An in vitro Model to Mimic Selection of Replication-Competent HIV-1 Intersubtype Recombination in Dual or Superinfected Patients

Bagaya, Bernard S.; Tian, Mingxing; Nickel, Gabrielle C.; Vega, José F.; Li, Yuejin; Ping, He; Klein, Katja; Mann, J. Adin; Jiang, Wei; Arts, Eric J.; Gao, Yong

doi:10.1016/j.jmb.2017.04.016

Cited by 5 publications

(4 citation statements)

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“…Hence, even if recombination among subtypes has no net effect on virus fitness, it is reasonable for recombinants of particular subtypes (e.g., A and D) to be, on average, less fit or more fit than their respective parental variants. Several groups have constructed inter-subtype recombinants and performed functional assays or competitive growth experiments in vitro against the parental strains [38, 39]. Overall, the experimental results are equivocal with some recombinants displaying a slight but significant fitness advantage over the parental strains, while other recombinants are less fit [40].…”

Section: Discussionmentioning

confidence: 99%

First-line HIV treatment failures in non-B subtypes and recombinants: a cross-sectional analysis of multiple populations in Uganda

Poon¹,

Ndashimye²,

Avino³

et al. 2019

AIDS Res Ther

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BackgroundOur understanding of HIV-1 and antiretroviral treatment (ART) is strongly biased towards subtype B, the predominant subtype in North America and western Europe. Efforts to characterize the response to first-line treatments in other HIV-1 subtypes have been hindered by the availability of large study cohorts in resource-limited settings. To maximize our statistical power, we combined HIV-1 sequence and clinical data from every available study population associated with the Joint Clinical Research Centre (JCRC) in Uganda. These records were combined with contemporaneous ART-naive records from Uganda in the Stanford HIVdb database.MethodsTreatment failures were defined by the presence of HIV genotype records with sample collection dates after the ART start dates in the JCRC database. Drug resistances were predicted by the Stanford HIVdb algorithm, and HIV subtype classification and recombination detection was performed with SCUEAL. We used Bayesian network analysis to evaluate associations between drug exposures and subtypes, and binomial regression for associations with recombination.ResultsThis is the largest database of first-line treatment failures () in Uganda to date, with a predicted statistical power of 80% to detect subtype associations at an odds ratio of . In the subset where drug regimen data were available, we observed that use of 3TC was associated with a higher rate of first line treatment failure, whereas regimens containing AZT and TDF were associated with reduced rates of failure. In the complete database, we found limited evidence of associations between HIV-1 subtypes and treatment failure, with the exception of a significantly lower frequency of failures among A/D recombinants that comprised about 7% of the population. First-line treatment failure was significantly associated with reduced numbers of recombination breakpoints across subtypes.ConclusionsExpanding access to first-line ART should confer the anticipated public health benefits in Uganda, despite known differences in the pathogenesis of HIV-1 subtypes. Furthermore, the impact of ART may actually be enhanced by frequent inter-subtype recombination in this region.Electronic supplementary materialThe online version of this article (10.1186/s12981-019-0218-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

First-line HIV treatment failures in non-B subtypes and recombinants: a cross-sectional analysis of multiple populations in Uganda

Poon¹,

Ndashimye²,

Avino³

et al. 2019

AIDS Res Ther

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“…In contrast to an abundance of field data, few experimental data are available concerning NoV recombination and the mechanism(s) involved remain poorly characterised [ 26 , 28 , 29 , 30 , 50 ]. An incremental step in the generation of any recombinant viral RNA and consequently any viable recombinant virus is the successful simultaneous infection of a single cell by (a minimum of) two viruses [ 32 , 33 , 34 , 35 ]. Under natural conditions, various environmental, host, and virus factors may influence the probability of synchronous coinfections and may determine the delay or even the absolute achievability of asynchronous cellular superinfections.…”

Section: Discussionmentioning

confidence: 99%

“…Following this, host coinfection, single cell coinfection, and recombination must be accomplished to generate a recombinant NoV RNA. An incipient recombinant viruses must then survive a process of functional selection to be maintained in the viral population [ 32 , 33 , 34 , 35 ]. The rise of recombinant viruses resulting from this process is influenced by different factors.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Synchronous and Asynchronous In Vitro Infections with Homologous Murine Norovirus Strains Reveals Time-Dependent Viral Interference Effects

Ludwig‐Begall

Felice

Toffoli

et al. 2021

Viruses

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Viral recombination is a key mechanism in the evolution and diversity of noroviruses. In vivo, synchronous single-cell coinfection by multiple viruses, the ultimate prerequisite to viral recombination, is likely to be a rare event and delayed secondary infections are a more probable occurrence. Here, we determine the effect of a temporal separation of in vitro infections with the two homologous murine norovirus strains MNV-1 WU20 and CW1 on the composition of nascent viral populations. WU20 and CW1 were either synchronously inoculated onto murine macrophage cell monolayers (coinfection) or asynchronously applied (superinfection with varying titres of CW1 at half-hour to 24-h delays). Then, 24 h after initial co-or superinfection, quantification of genomic copy numbers and discriminative screening of plaque picked infectious progeny viruses demonstrated a time-dependent predominance of primary infecting WU20 in the majority of viral progenies. Our results indicate that a time interval from one to two hours onwards between two consecutive norovirus infections allows for the establishment of a barrier that reduces or prevents superinfection.

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“…We asked whether the alteration of Phe 317 to the less-common tyrosine residue would alter CD4mc sensitivity in other HIV-1 strains. We introduced the F317Y change into the Envs of HIV-1 191084 , another clade A virus, and HIV-1 CRF02_AG253.11 , a Tier-3 clade AG recombinant virus (69,(73)(74)(75). In both HIV-1 strains, the F317Y change resulted in increased sensitivity to the CD4mcs (Fig.…”

Section: The Gp120 V3 Loop As a Determinant Of Cd4mc Susceptibility T...mentioning

confidence: 99%

V3 tip determinants of susceptibility to inhibition by CD4-mimetic compounds in natural clade A human immunodeficiency virus (HIV-1) envelope glycoproteins

Anang,

Zhang,

Fritschi

et al. 2023

Preprint

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CD4-mimetic compounds (CD4mcs) bind the human immunodeficiency virus (HIV-1) gp120 exterior envelope glycoprotein (Env) and compete for binding to CD4, the host receptor. CD4mcs prematurely trigger conformational changes in Env similar to those induced by CD4, leading to transient activation of infectivity followed by irreversible virus inactivation. Natural HIV-1 variants exhibit a wide range of susceptibilities to CD4mc inhibition, only a small fraction of which can be explained by variation in the gp120 Phe-43 cavity/vestibule where CD4mcs bind. Here, we study Envs from the resistant HIV-1BG505and the more sensitive HIV-1191955_A4clade A strains. The major determinant of the relative sensitivity of the HIV-1191955_A4Env to CD4mcs mapped to a single residue change (F317Y) in the tip of the gp120 V3 variable loop. In the Envs of several HIV-1 strains, replacement of the more prevalent Phe 317 with a tyrosine residue increased virus sensitivity to multiple CD4mcs. Tryptophan substitutions at residues 317 and 316 resulted in increases and decreases, respectively, in sensitivity to CD4mcs. Some of the gp120 V3 changes increased virus sensitivity to inactivation by both CD4mc and cold exposure, phenotypes indicative of increased Env triggerability. Infection of CD4-negative cells expressing the CCR5 coreceptor by these Env variants was triggered more efficiently by CD4mcs. For the panel of studied HIV-1 Envs, resistance to the CD4mcs was associated with decreased ability to support virus entry. These studies illustrate how variation in gp120 outside the CD4mc binding site can influence the sensitivity of natural HIV-1 strains to inhibition by these compounds.

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An in vitro Model to Mimic Selection of Replication-Competent HIV-1 Intersubtype Recombination in Dual or Superinfected Patients

Cited by 5 publications

References 46 publications

First-line HIV treatment failures in non-B subtypes and recombinants: a cross-sectional analysis of multiple populations in Uganda

First-line HIV treatment failures in non-B subtypes and recombinants: a cross-sectional analysis of multiple populations in Uganda

Analysis of Synchronous and Asynchronous In Vitro Infections with Homologous Murine Norovirus Strains Reveals Time-Dependent Viral Interference Effects

V3 tip determinants of susceptibility to inhibition by CD4-mimetic compounds in natural clade A human immunodeficiency virus (HIV-1) envelope glycoproteins

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