Failure to Detect Nelfinavir in the Cerebrospinal Fluid of HIV-1-Infected Patients With and Without AIDS Dementia Complex

Aweeka, Francesca; Jayewardene, Anura L.; Staprans, Silvija I.; Bellibas, S. Eralp; Kearney, Brian P.; Lizak, Patricia; Novakovic-Agopian, Tatjana; Rw, Price

doi:10.1097/00042560-199901010-00006

Cited by 95 publications

(44 citation statements)

References 12 publications

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“…Strikingly, resistance to apoptosis was seen within 1 hour of treatment with Nfv ( Figure 1B) at a minimal dose of 3.5 M, and concentrations of 7 M and 10 M caused significant inhibition of apoptosis ( Figure 1C). Nfv concentrations of 7 M are similar to trough levels of Nfv achieved in patients receiving treatment 36,37 ;…”

Section: Nfv Inhibits T-cell Apoptosis In a Time-and Dose-dependent Msupporting

confidence: 65%

Antiapoptotic mechanism of HIV protease inhibitors: preventing mitochondrial transmembrane potential loss

Phenix

Lum

Nie

et al. 2001

Blood

108

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Treatment of cells with the HIV drugs ritonavir, saquinavir, or nelfinavir (Nfv) inhibits apoptosis induced by a variety of stimuli. Because these drugs are protease inhibitors, they have been postulated to inhibit apoptosis by blocking caspase activity. This study shows that Nfv has no effect on caspase activity or on the transcription or synthesis of a variety of apoptosis regulatory molecules. Instead, Nfv inhibits mitochondrial transmembrane potential loss (⌬ m ) and the subsequent release of apoptotic mediators. Consequently, the antiapoptotic ef- IntroductionCurrent therapies used in the treatment of HIV-infected patients include combinations of inhibitors of reverse transcriptase and HIV protease. Multidrug therapy has reduced morbidity and mortality among patients infected with HIV 1-3 and has led to quantitative and qualitative improvements in host immune function. [4][5][6][7][8] Although increases in CD4 T-cell counts typically occur in parallel with a reduction in viral replication, these effects may be seen before significant changes in plasma RNA levels 9 or in the absence of antiviral effect. [10][11][12][13] These and other findings suggest that the protease inhibitor (PI) class of drugs may influence T-cell turnover in a manner that is independent of their role in viral suppression.Nonviral effects of HIV PIs have been evaluated recently. PIs influence proteasome activity, antigen presentation, cytotoxic Tlymphocyte activity, 14 lipoprotein metabolism, 15 adipocyte differentiation, 16,17 cytochrome P450 activity, 18 and adenosine triphosphate (ATP)-dependent drug export mechanisms. 19 Furthermore, PIs may affect the ability of cells to undergo both spontaneous apoptosis and apoptosis induced by a variety of stimuli. 9,[20][21][22][23] These data are consistent with the in vivo observation that apoptosis in both peripheral blood 24 and in lymphatic tissues 25 is rapidly decreased following initiation of PI-based therapy. In this study, we have evaluated the mechanism by which PIs inhibit apoptosis. Materials and methods CellsJurkat T cells and H9 cells (American Type Culture Collection, Rockville, MD) were cultured in RPMI 1640 medium (Gibco, Burlington, ON, Canada) supplemented with 10% or 20% fetal calf serum (Gibco), respectively, together with penicillin, streptomycin, and glutamine (SigmaAldrich, Oakville, ON, Canada), and were incubated at 37°C in a 5% CO 2 humidified environment. Cells were seeded in media supplemented with drugs as indicated at 0.3 ϫ 10 6 /mL and passaged every 2 days. DrugsAzidothymidine (AZT) was purchased from Sigma (Oakville, ON, Canada) and resuspended in water. Nelfinavir (Nfv), ritonavir, and saquinavir were generous gifts from Agouron Pharmaceuticals (La Jolla, CA), Abbott Laboratories (Abbott Park, IL), and Roche Laboratories (Nutley, NJ), respectively, and were resuspended in methanol. Induction and measurement of apoptosis and mitochondrial membrane permeability changesJurkat or H9 cells were cultured in the presence of AZT, Nfv, or diluent at indicated concen...

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Section: Nfv Inhibits T-cell Apoptosis In a Time-and Dose-dependent Msupporting

confidence: 65%

Antiapoptotic mechanism of HIV protease inhibitors: preventing mitochondrial transmembrane potential loss

Phenix

Lum

Nie

et al. 2001

Blood

108

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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: 80%

“…Our results are consistent with such a view, since we found a trend towards more segregation between CSF and plasma sequences in individuals with advanced disease. Dis- 3 , although this association did not reach statistical significance, owing perhaps to the small number of individuals studied with CD4 counts of Ͼ200 mm 3 . Anticipating that HIV from both systemic and CNS sources might be sampled from CSF in any given subject, we sought a CNS signature sequence in C2-V3 from both the entire data set as well as from a pruned data set by using phylogenetic criteria to exclude those individuals likely to have CSF virus produced by systemic sources.…”

Section: Discussionmentioning

confidence: 81%

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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

111

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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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“…This increased survival has contributed to the increased prevalence of ADC, even though incidence of the ADC has declined or remained stable. Poor penetration of the blood-brain barrier by many antiretroviral drugs, particularly protease inhibitors, has been suggested as a reason of continued occurrence of ADC (10). Yet some evidence suggests that despite poor CNS penetration of most antiretrovirals, effective antiretroviral therapy still may attenuate neurotoxicity from circulating monocytes and their tissue counterparts, macrophages (11).…”

Section: Discussionmentioning

confidence: 99%

Rapidly Progressed Acquired Immunodeficiency Syndrome Dementia Complex as an Initial Manifestation

et al. 2005

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We report a patient with acquired immunodeficiency syndrome dementia complex (ADC) that presented human immunodeficiency virus infection as an initial manifestation. A 34-year-old man developed disturbance of consciousness and severe abulia over 3 months. The CD4 lymphocyte count was 7.9/ l, while human immunodeficiency virus RNA in blood amounted to 4.2×10 4 copies/ml. T2-weighted magnetic resonance imaging showed diffusely high signal intensity in the deep white matter of both cerebral hemispheres. On the 20th hospital day, the patient died of sepsis caused by methicillin-resistant

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Failure to Detect Nelfinavir in the Cerebrospinal Fluid of HIV-1-Infected Patients With and Without AIDS Dementia Complex

Cited by 95 publications

References 12 publications

Antiapoptotic mechanism of HIV protease inhibitors: preventing mitochondrial transmembrane potential loss

Antiapoptotic mechanism of HIV protease inhibitors: preventing mitochondrial transmembrane potential loss

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

Rapidly Progressed Acquired Immunodeficiency Syndrome Dementia Complex as an Initial Manifestation

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