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Find video protocols related to scientific articles indexed in Pubmed.
Complex TCR repertoire dynamics underlie the CD8+ T-cell response to HIV-1.
J. Virol.
PUBLISHED: 10-17-2014
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Although CD8(+) T-cells are important for the control of HIV-1 in vivo, the precise correlates of immune efficacy remain unclear. In this study, we conducted a comprehensive analysis of viral sequence variation and T-cell receptor (TCR) repertoire composition across multiple epitope specificities in a group of antiretroviral treatment-naïve individuals chronically infected with HIV-1. A negative correlation was detected between changes in antigen-specific TCR repertoire diversity and CD8(+) T-cell response magnitude, reflecting clonotypic expansions and contractions related to alterations in cognate viral epitope sequences. These patterns were independent of the individual, evidenced by discordant clonotype-specific evolution against different epitopes in single subjects. Moreover, long-term asymptomatic HIV-1 infection was characterized by evolution of the TCR repertoire in parallel with viral replication. Collectively, these data suggest a continuous bidirectional process of adaptation between HIV-1 and virus-specific CD8(+) T-cell clonotypes orchestrated at the TCR/antigen interface.
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Infection with the frequently transmitted HIV-1 M41L variant has no influence on selection of tenofovir resistance.
J. Antimicrob. Chemother.
PUBLISHED: 09-28-2014
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In ?10% of newly diagnosed HIV-1 patients, drug-resistant viral variants are detected. In such transmitted HIV-1 variants, the thymidine analogue mutation (TAM) M41L is frequently observed as a single resistance mutation and these viral variants often belong to phylogenetic transmission clusters. The presence of at least three TAMs, in particular patterns with M41L/L210W, impairs the efficacy of the extensively used drug tenofovir. We investigated whether the presence of a single M41L mutation at baseline influences the selection of resistance to tenofovir and emtricitabine in vitro and in vivo.
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Dependence on the CCR5 coreceptor for viral replication explains the lack of rebound of CXCR4-predicted HIV variants in the Berlin patient.
Clin. Infect. Dis.
PUBLISHED: 04-23-2014
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The "Berlin patient" is the first patient cured of HIV-1 infection after allogeneic transplantation with nonfunctional CCR5 coreceptor stem cells. We demonstrate that CXCR4-predicted minority viruses present prior to transplantation were unable to rebound after transplantation due to their dependence on CCR5 for replication and high genetic barrier toward CXCR4 usage.
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Use of dolutegravir in two INI-experienced patients with multiclass resistance resulted in excellent virological and immunological responses.
J Int AIDS Soc
PUBLISHED: 01-01-2014
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Dolutegravir is a second generation integrase inhibitor with a proposed high genetic barrier to resistance. However, in clinical trials, decreased virological response was seen in a subset of patients with prior exposure to raltegravir and multiple integrase resistance mutations.
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Residual Viremia Is Preceding Viral Blips and Persistent Low-Level Viremia in Treated HIV-1 Patients.
PLoS ONE
PUBLISHED: 01-01-2014
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It has been suggested that low-level viremia or blips in HIV-infected patients on antiretroviral treatment are related to assay variation and/or increased sensitivity of new commercial assays. The 50-copy cut-off for virologic failure is, therefore, under debate.
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GS-8374, a Prototype Phosphonate-Containing Inhibitor of HIV-1 Protease, Effectively Inhibits Protease Mutants with Amino Acid Insertions.
J. Virol.
PUBLISHED: 12-26-2013
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Insertions in the protease (PR) region of HIV represent an interesting mechanism of antiviral resistance against HIV PR inhibitors (PIs). We analyzed the capability of GS-8374, a phosphonate-containing experimental HIV PI, to inhibit replication of patient-derived recombinant HIV strains bearing insertions and numerous other mutations in the PR region; correlated enzyme inhibition with the catalytic activities of corresponding recombinant PRs in vitro; and provided biochemical and structural analysis of the PR-inhibitor complex.Insertions in the protease (PR) region of HIV represent an interesting mechanism of antiviral resistance against HIV PR inhibitors (PIs). Here, we demonstrated improved ability of a phosphonate-containing experimental HIV PI GS-8374 relative to other PIs to effectively inhibit patient-derived recombinant HIV strains bearing PR insertions and numerous other mutations. We correlated enzyme inhibition with the catalytic activities of corresponding recombinant PRs in vitro and provided biochemical and structural analysis of the PR-inhibitor complex.
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Differential genotypic evolution of HIV-1 quasispecies in cerebrospinal fluid and plasma: a systematic review.
AIDS Rev
PUBLISHED: 09-05-2013
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HIV-1 enters the central nervous system by passing the blood-brain barrier during primary infection. Despite the introduction of combination antiretroviral therapy, the prevalence of HIV-associated neurocognitive disorders remains high and is probably related to ongoing viral neuropathological processes. The central nervous system forms a distinct physiological, cellular, and pharmacological environment. We aimed to systematically review whether the central nervous system also constitutes a distinct virological compartment, allowing differential genotypic evolution of HIV-1. Only original research papers that compared paired plasma/cerebrospinal fluid samples for drug resistance associated mutations as defined by the IAS-USA Drug Resistance Mutations Panel or compared viral envelope (env) patterns or coreceptor prediction were included. If available, HIV RNA levels were included in the analysis, with a relevant difference defined as 0.5 log10 copies/ml. Data from 35 reports with heterogeneous study design and methods was pooled and statistical analysis was performed as appropriate. A total of 555 subjects with 671 samples could be included in this review. We observed that compartmentalization of the central nervous system occurs frequently as reflected by differences in HIV viral load, resistance associated mutations, and viral coreceptor tropism preference.
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Maraviroc treatment in non-R5-HIV-1-infected patients results in the selection of extreme CXCR4-using variants with limited effect on the total viral setpoint.
J. Antimicrob. Chemother.
PUBLISHED: 05-14-2013
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Using deep sequencing methods, we intensively investigated the selective pressure of maraviroc on the viral population in four patients with dual/mixed HIV-1 experiencing treatment failure.
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Formation of a quaternary complex of HIV-1 reverse transcriptase with a nucleotide-competing inhibitor and its ATP enhancer.
J. Biol. Chem.
PUBLISHED: 04-18-2013
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Nucleotide-competing reverse transcriptase inhibitors were shown to bind reversibly to the nucleotide-binding site of the reverse transcriptase (RT) enzyme of human immunodeficiency virus type 1 (HIV-1). Here, we show that the presence of ATP can enhance the inhibitory effects of the prototype compound INDOPY-1. We employed a combination of cell-free and cell-based assays to shed light on the underlying molecular mechanism. Binding studies and site-specific footprinting experiments demonstrate the existence of a stable quaternary complex with HIV-1 RT, its nucleic acid substrate, INDOPY-1, and ATP. The complex is frozen in the post-translocational state that usually accommodates the incoming nucleotide substrate. Structure-activity relationship studies show that both the base and the phosphate moieties of ATP are elements that play important roles in enhancing the inhibitory effects of INDOPY-1. In vitro susceptibility measurements with mutant viruses containing amino acid substitutions K70G, V75T, L228R, and K219R in the putative ATP binding pocket revealed unexpectedly a hypersusceptible phenotype with respect to INDOPY-1. The same mutational cluster was previously shown to reduce susceptibility to the pyrophosphate analog phosphonoformic acid. However, in the absence of INDOPY-1, ATP can bind and act as a pyrophosphate donor under conditions that favor formation of the pre-translocated RT complex. We therefore conclude that the mutant enzyme facilitates simultaneous binding of INDOPY-1 and ATP to the post-translocated complex. Based on these data, we propose a model in which the bound ATP traps the inhibitor, which, in turn, compromises its dissociation.
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Evolution and viral characteristics of a long-term circulating resistant HIV-1 strain in a cluster of treatment-naive patients.
J. Antimicrob. Chemother.
PUBLISHED: 03-06-2013
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Transmitted resistant HIV may revert to wild-type in the absence of drug pressure due to reduced replication capacity (RC). We observed eight therapy-naive patients infected with HIV harbouring four mutations at nucleoside reverse transcriptase inhibitor (NRTI) resistance-related positions: M41L, T69S, L210E and T215S. If partial reverted resistance patterns like these are detected at baseline, concerns for more extensive resistance in the quasispecies often directs selection of first-line combination antiretroviral therapy (cART) towards more complex regimens.
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Clinical use of HIV integrase inhibitors: a systematic review and meta-analysis.
PLoS ONE
PUBLISHED: 01-09-2013
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Optimal regimen choice of antiretroviral therapy is essential to achieve long-term clinical success. Integrase inhibitors have swiftly been adopted as part of current antiretroviral regimens. The purpose of this study was to review the evidence for integrase inhibitor use in clinical settings.
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Telbivudine exerts no antiviral activity against HIV-1 in vitro and in humans.
Antivir. Ther. (Lond.)
PUBLISHED: 10-26-2011
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HIV-HBV-coinfected individuals who need to be treated only for their HBV infection have limited therapeutic options, since most approved anti-HBV agents have a risk of selecting for drug-resistant HIV mutants. In vivo data are inconclusive as to whether telbivudine (LdT) may exert antiviral effects against HIV. Thus, we investigated in further detail the antiviral activity and the biochemical properties of LdT against HIV-1.
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Evolutionary pathways of transmitted drug-resistant HIV-1.
J. Antimicrob. Chemother.
PUBLISHED: 04-18-2011
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Several large studies in Europe and the USA revealed that approximately 10% of all newly diagnosed patients harbour HIV-1 variants with at least one major resistance-associated mutation. In this review we discuss the underlying mechanisms that drive the evolution of drug-resistant viruses after transmission to the new host. In a comprehensive literature search 12 papers describing the evolution of 58 cases of transmitted resistant HIV-1 variants were found. Based on observations in the literature we propose three pathways describing the evolution of resistant HIV-1 after transmission to a new host. Firstly, reversion of the resistance mutation towards wild-type may rapidly occur when drug resistance mutations severely impact replicative capacity. Alternatively, a second pathway involves replacement of transmitted drug resistance mutations by atypical amino acids that also improve viral replication capacity. In the third evolutionary pathway the resistance mutations persist either because they do not significantly affect viral replication capacity or evolution is constrained by fixation through compensatory mutations. In the near future ultra-sensitive resistance tests may provide more insight into the presence of archived and minority variants and their clinical relevance. Meanwhile, clinical guidelines advise population sequence analysis of the baseline plasma sample to identify transmission of resistance. Given the limited sensitivity of this technique for minority populations and the delay between the moment of infection and time of analysis, knowledge of the described evolutionary mechanisms of transmitted drug resistance patterns is essential for clinical management and public health strategies.
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HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat.
Retrovirology
PUBLISHED: 04-15-2011
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Maturation inhibitors are an experimental class of antiretrovirals that inhibit Human Immunodeficiency Virus (HIV) particle maturation, the structural rearrangement required to form infectious virus particles. This rearrangement is triggered by the ordered cleavage of the precursor Gag polyproteins into their functional counterparts by the viral enzyme protease. In contrast to protease inhibitors, maturation inhibitors impede particle maturation by targeting the substrate of protease (Gag) instead of the protease enzyme itself. Direct cross-resistance between protease and maturation inhibitors may seem unlikely, but the co-evolution of protease and its substrate, Gag, during protease inhibitor therapy, could potentially affect future maturation inhibitor therapy. Previous studies showed that there might also be an effect of protease inhibitor resistance mutations on the development of maturation inhibitor resistance, but the exact mechanism remains unclear. We used wild-type and protease inhibitor resistant viruses to determine the impact of protease inhibitor resistance mutations on the development of maturation inhibitor resistance.
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Impact of the HIV-1 env genetic context outside HR1-HR2 on resistance to the fusion inhibitor enfuvirtide and viral infectivity in clinical isolates.
PLoS ONE
PUBLISHED: 03-15-2011
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Resistance mutations to the HIV-1 fusion inhibitor enfuvirtide emerge mainly within the drugs target region, HR1, and compensatory mutations have been described within HR2. The surrounding envelope (env) genetic context might also contribute to resistance, although to what extent and through which determinants remains elusive. To quantify the direct role of the env context in resistance to enfuvirtide and in viral infectivity, we compared enfuvirtide susceptibility and infectivity of recombinant viral pairs harboring the HR1-HR2 region or the full Env ectodomain of longitudinal env clones from 5 heavily treated patients failing enfuvirtide therapy. Prior to enfuvirtide treatment onset, no env carried known resistance mutations and full Env viruses were on average less susceptible than HR1-HR2 recombinants. All escape clones carried at least one of G36D, V38A, N42D and/or N43D/S in HR1, and accordingly, resistance increased 11- to 2800-fold relative to baseline. Resistance of full Env recombinant viruses was similar to resistance of their HR1-HR2 counterpart, indicating that HR1 and HR2 are the main contributors to resistance. Strictly X4 viruses were more resistant than strictly R5 viruses, while dual-tropic Envs featured similar resistance levels irrespective of the coreceptor expressed by the cell line used. Full Env recombinants from all patients gained infectivity under prolonged drug pressure; for HR1-HR2 viruses, infectivity remained steady for 3/5 patients, while for 2/5 patients, gains in infectivity paralleled those of the corresponding full Env recombinants, indicating that the env genetic context accounts mainly for infectivity adjustments. Phylogenetic analyses revealed that quasispecies selection is a step-wise process where selection of enfuvirtide resistance is a dominant factor early during therapy, while increased infectivity is the prominent driver under prolonged therapy.
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Maraviroc is able to inhibit dual-R5 viruses in a dual/mixed HIV-1-infected patient.
J. Antimicrob. Chemother.
PUBLISHED: 01-28-2011
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Maraviroc is the first licensed chemokine co-receptor 5 (CCR5) co-receptor antagonist in clinical practice. It is currently being used in patients harbouring exclusively CCR5-tropic virus. The objective of the study was to investigate the impact of maraviroc on viruses with different co-receptor preferences in a patient with a dual/mixed (D/M) infection.
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Mutation Q95K enhances N155H-mediated integrase inhibitor resistance and improves viral replication capacity.
J. Antimicrob. Chemother.
PUBLISHED: 08-24-2010
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The genetic barrier to development of raltegravir resistance is considered to be low, requiring at least one primary integrase mutation: Y143C, Q148H/K/R or N155H to confer raltegravir therapy failure. However, during continued raltegravir treatment failure, additional mutations may be selected. In a patient failing raltegravir therapy, we investigated the impact of multiple integrase mutations on resistance and viral replication. Furthermore, in vivo fitness was investigated during failure of raltegravir-containing highly active antiretroviral therapy and after raltegravir was discontinued from the regimen.
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HIV-1 reverse transcriptase connection domain mutations: dynamics of emergence and implications for success of combination antiretroviral therapy.
Clin. Infect. Dis.
PUBLISHED: 07-30-2010
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Factors promoting the emergence of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) connection domain mutations and their effect on antiretroviral therapy (ART) are still largely undetermined. We investigated this matter by analyzing genotypic resistance tests covering 400 amino acid positions in the RT of HIV-1 subtype B viruses and corresponding treatment histories and laboratory measurements.
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Epidemiological and biological evidence for a compensatory effect of connection domain mutation N348I on M184V in HIV-1 reverse transcriptase.
J. Infect. Dis.
PUBLISHED: 02-23-2010
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The connection domain mutation N348I confers resistance to zidovudine (AZT) and is associated with the lamivudine (3TC) mutation M184V. We explored the biochemical and virological influence of N348I in the context of M184V.
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Fifteen years of HIV Protease Inhibitors: raising the barrier to resistance.
Antiviral Res.
PUBLISHED: 07-30-2009
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HIV protease plays a crucial role in the viral life cycle and is essential for the generation of mature infectious virus particles. Detailed knowledge of the structure of HIV protease and its substrate has led to the design of specific HIV protease inhibitors. Unfortunately, resistance to all protease inhibitors (PIs) has been observed and the genetic basis of resistance has been well documented over the past 15 years. The arrival of the early PIs was a pivotal moment in the development of antiretroviral therapy. They made possible the dual class triple combination therapy that became known as HAART. However, the clinical utility of the first generation of PIs was limited by low bioavailability and high pill burdens, which ultimately reduced adherence and limited long-term viral inhibition. When therapy failure occurred multiple protease resistance mutations were observed, often resulting in broad class resistance. To combat PI-resistance development, second-generation approaches have been developed. The first advance was to increase the level of existing PIs in the plasma by boosting with ritonavir. The second was to develop novel PIs with high potency against the known PI-resistant HIV protease variants. Both approaches increased the number of protease mutations required for clinical resistance, thereby raising the genetic barrier. This review provides an overview of the history of protease inhibitor therapy, its current status and future perspectives. It forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.
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Failure of treatment with first-line lopinavir boosted with ritonavir can be explained by novel resistance pathways with protease mutation 76V.
J. Infect. Dis.
PUBLISHED: 07-25-2009
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Virological failure of first-line antiretroviral therapy based on lopinavir boosted with ritonavir (lopinavir/r) has rarely been associated with resistance in protease. We identified a new genotypic resistance pathway in 3 patients who experienced failure of first-line lopinavir/r treatment.
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HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review.
AIDS
PUBLISHED: 04-04-2009
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To assess the efficacy of ritonavir-boosted protease inhibitor monotherapy.
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Differential in vitro kinetics of drug resistance mutation acquisition in HIV-1 RT of subtypes B and C.
PLoS ONE
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HIV-1 subtype B is the most prevalent in developed countries and, consequently, it has been extensively studied. On the other hand, subtype C is the most prevalent worldwide and therefore is a reasonable target for future studies. Here we evaluate the acquisition of resistance and the viability of HIV-1 subtype B and C RT clones from different isolates that were subjected to in vitro selection pressure with zidovudine (ZDV) and lamivudine (3TC).
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Correlation of coreceptor usage and disease progression.
Curr Opin HIV AIDS
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Primary HIV-1 infection is usually initiated by viruses with an exclusive affinity for the C-C chemokine receptor type 5 (CCR5) coreceptor. Viral variants that are also able to bind the C-X-C chemokine receptor type 4 (CXCR4) coreceptor arise during the course of the disease in about 50% of the infected individuals and their emergence is associated with a faster disease progression. In this article we provide a historical overview of the events that led to the discovery of the relationship between viral phenotype, coreceptor tropism and pathogenesis.
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Human Immunodeficiency Virus Gag and protease: partners in resistance.
Retrovirology
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Human Immunodeficiency Virus (HIV) maturation plays an essential role in the viral life cycle by enabling the generation of mature infectious virus particles through proteolytic processing of the viral Gag and GagPol precursor proteins. An impaired polyprotein processing results in the production of non-infectious virus particles. Consequently, particle maturation is an excellent drug target as exemplified by inhibitors specifically targeting the viral protease (protease inhibitors; PIs) and the experimental class of maturation inhibitors that target the precursor Gag and GagPol polyproteins. Considering the different target sites of the two drug classes, direct cross-resistance may seem unlikely. However, coevolution of protease and its substrate Gag during PI exposure has been observed both in vivo and in vitro. This review addresses in detail all mutations in Gag that are selected under PI pressure. We evaluate how polymorphisms and mutations in Gag affect PI therapy, an aspect of PI resistance that is currently not included in standard genotypic PI resistance testing. In addition, we consider the consequences of Gag mutations for the development and positioning of future maturation inhibitors.
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Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity.
Retrovirology
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Mutations in the substrate of HIV-1 protease, especially changes in the NC/p1 cleavage site, can directly contribute to protease inhibitor (PI) resistance and also compensate for defects in viral replicative capacity (RC) due to a drug resistant protease. These NC/p1 changes are known to enhance processing of the Gag protein. To investigate the capacity of HIV-1 to modulate Gag cleavage and its consequences for PI resistance and RC, we performed a detailed enzymatic and virological analysis using a set of PI resistant NC/p1 variants (HXB2431V, HXB2436E+437T, HXB2437T and HXB2437V).
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.