scholarly journals Maintenance of the latent reservoir by pyroptosis and superinfection in a fractional order HIV transmission model

2019 ◽  
Vol 9 (3) ◽  
pp. 69-75 ◽  
Author(s):  
Ana R Carvalho ◽  
Carla M Pinto ◽  
João N Tavares
Keyword(s):  
Fractional Order ◽  
Hiv Transmission ◽  
Transmission Model ◽  
Wild Type Virus ◽  
Latent Reservoir ◽  
Type Virus ◽  
Wild Type ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Low Levels

We focus on the importance of pyroptosis and superinfection on the maintenance of thehuman immunodeficiency virus (HIV) latent reservoir on infected patients. The latent reservoir hasbeen found to be crucial to the persistence of low levels of viral loads found in HIV-infected patients,after many years of successfully suppressive anti-retroviral therapy (ART). This reservoir seems to actas an archive for strains of HIV no longer dominant in the blood, such as wild-type virus. When apatient decides to quit therapy there is a rapid turnover and the wild-type virus re-emerges. Thus, itis extremely important to understand the mechanisms behind the maintenance of this reservoir. Forthat, we propose a fractional order model for the dynamics of HIV, where pyroptosis and superinfectionare considered. The model is simulated for biological meaningful parameters and interesting patternsare found. Our results are interpreted for clinical appreciation.

scholarly journals Novel Single-Cell-Level Phenotypic Assay for Residual Drug Susceptibility and Reduced Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1

2004 ◽  
Vol 78 (4) ◽  
pp. 1718-1729 ◽  
Author(s):  
Haili Zhang ◽  
Yan Zhou ◽  
Cecily Alcock ◽  
Tara Kiefer ◽  
Daphne Monie ◽  
...  
Keyword(s):  
Drug Combination ◽  
Wild Type Virus ◽  
Replication Capacity ◽  
Drug Resistant ◽  
Type Virus ◽  
Wild Type ◽  
Cell Level ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-infected individuals who develop drug-resistant virus during antiretroviral therapy may derive benefit from continued treatment for two reasons. First, drug-resistant viruses can retain partial susceptibility to the drug combination. Second, therapy selects for drug-resistant viruses that may have reduced replication capacities relative to archived, drug-sensitive viruses. We developed a novel single-cell-level phenotypic assay that allows these two effects to be distinguished and compared quantitatively. Patient-derived gag-pol sequences were cloned into an HIV-1 reporter virus that expresses an endoplasmic reticulum-retained Env-green fluorescent protein fusion. Flow cytometric analysis of single-round infections allowed a quantitative analysis of viral replication over a 4-log dynamic range. The assay faithfully reproduced known in vivo drug interactions occurring at the level of target cells. Simultaneous analysis of single-round infections by wild-type and resistant viruses in the presence and absence of the relevant drug combination divided the benefit of continued nonsuppressive treatment into two additive components, residual virus susceptibility to the drug combination and selection for drug-resistant variants with diminished replication capacities. In some patients with drug resistance, the dominant circulating viruses retained significant susceptibility to the combination. However, in other cases, the dominant drug-resistant viruses showed no residual susceptibility to the combination but had a reduced replication capacity relative to the wild-type virus. In this case, simplification of the regimen might still allow adequate suppression of the wild-type virus. In a third pattern, the resistant viruses had no residual susceptibility to the relevant drug regimen but nevertheless had a replication capacity equivalent to that of wild-type virus. In such cases, there is no benefit to continued treatment. Thus, the ability to simultaneously analyze residual susceptibility and reduced replication capacity of drug-resistant viruses may provide a basis for rational therapeutic decisions in the setting of treatment failure.

scholarly journals The P236L Delavirdine-Resistant Human Immunodeficiency Virus Type 1 Mutant Is Replication Defective and Demonstrates Alterations in both RNA 5′-End- and DNA 3′-End-Directed RNase H Activities

1999 ◽  
Vol 73 (7) ◽  
pp. 5803-5813 ◽  
Author(s):  
Peter Gerondelis ◽  
Richard H. Archer ◽  
Chockalingam Palaniappan ◽  
Richard C. Reichman ◽  
Philip J. Fay ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Rnase H ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Replication Fitness ◽  
Hiv 1

ABSTRACT The nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) delavirdine (DLV) selects in vitro for the human immunodeficiency virus type 1 (HIV-1) RT mutation P236L, which confers high-level resistance to DLV but not other NNRTIs. Unexpectedly, P236L has developed infrequently in HIV-1 isolates obtained from patients receiving DLV; K103N is the predominant resistance mutation observed in that setting. We characterized the replication fitness of viruses derived from pNL4-3 containing P236L or K103N in both H9 and primary human peripheral blood mononuclear cell cultures infected in parallel with the two mutants. In the absence of DLV, p24 production by wild-type virus occurred more rapidly and to higher levels than with either mutant; P236L consistently demonstrated a two- to threefold decrease in p24 relative to K103N. At low levels of DLV, growth of wild-type virus was severely inhibited, and K103N replicated two- to threefold more efficiently than P236L. At high concentrations of DLV, P236L replication and K103N replication were both inhibited. Recombinant RTs containing K103N or P236L were analyzed for DNA polymerization on heteropolymeric RNA templates and RNase H degradation of RNA-DNA hybrids. Neither mutant demonstrated defects in polymerization. K103N demonstrated normal RNA 5′-end-directed RNase H cleavage and slowed DNA 3′-end-directed RNase H cleavage compared to wild-type RT. P236L demonstrated slowing of both DNA 3′-end- and RNA 5′-end-directed RNase H cleavage, consistent with its reduced replication efficiency relative to K103N. These data suggest that NNRTI resistance mutations can lead to reductions in the efficiency of RNase H cleavage, which may contribute to a reduction in the replication fitness of HIV-1.

scholarly journals Changes in Human Immunodeficiency Virus Type 1 Populations after Treatment Interruption in Patients Failing Antiretroviral Therapy

2001 ◽  
Vol 75 (14) ◽  
pp. 6410-6417 ◽  
Author(s):  
Allan J. Hance ◽  
Virginie Lemiale ◽  
Jacques Izopet ◽  
Denise Lecossier ◽  
Véronique Joly ◽  
...  
Keyword(s):  
Treatment Interruption ◽  
Wild Type Virus ◽  
Minority Populations ◽  
Type Virus ◽  
Wild Type ◽  
Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Drug Free ◽  
Hiv 1

ABSTRACT Mutations in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and protease that confer resistance to antiretroviral agents are usually accompanied by a reduction in the viral replicative capacity under drug-free conditions. Consequently, when antiretroviral treatment is interrupted in HIV-1-infected patients harboring drug-resistant virus, resistant quasi-species appear to be most often replaced within several weeks by wild-type virus. Using a real-time PCR-based technique for the selective quantification of resistant viral sequences in plasma, we have studied the kinetics of the switch from mutant to wild-type virus and evaluated the extent to which minority populations of resistant viruses not detected by genotyping persist in these individuals. Among 12 patients with viruses expressing the V82A or L90M resistance mutation who had undergone a 3-month interruption of therapy and for whom conventional genotyping had revealed an apparent total reconversion to wild-type virus, minority populations expressing these mutations, representing 0.1 to 21% of total virus, were still detectable in 9 cases. Kinetic studies demonstrated that viruses expressing resistance mutations could be detected for >5 months after the discontinuation of treatment in some patients. Most of the minority resistant genomes detected more than 3 months after the interruption of therapy carried only part of the mutations present in the resistant viruses prior to treatment interruption and appeared to result from the emergence of existing strains selected at earlier stages in the development of drug resistance. Thus, following the interruption of treatment, viral populations containing resistance mutations can persist for several months after the time when conventional genotyping techniques detect only wild-type virus. These populations include viral strains with only some of the resistance mutations initially present, strains that presumably express better fitness under drug-free conditions.

scholarly journals Relative Replicative Fitness of Zidovudine-Resistant Human Immunodeficiency Virus Type 1 Isolates In Vitro

1998 ◽  
Vol 72 (5) ◽  
pp. 3773-3778 ◽  
Author(s):  
P. Richard Harrigan ◽  
Stuart Bloor ◽  
Brendan A. Larder
Keyword(s):  
Selection Pressure ◽  
Wild Type Virus ◽  
Drug Selection ◽  
Type Virus ◽  
Wild Type ◽  
Replicative Fitness ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Replication of mixtures of two or more human immunodeficiency virus type 1 (HIV-1) variants would be expected to result in the eventual selection of the fittest virus due to Darwinian competition among the variants. The relative proportions of known HIV-1 variants (which may differ only by a single nucleotide from a standard “wild-type” virus, HIV-1HXB2) in mixed viral cultures were quantified by analysis of automated sequence signals of reverse transcriptase PCR products. With this method, the relative levels of replicative fitness of several zidovudine (3′-azidothymidine)-resistant HIV-1HXB2 variants were estimated under controlled in vitro conditions by measuring the rate of change in the proportions of viral variants as they replicated in cell cultures both in the presence and in the absence of drug selection pressure. These variants were engineered to contain commonly observed zidovudine resistance mutations in the HIV-1 reverse transcriptase (M41L, K70R, T215Y, and M41L+T215Y). In the absence of zidovudine, all variants tested displayed reduced replicative fitness compared to wild-type HIV-1HXB2. The order of relative fitness was wild type > K70R ≫ T215Y = M41L+T215Y > M41L. Mixed cultures in the presence of zidovudine showed a dose-dependent selection pressure against the wild-type virus which varied according to the resistance profile of each virus. The information gathered from this approach provides insight into competition among multiple HIV-1 variants, which likely occurs in vivo with drug selection pressure, and may be applicable in more complex mathematical models for predicting the emergence of HIV-1 variants after the initiation of antiretroviral therapy.

scholarly journals T-Cell-Line-Tropic Human Immunodeficiency Virus Type 1 That Is Made Resistant to Stromal Cell-Derived Factor 1α Contains Mutations in the Envelope gp120 but Does Not Show a Switch in Coreceptor Use

1998 ◽  
Vol 72 (5) ◽  
pp. 4032-4037 ◽  
Author(s):  
Dominique Schols ◽  
José A. Esté ◽  
Cecilia Cabrera ◽  
Erik De Clercq
Keyword(s):  
T Cell ◽  
Cell Line ◽  
Stromal Cell ◽  
Wild Type Virus ◽  
Type Virus ◽  
Resistant Virus ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Stromal Cell Derived Factor

ABSTRACT The NL4.3 T-cell-line-tropic human immunodeficiency virus type 1 strain is sensitive to the CXC chemokine stromal cell-derived factor 1α (SDF-1α), the natural ligand for CXC chemokine receptor 4 (CXCR4); the 50% inhibitory concentration (IC50) in MT-4 cells is 130 ng/ml. We generated resistant virus through passaging of the virus in the presence of increasing concentrations of SDF-1α. After 24 passages, the virus was no longer sensitive to SDF-1α (SDF-1αres virus) (IC50, >2 μg/ml) and became resistant to SDF-1β (IC50, >2 μg/ml) and to a specific CXCR4 monoclonal antibody (IC50, >20 μg/ml). The SDF-1αres virus was about 10-fold less sensitive than the wild-type virus to the bicyclam AMD3100, a specific CXCR4 antagonist. The SDF-1αres virus contained the following mutations in the gp120 molecule: N106K in the V1 loop; S134N and F145L in the V2 loop; F245I in the C2 loop; K269E, Q278H, I288V, and N293D in the V3 loop; a deletion of 5 amino acids (FNSTW) at positions 364 to 368 in the V4 loop; and R378T in the CD4 binding domain. Replication of the NL4.3 wild-type virus and the SDF-1αres virus was demonstrated in U87 cells that coexpressed CD4 and CXCR4 (U87.CD4.CXCR4) but not in U87.CD4.CCR5 cells. Thus, the resistant virus was not able to switch to the CC chemokine receptor 5 (CCR5) coreceptor (the main coreceptor for macrophage-tropic viruses). The SDF-1αres virus replicated in HOS.CD4 cells expressing CCR1, CCR2b, CCR3, CCR4, CCR5, and CXCR4 but also in HOS.CD4.pBABE cells. However, all HOS transfectant cells expressed a low level of CXCR4. Neither of the two virus strains was able to infect HOS.CXCR4 or HOS.CCR5 transfectants, demonstrating the necessity of the CD4 receptor. The T-cell-line-tropic SDF-1αres virus was thus able to overcome the inhibitory effect of SDF-1α through mutations in gp120 but still needed CXCR4 to enter the cells.

scholarly journals Interaction of Human Immunodeficiency Virus-Derived Vectors with Wild-Type Virus in Transduced Cells

1999 ◽  
Vol 73 (8) ◽  
pp. 7087-7092 ◽  
Author(s):  
Anatoly A. Bukovsky ◽  
Jin-Ping Song ◽  
Luigi Naldini
Keyword(s):  
Human Immunodeficiency Virus ◽  
Wild Type Virus ◽  
Type Virus ◽  
Measurable Effect ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Hiv 1

ABSTRACT The interaction of human immunodeficiency virus (HIV)-derived vectors with wild-type virus was analyzed in transduced cells. Vector transcripts upregulated by infection had no measurable effect on HIV type 1 (HIV-1) expression but competed efficiently for encapsidation, inhibiting the infectivity and spread of HIV-1 in culture and leading to mobilization and recombination of the vector. These effects were abrogated with a self-inactivating vector.

scholarly journals The Morphology and Composition of Influenza A Virus Particles Are Not Affected by Low Levels of M1 and M2 Proteins in Infected Cells

2005 ◽  
Vol 79 (12) ◽  
pp. 7926-7932 ◽  
Author(s):  
Svetlana V. Bourmakina ◽  
Adolfo García-Sastre
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Virus Particles ◽  
M1 Protein ◽  
Infected Cells ◽  
Low Levels ◽  
Viral Components

ABSTRACT We generated a recombinant influenza A virus (Mmut) that produced low levels of matrix (M1) and M2 proteins in infected cells. Mmut virus propagated to significantly lower titers than did wild-type virus in cells infected at low multiplicity. By contrast, virion morphology and incorporation of viral proteins and vRNAs into virus particles were similar to those of wild-type virus. We propose that a threshold amount of M1 protein is needed for the assembly of viral components into an infectious particle and that budding is delayed in Mmut virus-infected cells until sufficient levels of M1 protein accumulate at the plasma membrane.

scholarly journals Population Pharmacokinetics of Lopinavir Predict Suboptimal Therapeutic Concentrations in Treatment-Experienced Human Immunodeficiency Virus-Infected Children

2009 ◽  
Vol 53 (6) ◽  
pp. 2532-2538 ◽  
Author(s):  
Natella Rakhmanina ◽  
John van den Anker ◽  
Aline Baghdassarian ◽  
Steven Soldin ◽  
Keetra Williams ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Exposure ◽  
Regression Line ◽  
Central Compartment ◽  
Wild Type Virus ◽  
Population Pharmacokinetic ◽  
Type Virus ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Moderately Resistant

ABSTRACT In adult protease inhibitor (PI)-experienced patients, a lopinavir (LPV) phenotypic inhibitory quotient (PIQ) of >15 has been associated with a higher likelihood of viral suppression. The aims of this study were to develop a population pharmacokinetic (PK) model of LPV in children and to estimate the probability of achieving a PIQ of >15. HIV-infected, PI-experienced children receiving LPV were intensively sampled for 12 h to measure plasma LPV. The data were fitted to candidate PK models (using MM-USCPACK software), and the final model was used to simulate 1,000 children to determine the probability of achieving an LPV PIQ of >15. In 50 patients (4 to 18 years old), the median LPV plasma 12-hour-postdose concentration was 5.9 mg/liter (range, 0.03 to 16.2 mg/liter) lower than that reported in adults. After a delay, LPV was absorbed linearly into a central compartment whose size was dependent on the weight and age of the patient. Elimination was dependent on weight. The regression line of observed versus predicted LPV had an R 2 of 0.99 and a slope of 1.0. Visual predictive checks against all available measured concentrations showed good predictive ability of the model. The probability of achieving an LPV PIQ of >15 was >90% for wild-type virus but <10% for even moderately resistant virus. The currently recommended dose of LPV/ritonavir appears to be adequate for children infected with wild-type virus but is unlikely to provide adequate inhibitory concentrations for even moderately resistant human immunodeficiency virus (HIV). PI-experienced HIV-infected children will likely benefit from longitudinal, repeated LPV measurement in plasma to ensure that drug exposure is most often near the maximal end of the observed safe range.

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