residue. NC-p1, however, contains Asn at P1 and Ala at P2. In response to the V82A drug-resistant protease mutation, the P2 alanine of NC-p1 mutates to valine (AP2V). To provide a structural rationale for HIV-1 protease binding to the NC-p1 cleavage site, we solved the crystal structures of inactive (D25N) WT and V82A HIV-1 proteases in complex with their respective WT and AP2V mutant NC-p1 substrates. Overall, the WT NC-p1 peptide binds HIV-1 protease less optimally than the AP2V mutant, as indicated by the presence of fewer hydrogen bonds and fewer van der Waals contacts. AlaP2 does not fill the P2 pocket completely; PheP1 makes van der Waals interactions with Val82 that are lost with the V82A protease mutation. This loss is compensated by the AP2V mutation, which reorients the peptide to a conformation more similar to that observed in other substrate-protease complexes. Thus, the mutant substrate not only binds the mutant protease more optimally but also reveals the interdependency between the P1 and P2 substrate sites. This structural interdependency results from coevolution of the substrate with the viral protease.Human immunodeficiency virus type 1 (HIV-1) matures after the viral protease processes (35) the Gag and Pol polyproteins at 10 substrate locations (3, 15). Therefore, inhibition of HIV-1 protease represents an important avenue for antiviral therapy (13, 48). The substrate sequences cleaved by the protease are nonhomologous (3), with the sequence of the nucleocapsid-p1 (NC-p1) substrate being the most different. In spite of the poor sequence homology among the substrate sites, a series of substrate-protease crystal structures led us to hypothesize that substrate specificity in HIV-1 protease results from the enzyme's recognizing an asymmetric shape (or envelope) rather than a particular amino acid sequence (40). This shape results from the conformation that a particular substrate sequence can adopt, implying that an interdependency necessarily exists among the different substrate residue sites.All of the protease inhibitors whose designs were structure based bind competitively (8,18,28,52,53) at the active site. Since these inhibitors bind at the same site as the substrates, many protease residues contact both substrates and inhibitors. Drug resistance, which often develops in the presence of therapeutic protease inhibitors, results from high viral turnover, the infidelity of the viral reverse transcriptase (16,42,43), and selective pressure on the virus. With drug resistance, the protease no longer binds as tightly to inhibitors but r...

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Activity of a ritonavir plus saquinavir-containing regimen in patients with virologic evidence of indinavir or ritonavir failure

Cited by 95 publications

References 9 publications

Evolution of Phenotypic Drug Susceptibility and Viral Replication Capacity during Long-Term Virologic Failure of Protease Inhibitor Therapy in Human Immunodeficiency Virus-Infected Adults

Evolution of Phenotypic Drug Susceptibility and Viral Replication Capacity during Long-Term Virologic Failure of Protease Inhibitor Therapy in Human Immunodeficiency Virus-Infected Adults

Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance

Structural Basis for Coevolution of a Human Immunodeficiency Virus Type 1 Nucleocapsid-p1 Cleavage Site with a V82A Drug-Resistant Mutation in Viral Protease

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