Effect on HIV-1 viral replication capacity of DTG-resistance mutations in NRTI/NNRTI resistant viruses

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) evolves rapidly in response to host immune selection pressures. As a result, the functional properties of HIV-1 isolates from earlier in the epidemic may differ from those of isolates from later stages. However, few studies have investigated alterations in viral replication capacity (RC) over the epidemic. In the present study, we compare Gag-Protease-associated RC between early and late isolates in Japan (1994 to 2009). HIV-1 subtype B sequences from 156 antiretroviral-naïve Japanese with chronic asymptomatic infection were used to construct a chimeric NL4-3 strain encoding plasma-derivedgag-protease. Viral replication capacity was examined by infecting a long terminal repeat-driven green fluorescent protein-reporter T cell line. We observed a reduction in the RC of chimeric NL4-3 over the epidemic, which remained significant after adjusting for the CD4+T cell count and plasma virus load. The same outcome was seen when limiting the analysis to a single large cluster of related sequences, indicating that our results are not due to shifts in the molecular epidemiology of the epidemic in Japan. Moreover, the change in RC was independent of genetic distance between patient-derived sequences and wild-type NL4-3, thus ruling out potential temporal bias due to genetic similarity between patient and historic viral backbone sequences. Collectively, these data indicate that Gag-Protease-associated HIV-1 replication capacity has decreased over the epidemic in Japan. Larger studies from multiple geographical regions will be required to confirm this phenomenon.

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The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity

Journal of Virology ◽

10.1128/jvi.02904-13 ◽

2013 ◽

Vol 88 (3) ◽

pp. 1536-1547 ◽

Cited By ~ 10

Author(s):

H.-T. Xu ◽

S. P. Colby-Germinario ◽

M. Oliveira ◽

Y. Han ◽

Y. Quan ◽

...

Keyword(s):

Viral Replication ◽

Reverse Transcriptase ◽

Resistance Mutation ◽

Replication Capacity ◽

Viral Replication Capacity ◽

Hiv 1

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Impaired Replication Capacity of Acute/Early Viruses in Persons Who Become HIV Controllers

Journal of Virology ◽

10.1128/jvi.00286-10 ◽

2010 ◽

Vol 84 (15) ◽

pp. 7581-7591 ◽

Cited By ~ 93

Author(s):

Toshiyuki Miura ◽

Zabrina L. Brumme ◽

Mark A. Brockman ◽

Pamela Rosato ◽

Jennifer Sela ◽

...

Keyword(s):

Drug Resistance ◽

Viral Replication ◽

Acute Infection ◽

Viral Fitness ◽

Replication Capacity ◽

Transmitted Drug Resistance ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Hiv Controllers ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) controllers maintain viremia at <2,000 RNA copies/ml without antiretroviral therapy. Viruses from controllers with chronic infection were shown to exhibit impaired replication capacities, in part associated with escape mutations from cytotoxic-T-lymphocyte (CTL) responses. In contrast, little is known about viruses during acute/early infection in individuals who subsequently become HIV controllers. Here, we examine the viral replication capacities, HLA types, and virus sequences from 18 HIV-1 controllers identified during primary infection. g ag-protease chimeric viruses constructed using the earliest postinfection samples displayed significantly lower replication capacities than isolates from persons who failed to control viremia (P = 0.0003). Protective HLA class I alleles were not enriched in these early HIV controllers, but viral sequencing revealed a significantly higher prevalence of drug resistance mutations associated with impaired viral fitness in controllers than in noncontrollers (6/15 [40.0%] versus 10/80 [12.5%], P = 0.018). Moreover, of two HLA-B57-positive (B57+) controllers identified, both harbored, at the earliest time point tested, signature escape mutations within Gag that likewise impair viral replication capacity. Only five controllers did not express “protective” alleles or harbor viruses with drug resistance mutations; intriguingly, two of them displayed typical B57 signature mutations (T242N), suggesting the acquisition of attenuated viruses from B57+ donors. These data indicate that acute/early stage viruses from persons who become controllers have evidence of reduced replication capacity during the initial stages of infection which is likely associated with transmitted or acquired CTL escape mutations or transmitted drug resistance mutations. These data suggest that viral dynamics during acute infection have a major impact on HIV disease outcome.

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Viral Replication Capacity as a Correlate of HLA B57/B5801-Associated Nonprogressive HIV-1 Infection

The Journal of Immunology ◽

10.4049/jimmunol.179.5.3133 ◽

2007 ◽

Vol 179 (5) ◽

pp. 3133-3143 ◽

Cited By ~ 72

Author(s):

Marjon Navis ◽

Ingrid Schellens ◽

Debbie van Baarle ◽

José Borghans ◽

Peter van Swieten ◽

...

Keyword(s):

Viral Replication ◽

Replication Capacity ◽

Viral Replication Capacity ◽

Hiv 1

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HIV-1 Protease Codon 36 Polymorphisms and Differential Development of Resistance to Nelfinavir, Lopinavir, and Atazanavir in Different HIV-1 Subtypes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01828-09 ◽

2010 ◽

Vol 54 (7) ◽

pp. 2878-2885 ◽

Cited By ~ 17

Author(s):

Irene Lisovsky ◽

Susan M. Schader ◽

Jorge-Luis Martinez-Cajas ◽

Maureen Oliveira ◽

Daniela Moisi ◽

...

Keyword(s):

Viral Replication ◽

Resistance Mutation ◽

Fold Increase ◽

Replication Capacity ◽

Protease Gene ◽

Subtype C ◽

Phenotypic Analysis ◽

Subtype B ◽

Viral Replication Capacity ◽

Hiv 1

ABSTRACT The amino acid at position 36 of the HIV-1 protease differs among various viral subtypes, in that methionine is usually found in subtype B viruses but isoleucine is common in other subtypes. This polymorphism is associated with higher rates of treatment failure involving protease inhibitors (PIs) in non-subtype B-infected patients. To investigate this, we generated genetically homogeneous wild-type viruses from subtype B, subtype C, and CRF02_AG full-length molecular clones and showed that subtype C and CRF02_AG I36 viruses exhibited higher levels of resistance to various PIs than their respective M36 counterparts, while the opposite was observed for subtype B viruses. Selections for resistance with each variant were performed with nelfinavir (NFV), lopinavir (LPV), and atazanavir (ATV). Sequence analysis of the protease gene at week 35 revealed that the major NFV resistance mutation D30N emerged in NFV-selected subtype B viruses and in I36 subtype C viruses, despite polymorphic variation. A unique mutational pattern developed in subtype C M36 viruses selected with NFV or ATV. The presence of I47A in LPV-selected I36 CRF02_AG virus conferred higher-level resistance than L76V in LPV-selected M36 CRF02_AG virus. Phenotypic analysis revealed a >1,000-fold increase in NFV resistance in I36 subtype C NFV-selected virus with no apparent impact on viral replication capacity. Thus, the position 36 polymorphism in the HIV-1 protease appears to have a differential effect on both drug susceptibility and the viral replication capacity, depending on both the viral subtype and the drug being evaluated.

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HIV-1 Sequence Variation and Viral Replication Capacity

Multiple Testing Procedures with Applications to Genomics - Springer Series in Statistics ◽

10.1007/978-0-387-49317-6_11 ◽

2008 ◽

pp. 477-487

Keyword(s):

Viral Replication ◽

Sequence Variation ◽

Replication Capacity ◽

Viral Replication Capacity ◽

Hiv 1

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Multiple Testing and Data Adaptive Regression: An Application to HIV-1 Sequence Data.

Statistical Applications in Genetics and Molecular Biology ◽

10.2202/1544-6115.1110 ◽

2005 ◽

Vol 4 (1) ◽

Cited By ~ 2

Author(s):

Merrill D. Birkner ◽

Sandra E. Sinisi ◽

Mark J. van der Laan

Keyword(s):

Viral Replication ◽

Multiple Testing ◽

Sequence Data ◽

Replication Capacity ◽

Multiple Testing Procedure ◽

Testing Procedures ◽

Multiple Testing Procedures ◽

Viral Replication Capacity ◽

Data Adaptive ◽

Hiv 1

Analysis of viral strand sequence data and viral replication capacity could potentially lead to biological insights regarding the replication ability of HIV-1. Determining specific target codons on the viral strand will facilitate the manufacturing of target-specific antiretrovirals. Various algorithmic and analysis techniques can be applied to this application. In this paper, we apply two techniques to a data set consisting of 317 patients, each with 282 sequenced protease and reverse transcriptase codons. The first application is recently developed multiple testing procedures to find codons which have significant univariate associations with the replication capacity of the virus. A single-step multiple testing procedure (Pollard and van der Laan 2003) method was used to control the family wise error rate (FWER) at the five percent alpha level as well as the application of augmentation multiple testing procedures to control the generalized family wise error (gFWER) or the tail probability of the proportion of false positives (TPPFP). We also applied a data adaptive multiple regression algorithm to obtain a prediction of viral replication capacity based on an entire mutant/non-mutant sequence profile. This is a loss-based, cross-validated Deletion/Substitution/Addition regression algorithm (Sinisi and van der Laan 2004), which builds candidate estimators in the prediction of a univariate outcome by minimizing an empirical risk. These methods are two separate techniques with distinct goals used to analyze this structure of viral data.

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Persistence of frequently transmitted drug-resistant HIV-1 variants can be explained by high viral replication capacity

Retrovirology ◽

10.1186/s12977-014-0105-9 ◽

2014 ◽

Vol 11 (1) ◽

Cited By ~ 11

Author(s):

Marieke Pingen ◽

Annemarie MJ Wensing ◽

Katrien Fransen ◽

Annelies De Bel ◽

Dorien de Jong ◽

...

Keyword(s):

Viral Replication ◽

Replication Capacity ◽

Drug Resistant ◽

Viral Replication Capacity ◽

Hiv 1

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Role of the K101E Substitution in HIV-1 Reverse Transcriptase in Resistance to Rilpivirine and Other Nonnucleoside Reverse Transcriptase Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01536-13 ◽

2013 ◽

Vol 57 (11) ◽

pp. 5649-5657 ◽

Cited By ~ 9

Author(s):

Hong-Tao Xu ◽

Susan P. Colby-Germinario ◽

Wei Huang ◽

Maureen Oliveira ◽

Yingshan Han ◽

...

Keyword(s):

Viral Replication ◽

Reverse Transcriptase ◽

Salt Bridge ◽

Transcriptase Inhibitor ◽

Drug Susceptibility ◽

Replication Capacity ◽

Nonnucleoside Reverse Transcriptase Inhibitor ◽

Viral Replication Capacity ◽

The Impact ◽

Hiv 1

ABSTRACTResistance to the recently approved nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV) commonly involves substitutions at positions E138K and K101E in HIV-1 reverse transcriptase (RT), together with an M184I substitution that is associated with resistance to coutilized emtricitabine (FTC). Previous biochemical and virological studies have shown that compensatory interactions between substitutions E138K and M184I can restore enzyme processivity and the viral replication capacity. Structural modeling studies have also shown that disruption of the salt bridge between K101 and E138 can affect RPV binding. The current study was designed to investigate the impact of K101E, alone or in combination with E138K and/or M184I, on drug susceptibility, viral replication capacity, and enzyme function. We show here that K101E can be selected in cell culture by the NNRTIs etravirine (ETR), efavirenz (EFV), and dapivirine (DPV) as well as by RPV. Recombinant RT enzymes and viruses containing K101E, but not E138K, were highly resistant to nevirapine (NVP) and delavirdine (DLV) as well as ETR and RPV, but not EFV. The addition of K101E to E138K slightly enhanced ETR and RPV resistance compared to that obtained with E138K alone but restored susceptibility to NVP and DLV. The K101E substitution can compensate for deficits in viral replication capacity and enzyme processivity associated with M184I, while M184I can compensate for the diminished efficiency of DNA polymerization associated with K101E. The coexistence of K101E and E138K does not impair either viral replication or enzyme fitness. We conclude that K101E can play a significant role in resistance to RPV.

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