scholarly journals HIV-1 Tropism Evolution after Short-Term Maraviroc Monotherapy in HIV-1-Infected Patients

2012 ◽  
Vol 56 (7) ◽  
pp. 3981-3983 ◽  
Author(s):  
Alejandro Gonzalez-Serna ◽  
María Concepción Romero-Sánchez ◽  
Sara Ferrando-Martinez ◽  
Miguel Genebat ◽  
Francesc Vidal ◽  
...  
Keyword(s):  
Virological Response ◽  
Ccr5 Antagonist ◽  
Clinical Test ◽  
Short Term ◽  
Viral Tropism ◽  
Viral Loads ◽  
Hiv Rna ◽  
Hiv 1 ◽  
Shed Light

ABSTRACTWe analyzed the evolution of viral tropism after 8 days of maraviroc monotherapy, i.e., we used the maraviroc clinical test (MCT), in 21 patients with and 14 without virological response to the drug (MCT+and MCT−patients, respectively). No increases in CXCR4 inferred viral loads (X4IVLs) were observed in MCT+patients, while X4IVLs increased only in MCT−patients, with X4IVLs of >2 log10HIV RNA copies/ml. These results shed light on the evolution of viral tropism under a CCR5 antagonistin vivo.

scholarly journals Virological Response after Short-Term CCR5 Antagonist Exposure in HIV-Infected Patients: Frequency of Subjects with Virological Response and Associated Factors

2011 ◽  
Vol 55 (10) ◽  
pp. 4664-4669 ◽  
Author(s):  
Ezequiel Ruiz-Mateos ◽  
Alejandro González-Serna ◽  
Miguel Genebat ◽  
Kawthar Machmach ◽  
Francesc Vidal ◽  
...  
Keyword(s):  
T Cell ◽  
Virological Response ◽  
Undetectable Viral Load ◽  
Ccr5 Antagonist ◽  
Clinical Test ◽  
Short Term ◽  
Hiv Rna ◽  
Cell Counts ◽  
Treatment Naïve ◽  
The Moment

ABSTRACTThe virological response after an 8-day maraviroc monotherapy has been proposed to be an alternative method to determine whether an CCR5 antagonist should be prescribed to HIV-infected patients. The frequency of patients eligible for a combined antiretroviral therapy which includes maraviroc on the basis of the result of this clinical test is not well-known at the moment. In the same way, clinical and immunovirological factors associated with the virological response after antagonist exposure need to be determined. Ninety consecutive HIV-infected patients were exposed to an 8-day maraviroc monotherapy. The virological response was considered positive if either a reduction of ≥1-log10HIV RNA copies/ml or an undetectable viral load (<40 HIV RNA copies/ml) was achieved. CXCR4- and CCR5-tropic virus levels were determined by using patients' viral isolates and multiple rounds of infection of indicator cell lines (U87-CXCR4 and U87-CCR5). The frequency of patients with a positive virological response was 72.2% (94.7% and 66.2% for treatment-naïve and pretreated patients, respectively). The positive response rates dramatically decreased in patients with lower CD4+T-cell counts. The CXCR4-tropic virus level was the only variable independently associated with the virological response after short-term maraviroc exposure. Lower CD4+T-cell strata were associated with higher CXCR4-tropic virus levels. These results support the suggestion that CCR5 antagonists should be an early treatment option before the expansion of CXCR4-tropic strains.

scholarly journals Correlation of the Virological Response to Short-Term Maraviroc Monotherapy with Standard and Deep-Sequencing-Based Genotypic Tropism Prediction Methods

2011 ◽  
Vol 56 (3) ◽  
pp. 1202-1207 ◽  
Author(s):  
A. Gonzalez-Serna ◽  
R. A. McGovern ◽  
P. R. Harrigan ◽  
F. Vidal ◽  
A. F. Y. Poon ◽  
...  
Keyword(s):  
Deep Sequencing ◽  
Virological Response ◽  
Drug Exposure ◽  
False Positive Rate ◽  
Clinical Test ◽  
Testing Methods ◽  
Short Term ◽  
Short Term Exposure ◽  
Positive Rate

ABSTRACTGenotypic tropism testing methods are emerging as the first step before prescription of the CCR5 antagonist maraviroc (MVC) to HIV-infected patients in Europe. Studies validating genotypic tests have included other active drugs that could have potentially convoluted the effects of MVC. The maraviroc clinical test (MCT) is anin vivodrug sensitivity test based on the virological response to a short-term exposure to MVC monotherapy. Thus, our aim was to compare the results of genotypic tropism testing methods with the short-term virological response to MVC monotherapy. A virological response in the MCT was defined as a ≥1-log10decrease in HIV RNA or undetectability after 8 days of drug exposure. Seventy-three patients undergoing the MCT were included in this study. We used both standard genotypic methods (n= 73) and deep sequencing (n= 27) on MCT samples at baseline. For the standard methods, the most widely used genotypic algorithms for analyzing the V3 loop sequence, geno2pheno and PSSM, were used. For deep sequencing, the geno2pheno algorithm was used with a false-positive rate cutoff of 3.5. The discordance rates between the standard genotypic methods and the virological response were approximately 20% (including mostly patients without a virological response). Interestingly, these discordance rates were similar to that obtained from deep sequencing (18.5%). The discordance rates between the genotypic methods (tropism assays predictive of the use of the CCR5 coreceptor) and the MCT (in vivoMVC sensitivity assay) indicate that the algorithms used by genotypic methods are still not sufficiently optimized.

scholarly journals Utility of HIV-1 DNA genotype in determining antiretroviral resistance in patients with low or undetectable HIV RNA viral loads

2018 ◽  
Vol 73 (11) ◽  
pp. 3129-3136 ◽  
Author(s):  
Narjis Boukli ◽  
Anders Boyd ◽  
Marianne Collot ◽  
Jean-Luc Meynard ◽  
Pierre-Marie Girard ◽  
...  
Keyword(s):  
Viral Loads ◽  
Hiv Rna ◽  
Antiretroviral Resistance ◽  
Hiv 1

scholarly journals The characteristics of the HIV-1 Env glycoprotein contribute to viral pathogenesis

2021 ◽  
Author(s):  
Silvia Perez-Yanes ◽  
Maria Pernas ◽  
Silvia Marfil ◽  
Romina Cabrera-Rodríguez ◽  
Raquel Ortiz ◽  
...  
Keyword(s):  
Functional Characteristic ◽  
Elite Controllers ◽  
Clinical Progression ◽  
Viral Control ◽  
Clinical Phenotypes ◽  
Viral Loads ◽  
Variable Contribution ◽  
Gp120 Subunit ◽  
Hiv 1

The understanding of HIV-1 pathogenesis and clinical progression is incomplete because of the variable contribution of host, immune and viral factors. The involvement of viral factors has been investigated in extreme clinical phenotypes from rapid progressors to long-term non-progressors (LTNPs). Among HIV-1 proteins, the envelope glycoprotein complex (Env) has concentrated many studies for its important role in the immune response and in the first steps of viral replication. In this study, we analyzed the contribution of 41 Envs from 24 patients with different clinical progression rates and viral loads (VLs), LTNP-Elite Controllers (LTNP-ECs); Viremic LTNPs (vLTNPs), and non-controller’s individuals contemporary to LTNPs or recent, named Old and Modern progressors. We analyzed the Env expression, the fusion and cell-to-cell transfer capacities as well as viral infectivity. The sequence and phylogenetic analysis of Envs were also performed. In every functional characteristic, the Envs from subjects with viral control (LTNP-ECs and vLTNPs) showed significant lower performance compared to those from the progressor individuals (Old and Modern). Regarding sequence analysis, the variable loops of the gp120 subunit of the Env (i.e., V2, V4 and mainly V5) of the progressor individuals showed longer and more glycosylated sequences than controller subjects. Therefore, HIV-1 Envs presenting poor viral functions and shorter sequences were associated with viremic control and the non-progressor clinical phenotype, whereas functional Envs were associated with the lack of virological control and progressor clinical phenotypes. These correlations support the central role of Env genotypic and phenotypic characteristics in the in vivo HIV-1 infection and pathogenesis.

scholarly journals Gag-Specific Cellular Immunity DeterminesIn VitroViral Inhibition andIn VivoVirologic Control following Simian Immunodeficiency Virus Challenges of Vaccinated Rhesus Monkeys

2012 ◽  
Vol 86 (18) ◽  
pp. 9583-9589 ◽  
Author(s):  
Kathryn E. Stephenson ◽  
Hualin Li ◽  
Bruce D. Walker ◽  
Nelson L. Michael ◽  
Dan H. Barouch
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Monkeys ◽  
Viral Inhibition ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Virologic Control ◽  
Cellular Immune ◽  
Hiv 1

A comprehensive vaccine for human immunodeficiency virus type 1 (HIV-1) would block HIV-1 acquisition as well as durably control viral replication in breakthrough infections. Recent studies have demonstrated that Env is required for a vaccine to protect against acquisition of simian immunodeficiency virus (SIV) in vaccinated rhesus monkeys, but the antigen requirements for virologic control remain unclear. Here, we investigate whether CD8+T lymphocytes from vaccinated rhesus monkeys mediate viral inhibitionin vitroand whether these responses predict virologic control following SIV challenge. We observed that CD8+lymphocytes from 23 vaccinated rhesus monkeys inhibited replication of SIVin vitro. Moreover, the magnitude of inhibition prior to challenge was inversely correlated with set point SIV plasma viral loads after challenge. In addition, CD8 cell-mediated viral inhibition in vaccinated rhesus monkeys correlated significantly with Gag-specific, but not Pol- or Env-specific, CD4+and CD8+T lymphocyte responses. These findings demonstrate thatin vitroviral inhibition following vaccination largely reflects Gag-specific cellular immune responses and correlates within vivovirologic control following infection. These data suggest the importance of including Gag in an HIV-1 vaccine in which virologic control is desired.

scholarly journals Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART

2017 ◽  
Vol 114 (18) ◽  
pp. E3659-E3668 ◽  
Author(s):  
Ann Wiegand ◽  
Jonathan Spindler ◽  
Feiyu F. Hong ◽  
Wei Shao ◽  
Joshua C. Cyktor ◽  
...  
Keyword(s):  
Single Cell ◽  
Mononuclear Cells ◽  
Single Cells ◽  
Constitutive Expression ◽  
Multiple Time ◽  
Hiv Rna ◽  
Infected Cells ◽  
The Impact ◽  
Hiv 1

Little is known about the fraction of human immunodeficiency virus type 1 (HIV-1) proviruses that express unspliced viral RNA in vivo or about the levels of HIV RNA expression within single infected cells. We developed a sensitive cell-associated HIV RNA and DNA single-genome sequencing (CARD-SGS) method to investigate fractional proviral expression of HIV RNA (1.3-kb fragment of p6, protease, and reverse transcriptase) and the levels of HIV RNA in single HIV-infected cells from blood samples obtained from individuals with viremia or individuals on long-term suppressive antiretroviral therapy (ART). Spiking experiments show that the CARD-SGS method can detect a single cell expressing HIV RNA. Applying CARD-SGS to blood mononuclear cells in six samples from four HIV-infected donors (one with viremia and not on ART and three with viremia suppressed on ART) revealed that an average of 7% of proviruses (range: 2–18%) expressed HIV RNA. Levels of expression varied from one to 62 HIV RNA molecules per cell (median of 1). CARD-SGS also revealed the frequent expression of identical HIV RNA sequences across multiple single cells and across multiple time points in donors on suppressive ART consistent with constitutive expression of HIV RNA in infected cell clones. Defective proviruses were found to express HIV RNA at levels similar to those proviruses that had no obvious defects. CARD-SGS is a useful tool to characterize fractional proviral expression in single infected cells that persist despite ART and to assess the impact of experimental interventions on proviral populations and their expression.

scholarly journals Direct Evidence of Lower Viral Replication Rates In Vivo in Human Immunodeficiency Virus Type 2 (HIV-2) Infection than in HIV-1 Infection

2007 ◽  
Vol 81 (10) ◽  
pp. 5325-5330 ◽  
Author(s):  
Adam MacNeil ◽  
Abdoulaye Dieng Sarr ◽  
Jean-Louis Sankalé ◽  
Seema Thakore Meloni ◽  
Souleymane Mboup ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Mrna ◽  
Viral Dna ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Studies have shown that human immunodeficiency virus type 2 (HIV-2) is less pathogenic than HIV-1, with a lower rate of disease progression. Similarly, plasma viral loads are lower in HIV-2 infection, suggesting that HIV-2 replication is restricted in vivo in comparison to that of HIV-1. However, to date, in vivo studies characterizing replication intermediates in the viral life cycle of HIV-2 have been limited. In order to test the hypothesis that HIV-2 has a lower replication rate in vivo than HIV-1 does, we quantified total viral DNA, integrated proviral DNA, cell-associated viral mRNA, and plasma viral loads in peripheral blood samples from groups of therapy-naïve HIV-1-infected (n = 21) and HIV-2-infected (n = 18) individuals from Dakar, Senegal, with CD4+ T-cell counts of >200/μl. Consistent with our previous findings, total viral DNA loads were similar between HIV-1 and HIV-2 and plasma viral loads were higher among HIV-1-infected individuals. Proportions of DNA in the integrated form were also similar between these viruses. In contrast, levels of viral mRNA were lower in HIV-2 infection. Our study indicates that HIV-2 is able to establish a stable, integrated proviral infection in vivo, but that accumulation of viral mRNA is attenuated in HIV-2 infection relative to that in HIV-1 infection. The differences in viral mRNA are consistent with the differences in plasma viral loads between HIV-1 and HIV-2 and suggest that lower plasma viral loads, and possibly the attenuated pathogenesis of HIV-2, can be explained by lower rates of viral replication in vivo.

scholarly journals Increased Neutralization Sensitivity and Reduced Replicative Capacity of Human Immunodeficiency Virus Type 1 after Short-Term In Vivo or In Vitro Passage through Chimpanzees

2000 ◽  
Vol 74 (17) ◽  
pp. 7699-7707 ◽  
Author(s):  
Tim Beaumont ◽  
Silvia Broersen ◽  
Ad van Nuenen ◽  
Han G. Huisman ◽  
Ana-Maria de Roda Husman ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Short Term ◽  
Neutralization Sensitivity ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Development of disease is extremely rare in chimpanzees when inoculated with either T-cell-line-adapted neutralization-sensitive or primary human immunodeficiency virus type 1 (HIV-1), at first excluding a role for HIV-1 neutralization sensitivity in the clinical course of infection. Interestingly, we observed that short-term in vivo and in vitro passage of primary HIV-1 isolates through chimpanzee peripheral blood mononuclear cells (PBMC) resulted in a neutralization-sensitive phenotype. Furthermore, an HIV-1 variant reisolated from a chimpanzee 10 years after experimental infection was still sensitive to neutralization by soluble CD4, the CD4 binding site recognizing antibody IgG1b12 and autologous chimpanzee serum samples, but had become relatively resistant to neutralization by polyclonal human sera and neutralizing monoclonal antibodies. The initial adaptation of HIV-1 to replicate in chimpanzee PBMC seemed to coincide with a selection for viruses with low replicative kinetics. Neither coreceptor usage nor the expression level of CD4, CCR5, or CXCR4 on chimpanzee PBMC compared to human cells could explain the phenotypic changes observed in these chimpanzee-passaged viruses. Our data suggest that the increased neutralization sensitivity of HIV-1 after replication in chimpanzee cells may in part contribute to the long-term asymptomatic HIV-1 infection in experimentally infected chimpanzees.

Photopheresis in HIV-1 Infected Patients (pt) using Benzoporphyrin Derivative (BPD-MA) Induces Apoptosis in CD4 Cells, Increases Intracellular Expression of Chemokines and Decreases HIV Infectivity and Viral Load.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3836-3836
Author(s):  
Zale P. Bernstein ◽  
Thomas Dougherty ◽  
Stanley A. Schwartz ◽  
Sandra Gollnick ◽  
Carleton Stewart ◽  
...  
Keyword(s):  
Viral Load ◽  
Immune System ◽  
Ex Vivo ◽  
Light Exposure ◽  
Area Under The Curve ◽  
Additional Patient ◽  
Viral Control ◽  
Viral Loads ◽  
Hiv 1

Abstract HIV is able to elude both cellular and humoral arms of the immune system; thereby making viral control difficult. Extra corporeal photochemotherapy (ECP) or photopheresis is an immunomodulatory therapy in which lymphocytes are reinfused into the host after exposure to a photoactive compound and ultraviolet A light. It is an effective therapeutic approach to several disorders of the immune system including acute and chronic graft-versus-host disease, scleroderma, and cutaneous T-cell lymphoma. This process may offer a novel approach to viral control with minimal or no toxicity. We initiated an ex vivo and subsequently a clinical pilot trial utilizing Benzoporphyrin Derivative as the photosensitive compound. Ex vivo dosing studies identified the minimum energy levels of light exposure and concentrations of BPD that eradicated both cell-free and cell-associated HIV-1 infectivity without destroying the virus particles or infected leukocytes. Leukocytes so treated remained viable. They did demonstrate altered cytokine and chemokine expression with apoptosis induced in a minority of CD4 but not CD8 positive cells. A pilot in vivo, 24 week clinical trial in seven HIV-1 infected patients (all were required, upon entry, to have viral loads of > 10,000) using the photopheresis parameters established above demonstrated that the treatment was well tolerated and beneficial. Three individuals who had rapidly rising viral loads prior to initiating therapy stabilized once treatment began. Two of which had a (sustained) greater than.5 log decrement and 5 had stable plasma viral loads (less than a.5 log increment or decrement) with varied effects on absolute CD4 and CD8 positive lymphocytes counts. One subject achieved a greater than 1 log decrement in HIV-1 plasma viral load also developed undetectable in vivo cell-free and cell-associated HIV-1 infectivity while demonstrating an increased in vitro lymphocyte mitogen stimulation index. Subsequently, under amended protocol 3 additional 12 month courses were administered to one additional patient and two of the previous enrollees. The area under the curve for viral load (viral load x # of weeks) for these ten courses of therapy showed a significant decrease from pre to post therapy (p 0.007). There were no significant changes in CD4 or CD8 numbers area under the curve (CD4 number # of weeks and CD8 number x # of weeks). None of the subjects developed an AIDS defining illness during the course of therapy nor were there any treatment associated toxicities. These studies suggest that ECP augments activity of various arms of the immune system without any significant toxicity and may be effective in controlling HIV replication. We have now instituted a Phase II study utilizing long-term photopheresis (twice monthly for 48 weeks) to further determine efficacy and mechanism of activity.

Photopheresis in HIV-1 Infected Patients (Pt) Using Benzoporphyrin Derivative (BPD-MA) Induces Apoptosis in CD4 Cells, Increases Cytolytic T-Cell Activity, Intracellular Expression of Chemokines, and Decreases HIV Infectivity and Viral Load.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1257-1257
Author(s):  
Zale P. Bernstein ◽  
Thomas Dougherty ◽  
Stanley Schwartz ◽  
Sandra Gollnick ◽  
Carleton Stewart ◽  
...  
Keyword(s):  
Viral Load ◽  
Immune System ◽  
T Cell ◽  
Ex Vivo ◽  
Cell Activity ◽  
Area Under The Curve ◽  
Viral Control ◽  
Viral Loads ◽  
Hiv 1

Abstract HIV is able to elude both cellular and humoral arms of the immune system; thereby making viral control difficult. Extra corporeal photochemotherapy (ECP) or photopheresis is an immunomodulatory therapy in which lymphocytes are reinfused into the host after exposure to a photoactive compound and ultraviolet A light. It is an effective therapeutic approach to several disorders of the immune system including acute and chronic graft-versus-host disease, scleroderma, and cutaneous T-cell lymphoma. This process may offer a novel approach to viral control with minimal or no toxicity. We initiated an ex vivo and subsequently a clinical pilot trial utilizing Benzoporphyrin Derivative as the photosensitive compound. Ex vivo dosing studies identified the minimum energy levels of light exposure and concentrations of BPD that eradicated both cell-free and cell-associated HIV-1 infectivity without destroying the virus particles or infected leukocytes. Leukocytes so treated remained viable. They did demonstrate altered cytokine and chemokine expression with apoptosis induced in a minority of CD4 but not CD8 positive cells. Furthermore, there was a statistically significant increase in cytolytic T-cell activity expressed as percentage of granzyme-B release. A pilot in vivo, 24 week clinical trial in seven HIV-1 infected patients (all were required, upon entry, to have viral loads of &gt; 10,000) using the photopheresis parameters established above demonstrated that the treatment was well tolerated and beneficial. Three individuals who had rapidly rising viral loads prior to initiating therapy stabilized once treatment began. Two of which had a (sustained) greater than .5 log decrement and 5 had stable plasma viral loads (less than a .5 log increment or decrement) with varied effects on absolute CD4 and CD8 positive lymphocytes counts. One subject achieved a greater than 1 log decrement in HIV-1 plasma viral load also developed undetectable in vivo cell-free and cell-associated HIV-1 infectivity while demonstrating an increased in vitro lymphocyte mitogen stimulation index. Subsequently, under amended and successor protocol 5 additional 12 month courses were administered to three additional patients and two of the previous enrollees. The area under the curve for viral load (viral load x # of weeks) for these twelve courses of therapy showed a significant decrease from pre to post therapy (p 0.007). There were no significant changes in CD4 or CD8 numbers area under the curve (CD4 number # of weeks and CD8 number x # of weeks). None of the subjects developed an AIDS defining illness during the course of therapy nor were there any treatment associated toxicities. These studies suggest that ECP augments activity of various arms of the immune system without any significant toxicity and may be effective in controlling HIV replication. We now plan a randomized Phase II study utilizing long-term photopheresis (twice monthly for 48 weeks) in addition to anti-retroviral therapy versus anti-retroviral therapy alone to further determine efficacy and mechanism of activity.

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