Presence of CXCR4-Using HIV-1 in Patients With Recently Diagnosed Infection: Correlates and Evidence for Transmission

Chalmet, Kristen; Dauwe, Kenny; Foquet, Lander; Baatz, Franky; Seguin-Devaux, Carole; Gucht, Beatrijs Van Der; Vogelaers, Dirk; Vandekerckhove, Linos; Plum, Jean; Verhofstede, Chris

doi:10.1093/infdis/jir714

Cited by 78 publications

(84 citation statements)

References 48 publications

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“…Several previously reported studies used deep sequencing to predict HIV-1 coreceptor usage by sequencing of the HIV-1 env V3 region (26,(45)(46)(47)(48). Most of those studies used 454 sequencing, which was limited by homopolymer errors and relative low throughput compared to the Illumina or IonTorrent platform (25).…”

Section: Discussionmentioning

confidence: 99%

Deep Sequencing of the HIV-1 env Gene Reveals Discrete X4 Lineages and Linkage Disequilibrium between X4 and R5 Viruses in the V1/V2 and V3 Variable Regions

Zhou

Bednar

Sturdevant

et al. 2016

J Virol

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HIV-1 requires the CD4 receptor and a coreceptor (CCR5 [R5 phenotype] or CXCR4 [X4 phenotype]) to enter cells. Coreceptor tropism can be assessed by either phenotypic or genotypic analysis, the latter using bioinformatics algorithms to predict tropism based on the env V3 sequence. We used the Primer ID sequencing strategy with the MiSeq sequencing platform to reveal the structure of viral populations in the V1/V2 and C2/V3 regions of the HIV-1 env gene in 30 late-stage and 6 early-stage subjects. We also used endpoint dilution PCR followed by cloning of env genes to create pseudotyped virus to explore the link between genotypic predictions and phenotypic assessment of coreceptor usage. We found out that the most stringently sequence-based calls of X4 variants (Geno2Pheno false-positive rate [FPR] of <2%) formed distinct lineages within the viral population, and these were detected in 24 of 30 late-stage samples (80%), which was significantly higher than what has been seen previously by using other approaches. Non-X4 lineages were not skewed toward lower FPR scores in X4-containing populations. Phenotypic assays showed that variants with an intermediate FPR (2 to 20%) could be either X4/dual-tropic or R5 variants, although the X4 variants made up only about 25% of the lineages with an FPR of <10%, and these variants carried a distinctive sequence change. Phylogenetic analysis of both the V1/V2 and C2/V3 regions showed evidence of recombination within but very little recombination between the X4 and R5 lineages, suggesting that these populations are genetically isolated. IMPORTANCEPrimer ID sequencing provides a novel approach to study genetic structures of viral populations. X4 variants may be more prevalent than previously reported when assessed by using next-generation sequencing (NGS) and with a greater depth of sampling than single-genome amplification (SGA). Phylogenetic analysis to identify lineages of sequences with intermediate FPR values may provide additional information for accurately predicting X4 variants by using V3 sequences. Limited recombination occurs between X4 and R5 lineages, suggesting that X4 and R5 variants are genetically isolated and may be replicating in different cell types or that X4/R5 recombinants have reduced fitness. H uman immunodeficiency virus type 1 (HIV-1) requires the CD4 receptor and a coreceptor to infect host cells. Entry is mediated by the viral envelope protein (Env), which is processed to give two associated subunits, gp120 and gp41, that assemble into a trimeric structure embedded in the viral envelope/membrane. The binding of gp120 to CD4 triggers a structural change that exposes its variable region 3 (V3) loop, which is part of the coreceptor domain (1, 2). The majority of transmitted/founder (T/F) viruses and viruses isolated from the clinically latent stage in HIV-infected subjects use CCR5 as the coreceptor, making the virus CCR5 tropic (or an R5 virus). The virus can evolve to use CXCR4 (CXCR4 tropic [or an X4 virus]), and viruses that have switched core...

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Section: Discussionmentioning

confidence: 99%

Deep Sequencing of the HIV-1 env Gene Reveals Discrete X4 Lineages and Linkage Disequilibrium between X4 and R5 Viruses in the V1/V2 and V3 Variable Regions

Zhou

Bednar

Sturdevant

et al. 2016

J Virol

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“…Early in the course of infection, most HIV isolates utilize CCR5 (56,74,86); however, several recent reports have demonstrated that CXCR4-utilizing viral subpopulations are found in as many as 10 to 50% of recently infected individuals (1,14). In addition, CXCR4-utilizing viruses emerge in many patients later in the course of infection (55,66).…”

Section: Cd45romentioning

confidence: 99%

Latent HIV-1 Infection Occurs in Multiple Subsets of Hematopoietic Progenitor Cells and Is Reversed by NF-κB Activation

McNamara

Ganesh

Collins

2012

J Virol

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The ability of HIV-1 to establish a latent infection presents a barrier to curing HIV. The best-studied reservoir of latent virus in vivo is resting memory CD4 + T cells, but it has recently been shown that CD34 + hematopoietic progenitor cells (HPCs) can also become latently infected by HIV-1 in vitro and in vivo . CD34 + cells are not homogenous, however, and it is not yet known which types of CD34 + cells support a latent infection. Furthermore, the mechanisms through which latency is established in this cell type are not yet known. Here we report the development of a primary cell model for latent HIV-1 infection in HPCs. We demonstrate that in this model, latent infection can be established in all subsets of HPCs examined, including HPCs with cell surface markers consistent with immature hematopoietic stem and progenitor cells. We further show that the establishment of latent infection in these cells can be reversed by tumor necrosis factor alpha (TNF-α) through an NF-κB-dependent mechanism. In contrast, we do not find evidence for a role of positive transcription elongation factor b (P-TEFb) in the establishment of latent infection in HPCs. Finally, we demonstrate that prostratin and suberoylanilide hydroxamic acid (SAHA), but not hexamethylene bisacetamide (HMBA) or 5-aza-2′-deoxycytidine (Aza-CdR), reactivate latent HIV-1 in HPCs. These findings illuminate the mechanisms through which latent infection can be established in HPCs and suggest common pathways through which latent virus could be reactivated in both HPCs and resting memory T cells to eliminate latent reservoirs of HIV-1.

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“…This has made it possible to seek genotypic and phenotypic differences between T/F Env proteins and those derived from chronically infected individuals (chronic control [CC] Envs). Several phenotypic characteristics are clearly associated with transmission: T/F Envs virtually always use CCR5 rather than CXCR4 or other noncanonical coreceptors (2,(16)(17)(18) and generally infect T cells but not macrophages (2,13,15,19) as a result of requiring relatively high levels of CD4 to mediate virus entry (20)(21)(22)(23)(24)(25). Other phenotypic and genotypic traits that have been linked to transmission are less well defined: Envs isolated from acute infection have sometimes been reported to be more neutralization sensitive (19), have on average fewer putative N-linked glycosylation sites (1,26), and have shorter variable loops (1,(27)(28)(29) compared to Envs isolated from chronically infected individuals.…”

mentioning

confidence: 99%

Transmitted/Founder and Chronic HIV-1 Envelope Proteins Are Distinguished by Differential Utilization of CCR5

Parker

Iyer

Wilen

et al. 2013

J Virol

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Presence of CXCR4-Using HIV-1 in Patients With Recently Diagnosed Infection: Correlates and Evidence for Transmission

Cited by 78 publications

References 48 publications

Deep Sequencing of the HIV-1 env Gene Reveals Discrete X4 Lineages and Linkage Disequilibrium between X4 and R5 Viruses in the V1/V2 and V3 Variable Regions

Deep Sequencing of the HIV-1 env Gene Reveals Discrete X4 Lineages and Linkage Disequilibrium between X4 and R5 Viruses in the V1/V2 and V3 Variable Regions

Latent HIV-1 Infection Occurs in Multiple Subsets of Hematopoietic Progenitor Cells and Is Reversed by NF-κB Activation

Transmitted/Founder and Chronic HIV-1 Envelope Proteins Are Distinguished by Differential Utilization of CCR5

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