scholarly journals Characterizing the Diverse Mutational Pathways Associated with R5-Tropic Maraviroc Resistance: HIV-1 That Uses the Drug-Bound CCR5 Coreceptor

2015 ◽  
Vol 89 (22) ◽  
pp. 11457-11472 ◽  
Author(s):  
Xiaowei Jiang ◽  
Felix Feyertag ◽  
Conor J. Meehan ◽  
Grace P. McCormack ◽  
Simon A. Travers ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Treatment Failure ◽  
Positive Selection ◽  
Antiretroviral Drugs ◽  
Viral Population ◽  
Cell Protein ◽  
V3 Loop ◽  
Evolutionary Analysis ◽  
Resistance Pathway ◽  
Hiv 1

ABSTRACTEntry inhibitors represent a potent class of antiretroviral drugs that target a host cell protein, CCR5, an HIV-1 entry coreceptor, and not viral protein. Lack of sensitivity can occur due to preexisting virus that uses the CXCR4 coreceptor, while true resistance occurs through viral adaptation to use a drug-bound CCR5 coreceptor. To understand this R5 resistance pathway, we analyzed >500 envelope protein sequences and phenotypes from viruses of 20 patients from the clinical trials MOTIVATE 1 and 2, in which treatment-experienced patients received maraviroc plus optimized background therapy. The resistant viral population was phylogenetically distinct and associated with a genetic bottleneck in each patient, consistent withde novoemergence of resistance. Recombination analysis showed that the C2-V3-C3 region tends to genotypically correspond to the recombinant's phenotype, indicating its primary importance in conferring resistance. Between patients, there was a notable lack of commonality in the specific sites conferring resistance, confirming the unusual nature of R5-tropic resistance. We used coevolutionary and positive-selection analyses to characterize the genotypic determinants of resistance and found that (i) there are complicated covariation networks, indicating frequent coevolutionary/compensatory changes in the context of protein structure; (ii) covarying sites under positive selection are enriched in resistant viruses; (iii) CD4 binding sites form part of a unique covariation network independent of the V3 loop; and (iv) the covariation network formed between the V3 loop and other regions of gp120 and gp41 intersects sites involved in glycosylation and protein secretion. These results demonstrate that while envelope sequence mutations are the key to conferring maraviroc resistance, the specific changes involved are context dependent and thus inherently unpredictable.IMPORTANCEThe entry inhibitor drug maraviroc makes the cell coreceptor CCR5 unavailable for use by HIV-1 and is now used in combination antiretroviral therapy. Treatment failure with drug-resistant virus is particularly interesting because it tends to be rare, with lack of sensitivity usually associated with the presence of CXCR4-using virus (CXCR4 is the main alternative coreceptor HIV-1 uses, in addition to CD4). We analyzed envelope sequences from HIV-1, obtained from 20 patients who enrolled in maraviroc clinical trials and experienced treatment failure, without detection of CXCR4-using virus. Evolutionary analysis was employed to identify molecular changes that confer maraviroc resistance. We found that in these individuals, resistant viruses form a distinct population that evolved once and was successful as a result of drug pressure. Further evolutionary analysis placed the complex network of interdependent mutational changes into functional groups that help explain the impediments to the emergence of maraviroc-associated R5 drug resistance.

scholarly journals Analysis of Low-Frequency Mutations Associated with Drug Resistance to Raltegravir before Antiretroviral Treatment

2010 ◽  
Vol 55 (3) ◽  
pp. 1114-1119 ◽  
Author(s):  
Jia Liu ◽  
Michael D. Miller ◽  
Robert M. Danovich ◽  
Nathan Vandergrift ◽  
Fangping Cai ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
Low Frequency ◽  
Hiv Treatment ◽  
Viral Population ◽  
Virologic Suppression ◽  
Resistance Mutations ◽  
The Difference ◽  
Allele Specific Sequencing ◽  
Hiv 1

ABSTRACTRaltegravir is highly efficacious in the treatment of HIV-1 infection. The prevalence and impact on virologic outcome of low-frequency resistant mutations among HIV-1-infected patients not previously treated with raltegravir have not been fully established. Samples from HIV treatment-experienced patients entering a clinical trial of raltegravir treatment were analyzed using a parallel allele-specific sequencing (PASS) assay that assessed six primary and six secondary integrase mutations. Patients who achieved and sustained virologic suppression (success patients,n= 36) and those who experienced virologic rebound (failure patients,n= 35) were compared. Patients who experienced treatment failure had twice as many raltegravir-associated resistance mutations prior to initiating treatment as those who achieved sustained virologic success, but the difference was not statistically significant. The frequency of nearly all detected resistance mutations was less than 1% of viral population, and the frequencies of mutations between the success and failure groups were similar. Expansion of pre-existing mutations (one primary and five secondary) was observed in 16 treatment failure patients in whom minority resistant mutations were detected at baseline, suggesting that they might play a role in the development of drug resistance. Two or more mutations were found in 13 patients (18.3%), but multiple mutations were not present in any single viral genome by linkage analysis. Our study demonstrates that low-frequency primary RAL-resistant mutations were uncommon, while minority secondary RAL-resistant mutations were more frequently detected in patients naïve to raltegravir. Additional studies in larger populations are warranted to fully understand the clinical implications of these mutations.

scholarly journals Origin of Human Immunodeficiency Virus Type 1 Quasispecies Emerging after Antiretroviral Treatment Interruption in Patients with Therapeutic Failure

2002 ◽  
Vol 76 (14) ◽  
pp. 7000-7009 ◽  
Author(s):  
Gustavo H. Kijak ◽  
Viviana Simon ◽  
Peter Balfe ◽  
Jeroen Vanderhoeven ◽  
Sandra E. Pampuro ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Treatment Failure ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Treatment Interruption ◽  
Viral Population ◽  
Drug Resistant ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure.

scholarly journals A de novo approach to inferring within-host fitness effects during untreated HIV-1 infection

2019 ◽  
Author(s):  
Christopher J. R. Illingworth ◽  
Jayna Raghwani ◽  
David Serwadda ◽  
Nelson K. Sewankambo ◽  
Merlin L. Robb ◽  
...  
Keyword(s):  
Positive Selection ◽  
Sequence Data ◽  
Viral Population ◽  
Clonal Interference ◽  
Neutralising Antibodies ◽  
Host Diversity ◽  
Fitness Effects ◽  
Ctl Escape ◽  
Hiv 1

AbstractIn the absence of effective antiviral therapy, HIV-1 evolves in response to the within-host environment, of which the immune system is an important aspect. During the earliest stages of infection, this process of evolution is very rapid, driven by a small number of CTL escape mechanisms. As the infection progresses, immune escape variants evolve under reduced magnitudes of selection, while competition between an increasing number of polymorphic alleles (i.e., clonal interference) makes it difficult to quantify the magnitude of selection acting upon specific variant alleles. To tackle this complex problem, we developed a novel multi-locus inference method to evaluate the role of selection during the chronic stage of within-host infection. We applied this method to targeted sequence data from the p24 and gp41 regions of HIV-1 collected from 34 patients with long-term untreated HIV-1 infection. We identify a broad distribution of beneficial fitness effects during infection, with a small number of variants evolving under strong selection and very many variants evolving under weaker selection. The uniquely large number of infections analysed granted a previously unparalleled statistical power to identify loci at which selection could be inferred to act with statistical confidence. Our model makes no prior assumptions about the nature of alleles under selection, such that any synonymous or non-synonymous variant may be inferred to evolve under selection. However, the majority of variants inferred with confidence to be under selection were non-synonymous in nature, and in nearly all cases were associated with either CTL escape in p24 or neutralising antibody escape in gp41. Sites inferred to be under selection in multiple hosts have high within-host and between-host diversity albeit not all sites with high between-host diversity were inferred to be under selection at the within-host level. Our identification of selection at sites associated with resistance to broadly neutralising antibodies (bNAbs) highlights the need to fully understand the role of selection in untreated individuals when designing bNAb based therapies.Author SummaryDuring the within-host evolution of HIV-1, the diversity of the viral population increases, with many beneficial variants competing against each other. This competition, known as clonal interference, makes the identification of variants under positive selection a challenging task. We here apply a novel method for the inference of selection to targeted within-host sequence data describing changes in the p24 and gp41 genes during HIV-1 infection in 34 patients. Our method adopts a parsimonious approach, assigning selection to the smallest number of variants necessary to explain the evolution of the system. The large size of our dataset allows for the confident identification of variants under selection, alleles at certain loci being repeatedly inferred as under selection within multiple individuals. While early CTL escape mutations have been identified to evolve under strong positive selection, we identify a distribution of beneficial fitness effects in which a large number of mutations are under weak selection. Variants that were confidently identified under selection were primarily found to be associated with either CTL escape in p24 or neutralising antibody escape in gp41, including sites associated with escape from broadly neutralising antibodies. We find that the most frequently selected loci have high diversity both within-host and at the between-host level.

scholarly journals Identification of Emerging Macrophage-Tropic HIV-1 R5 Variants in Brain Tissue of AIDS Patients without Severe Neurological Complications

2017 ◽  
Vol 91 (20) ◽  
Author(s):  
Maria Paz Gonzalez-Perez ◽  
Paul J. Peters ◽  
Olivia O'Connell ◽  
Nilsa Silva ◽  
Carole Harbison ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Neurological Disease ◽  
Antiretroviral Drugs ◽  
Viral Population ◽  
Term Therapy ◽  
Macrophage Infection ◽  
Aids Patients ◽  
Immune Tissue ◽  
The Brain ◽  
Hiv 1

ABSTRACT Untreated HIV-positive (HIV-1+) individuals frequently suffer from HIV-associated neurocognitive disorders (HAND), with about 30% of AIDS patients suffering severe HIV-associated dementias (HADs). Antiretroviral therapy has greatly reduced the incidence of HAND and HAD. However, there is a continuing problem of milder neurocognitive impairments in treated HIV+ patients that may be increasing with long-term therapy. In the present study, we investigated whether envelope (env) genes could be amplified from proviral DNA or RNA derived from brain tissue of 12 individuals with normal neurology or minor neurological conditions (N/MC individuals). The tropism and characteristics of the brain-derived Envs were then investigated and compared to those of Envs derived from immune tissue. We showed that (i) macrophage-tropic R5 Envs could be detected in the brain tissue of 4/12 N/MC individuals, (ii) macrophage-tropic Envs in brain tissue formed compartmentalized clusters distinct from non-macrophage-tropic (non-mac-tropic) Envs recovered from the spleen or brain, (iii) the evidence was consistent with active viral expression by macrophage-tropic variants in the brain tissue of some individuals, and (iv) Envs from immune tissue of the N/MC individuals were nearly all tightly non-mac-tropic, contrasting with previous data for neuro-AIDS patients where immune tissue Envs mediated a range of macrophage infectivities, from background levels to modest infection, with a small number of Envs from some patients mediating high macrophage infection levels. In summary, the data presented here show that compartmentalized and active macrophage-tropic HIV-1 variants are present in the brain tissue of individuals before neurological disease becomes overt or serious. IMPORTANCE The detection of highly compartmentalized macrophage-tropic R5 Envs in the brain tissue of HIV patients without serious neurological disease is consistent with their emergence from a viral population already established there, perhaps from early disease. The detection of active macrophage-tropic virus expression, and probably replication, indicates that antiretroviral drugs with optimal penetration through the blood-brain barrier should be considered even for patients without neurological disease (neuro-disease). Finally, our data are consistent with the brain forming a sanctuary site for latent virus and low-level viral replication in the absence of neuro-disease.

Use of Antiretroviral Drugs to Prevent HIV-1 Transmission Through Breast-feeding: From Animal Studies to Randomized Clinical Trials

2004 ◽  
Vol 35 (2) ◽  
pp. 178-187 ◽  
Author(s):  
Philippe Gaillard ◽  
Mary-Glenn Fowler ◽  
Francois Dabis ◽  
Hoosen Coovadia ◽  
Charles van der Horst ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Breast Feeding ◽  
Animal Studies ◽  
Randomized Clinical Trials ◽  
Antiretroviral Drugs ◽  
Hiv 1

scholarly journals Interferon Alpha Subtype-Specific Suppression of HIV-1 InfectionIn Vivo

2016 ◽  
Vol 90 (13) ◽  
pp. 6001-6013 ◽  
Author(s):  
Kerry J. Lavender ◽  
Kathrin Gibbert ◽  
Karin E. Peterson ◽  
Erik Van Dis ◽  
Sandra Francois ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Interferon Alpha ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antiretroviral Drugs ◽  
Human Interferon ◽  
Human Immune System ◽  
Antiviral Protein ◽  
Hiv 1

ABSTRACTAlthough all 12 subtypes of human interferon alpha (IFN-α) bind the same receptor, recent results have demonstrated that they elicit unique host responses and display distinct efficacies in the control of different viral infections. The IFN-α2 subtype is currently in HIV-1 clinical trials, but it has not consistently reduced viral loads in HIV-1 patients and is not the most effective subtype against HIV-1in vitro. We now demonstrate in humanized mice that, when delivered at the same high clinical dose, the human IFN-α14 subtype has very potent anti-HIV-1 activity whereas IFN-α2 does not. In both postexposure prophylaxis and treatment of acute infections, IFN-α14, but not IFN-α2, significantly suppressed HIV-1 replication and proviral loads. Furthermore, HIV-1-induced immune hyperactivation, which is a prognosticator of disease progression, was reduced by IFN-α14 but not IFN-α2. Whereas ineffective IFN-α2 therapy was associated with CD8+T cell activation, successful IFN-α14 therapy was associated with increased intrinsic and innate immunity, including significantly higher induction of tetherin and MX2, increased APOBEC3G signature mutations in HIV-1 proviral DNA, and higher frequencies of TRAIL+NK cells. These results identify IFN-α14 as a potent new therapeutic that operates via mechanisms distinct from those of antiretroviral drugs. The ability of IFN-α14 to reduce both viremia and proviral loadsin vivosuggests that it has strong potential as a component of a cure strategy for HIV-1 infections. The broad implication of these results is that the antiviral efficacy of each individual IFN-α subtype should be evaluated against the specific virus being treated.IMPORTANCEThe naturally occurring antiviral protein IFN-α2 is used to treat hepatitis viruses but has proven rather ineffective against HIV in comparison to triple therapy with the antiretroviral (ARV) drugs. Although ARVs suppress the replication of HIV, they fail to completely clear infections. Since IFN-α acts by different mechanism than ARVs and has been shown to reduce HIV proviral loads, clinical trials are under way to test whether IFN-α2 combined with ARVs might eradicate HIV-1 infections. IFN-α is actually a family of 12 distinct proteins, and each IFN-α subtype has different efficacies toward different viruses. Here, we use mice that contain a human immune system, so they can be infected with HIV. With this model, we demonstrate that while IFN-α2 is only weakly effective against HIV, IFN-α14 is extremely potent. This discovery identifies IFN-α14 as a more powerful IFN-α subtype for use in combination therapy trials aimed toward an HIV cure.

scholarly journals Use of plasma albumin, hepatic lipase and lipoprotein lipase enzyme as predictive markers of treatment failure in HIV-1 infected individuals in federal medical center, Lokoja, Nigeria

2020 ◽  
Vol 11 (SPL4) ◽  
pp. 3137-3149
Author(s):  
Paul I Emeje ◽  
Chinedum C Onyenekwe ◽  
Nkiruka R. Ukibe ◽  
Joseph E. Ahaneku ◽  
Ofia A. Kalu ◽  
...  
Keyword(s):  
Viral Load ◽  
Treatment Failure ◽  
Lipoprotein Lipase ◽  
Biochemical Markers ◽  
Hepatic Lipase ◽  
Antiretroviral Drugs ◽  
Predictive Markers ◽  
Cd4 Count ◽  
Control Group ◽  
Hiv 1

This was a cross-sectional study aimed to evaluate the use of albumin, hepatic lipase (HL) and lipoprotein lipase (LPL) enzyme as predictive markers of treatment failure in HIV-1 infected individuals. 154 participants {40 (group A), 35 (group B) on antiretroviral drugs (Test group) and 79 (group C) HIV naive participants (Control group)} aged 18 and 65 years were randomly recruited. Blood sample was collected from each test participant 6 months apart and once from control for determination of Albumin, HL, LPL, viral load (VL), CD4+  cells count. VL was significantly decreased while, Albumin, HL and LPL activities were significantly higher in test participants when compared with control P ≤ 0.05 respectively). Biochemical markers in test participants at 6 months of therapy were significantly lower compared with 12 months of therapy (P ≤ 0.05). Albumin and VL correlated positively with CD4  count while,  lamivudine, nevirapine, tenofovir, HL, LPL correlated strongly and negatively with VL (P < 0.05 respectively). The high sensitivities and positive predictive value of albumin showed their predictive superiority over CD4+ count, HL, LPL and antiretroviral drug concentrations.The study thus, concludes that hypoalbuminemia with decreased HL and LPL activities were associated with unsuppressed viral load above 1000 copies/ml. This suggests that albumin; HL and LPL are good biochemical markers for prediction of treatment failure or success in participants on antiretroviral drugs.

The Changes of Positive Selection Within env Gene of HIV-1 B’, CRF07_BC and CRF08_BC from China Over Time

2017 ◽  
Vol 15 (1) ◽  
pp. 31-37 ◽  
Author(s):  
Tingting Li ◽  
Binlian Sun ◽  
Yanyan Jiang ◽  
Haiyan Zeng ◽  
Yanpeng Li ◽  
...  
Keyword(s):  
Positive Selection ◽  
Hiv 1 ◽  
Over Time

Elucidating the Disparate Inhibitory Mechanisms of Novel 1-Heteroaryl1,3-Propanediamine Derivatives and Maraviroc towards C-C Chemokine Receptor 5: Insights for Structural Modifications in HIV-1 Drug Discovery

2020 ◽  
Vol 17 ◽  
Author(s):  
Patrick Appiah-Kubi ◽  
Fisayo Andrew Olotu ◽  
Mahmoud E. S. Soliman
Keyword(s):  
Drug Discovery ◽  
Chemokine Receptor ◽  
Competitive Inhibition ◽  
Dynamic Effect ◽  
Triazole Ring ◽  
Internal Dynamic ◽  
V3 Loop ◽  
Structural Modifications ◽  
Hiv 1 ◽  
Chemokine Receptor 5

Introduction: Blocking Human Immunodeficiency Virus type 1 (HIV-1) entry via C-C chemokine receptor 5 (CCR5) inhibition has remained an essential strategy in HIV drug discovery. This underlies the development of CCR5 blockers, such as Maraviroc, which, however, elicits undesirable side effects despite its potency. Background: Recent lead optimization efforts led to the discovery of novel 1-heteroaryl-1,3-propanediamine derivatives; Compd-21 and -34, which were ~3 times more potent than Maraviroc, with improved pharmacokinetics. However, atomistic molecular interaction mechanism of how slight structural variance between these inhibitors significantly affects their binding profiles have not been elucidated. Method: This study employed explicit lipid bilayer molecular dynamics (MD) simulations, and advance analyses to explore these inhibitory discrepancies. Results: Findings revealed that the thiophene moiety substitution common to Compd-21 and -34 enhanced their CCR5- inhibitory activities due to complementary high-affinity interactions with Trp862.60, Tyr1083.32, Tyr2516.51, Glu2837.39. These cumulatively accounted for their ΔGbind which were higher than Maraviroc. Binding dynamics further revealed that the compounds mediated direct competitive inhibition at CCR5 by blocking the gp120 V3 loop. Furthermore, constituent tropane and triazole moieties in the compounds commonly engaged in interactions with Glu2837.39 and Trp862.60, respectively. Structural analyses also revealed that both Compd-21 and -34 elicited distinct internal dynamic effect on CCR5 relative to Maraviroc. Conclusion: Structural modifications at the thiophene substituent and the addition of new functional groups to the triazole ring may enhance inhibitor competition with gp120 V3-loop. Findings herein highlighted would contribute to future structure-based design of inhibitors of HIV-1 CCR5 with improved potencies.

Sign in / Sign up

Export Citation Format

Share Document