Differences in the detection of three HIV-1 protease inhibitors in non-blood compartments: Clinical correlations

Lafeuillade, Alain; Solas, Caroline; Halfon, Philippe; Chadapaud, Stéphane; Hittinger, Gilles; Lacarelle, Bruno

doi:10.1310/wmwl-6w9y-pxv2-x148

Cited by 79 publications

(59 citation statements)

References 27 publications

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“…Possible explanations for these discrepant findings are differences in the complexity and composition of antiretroviral regimens the study subjects received. Whereas many earlier studies had focused on resistance to zidovudine, a drug with reasonably good CSF penetration, many contemporary regimens include drugs with marginal CSF penetration, such as the protease inhibitors (3,28,50,52). Heterogeneity of drug concentrations has been predicted to promote the emergence of resistance (41) and may also explain the maintenance of populations of virus with differing resistance patterns in this and other recent studies (14,91).…”

Section: Discussionmentioning

confidence: 81%

Genetic Composition of Human Immunodeficiency Virus Type 1 in Cerebrospinal Fluid and Blood without Treatment and during Failing Antiretroviral Therapy

Strain

Letendre

Pillai

et al. 2005

J Virol

132

114

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Human immunodeficiency virus (HIV) infection of the central nervous system (CNS)is a significant cause of morbidity. The requirements for HIV adaptation to the CNS for neuropathogenesis and the value of CSF virus as a surrogate for virus activity in brain parenchyma are not well established. We studied 18 HIV-infected subjects, most with advanced immunodeficiency and some neurocognitive impairment but none with evidence of opportunistic infection or malignancy of the CNS. Clonal sequences of C2-V3 env and population sequences of pol from HIV RNA in cerebrospinal fluid (CSF) and plasma were correlated with clinical and virologic variables. Most (14 of 18) subjects had partitioning of C2-V3 sequences according to compartment, and 9 of 13 subjects with drug resistance exhibited discordant resistance patterns between the two compartments. Regression analyses identified three to seven positions in C2-V3 that discriminated CSF from plasma HIV. The presence of compartmental differences at one or more of the identified positions in C2-V3 was highly associated with the presence of discordant resistance (P ‫؍‬ 0.007), reflecting the autonomous replication of HIV and the independent evolution of drug resistance in the CNS. Discordance of resistance was associated with severity of neurocognitive deficits (P ‫؍‬ 0.07), while low nadir CD4 counts were linked both to the severity of neurocognitive deficits and to discordant resistance patterns (P ‫؍‬ 0.05 and 0.09, respectively). These observations support the study of CSF HIV as an accessible surrogate for HIV virions in the brain, confirm the high frequency of discordant resistance in subjects with advanced disease in the absence of opportunistic infection or malignancy of the CNS, and begin to identify genetic patterns in HIV env associated with adaptation to the CNS.

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Section: Discussionmentioning

confidence: 81%

Genetic Composition of Human Immunodeficiency Virus Type 1 in Cerebrospinal Fluid and Blood without Treatment and during Failing Antiretroviral Therapy

Strain

Letendre

Pillai

et al. 2005

J Virol

132

114

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“…In two cases (subjects 1115 and 1113) the reappearance of a variant with wild-type mobility and the viral load changes suggest that poor compliance might indeed account for the persistence of the wild-type pro sequences. Second, variants with high RTV susceptibility could be replicating in RTV-inaccessible compartments, such as the central nervous system (23,33,66). And third, the fitness loss associated with the evolution of resistance in the sequence background of these pro genes may have resulted in fitness levels that were similar to those of the wild type in the presence of RTV.…”

Section: Discussionmentioning

confidence: 99%

“…The activity of reverse transcriptase in culture supernatants was measured as described previously (6) with the following modifications. The radionucleotide incorporated into the nascent DNA strand was 33 P, a vacuum manifold (Bio-Rad) was used to capture the newly synthesized DNA on anionexchange paper, and storage phosphor autoradiography (Storm 840 PhosphorImager; Molecular Devices) was used to quantitate incorporated radioactivity.…”

mentioning

confidence: 99%

Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir

Resch¹,

Parkin

Watkins

et al. 2005

J Virol

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We examined the population dynamics of human immunodeficiency virus type 1 pro variants during the evolution of resistance to the protease inhibitor ritonavir (RTV) in vivo. pro variants were followed in subjects who had added RTV to their previously failed reverse transcriptase inhibitor therapy using a heteroduplex tracking assay designed to detect common resistance-associated mutations. In most cases the initial variant appeared rapidly within 2 to 3 months followed by one or more subsequent population turnovers. Some of the subsequent transitions between variants were rapid, and some were prolonged with the coexistence of multiple variants. In several cases variants without resistance mutations persisted despite the emergence of new variants with an increasing number of resistance-associated mutations. Based on the rate of turnover of pro variants in the RTV-treated subjects we estimated that the mean fitness of newly emerging variants was increased 1.2-fold (range, 1.02 to 1.8) relative to their predecessors. A subset of pro genes was introduced into infectious molecular clones. The corresponding viruses displayed impaired replication capacity and reduced susceptibility to RTV. A subset of these clones also showed increased susceptibility to two nonnucleoside reverse transcriptase inhibitors and the protease inhibitor saquinavir. Finally, a significant correlation between the reduced replication capacity and reduced processing at the gag NC-p1 processing site was noted. Our results reveal a complexity of patterns in the evolution of resistance to a protease inhibitor. In addition, these results suggest that selection for resistance to one protease inhibitor can have pleiotropic effects that can affect fitness and susceptibility to other drugs.Protease inhibitors (PIs) potently inhibit human immunodeficiency virus type 1 (HIV-1) replication, and their initial introduction into combination antiretroviral therapy was associated with a significant decrease of HIV-1-associated mortality and morbidity (41, 45). However, in clinical practice, virologic failure of protease inhibitor-containing therapy occurs in a significant fraction of the treated population (19,22,42,46,52,70). Virologic failure of protease inhibitor treatment is often due to the selection of HIV-1 strains with mutations in the pro gene, which encodes the viral protease (PR), and in specific protease cleavage sites encoded in the gag gene that collectively confer reduced drug susceptibility to the harboring strain (11,12,28,36,43,47,72).The resistance mutations are hypothesized to be largely preexisting, generated by the highly error-prone and rapid replication of HIV-1 in large virus populations (5, 10, 57). However, in PI-naïve subjects, some critical resistance mutations cannot be detected or can only be detected at very low levels, suggesting that these mutations may confer a selective disadvantage relative to wild-type HIV-1 strains (3,18,25,32,34,63). Indeed, it has been shown that the catalytic efficiency of protease is reduced by PI resis...

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“…Despite intraclass variability, ratios of ARV levels between seminal plasma and blood are typically lower for PIs than NRTIs or NNRTIs. [44][45][46][47][48][49][50][51][52][53][54][55] We could not, however, definitively evaluate the impact of ARVs on viral decay rate in seminal plasma because of infrequent sampling following ARV initiation.…”

Section: Figmentioning

confidence: 99%

HIV Dynamics in Seminal Plasma during Primary HIV Infection

Stekler

Sycks

Holte

et al. 2008

AIDS Research and Human Retroviruses

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HIV dynamics in seminal plasma during primary HIV infection was evaluated through an observational study of individuals with primary HIV infection at the University of Washington Primary Infection Clinic. Seminal plasma HIV RNA was quantified using a real-time reverse transcription PCR assay. Blood plasma RNA was quantified by bDNA or PCR-based assays. Longitudinal analyses of HIV RNA levels over time used random effects regression analysis. From 1993 to 2005, 110 men collected 327 semen specimens. Initial blood and seminal plasma RNA levels in untreated men were only moderately correlated (Spearman r ϭ 0.38, p ϭ 0.0002). Estimated peak and set point levels were lower in semen than blood by 0.8 (p ϭ 0.001) and 0.7 (p Ͻ 0.001) log 10

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Differences in the detection of three HIV-1 protease inhibitors in non-blood compartments: Clinical correlations

Cited by 79 publications

References 27 publications

Genetic Composition of Human Immunodeficiency Virus Type 1 in Cerebrospinal Fluid and Blood without Treatment and during Failing Antiretroviral Therapy

Genetic Composition of Human Immunodeficiency Virus Type 1 in Cerebrospinal Fluid and Blood without Treatment and during Failing Antiretroviral Therapy

Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir

HIV Dynamics in Seminal Plasma during Primary HIV Infection

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