Increased replication capacity following evolution of PYxE insertion in Gag‐p6 is associated with enhanced virulence in HIV‐1 subtype C from East Africa

Aralaguppe, Shambhu G.; Winner, Dane; Singh, Kamalendra; Sarafianos, Stefan G.; Quiñones‐Mateu, Miguel E.; Sönnerborg, Anders; Neogi, Ujjwal

doi:10.1002/jmv.24610

Cited by 12 publications

(18 citation statements)

References 16 publications

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“…This correlation suggests that HIV-1C strains with a PYxE insertion have a growth advantage compared to wild type HIV-1C. This is also in line with our earlier study that HIV-1C PYQEi viruses are more replication competent as well as more pathogenic (17).…”

Section: Resultssupporting

confidence: 89%

“…Furthermore, the insertion appears more frequent among patients on antiretroviral therapy, e.g., ritonavir-boosted protease inhibitors (PI), compared to therapy naïve patients in India, and more frequent in therapy-failure patients in South Africa (15, 16). Moreover, lower pre-therapy CD4 + T cell counts, higher plasma viral loads, and reduced increase in CD4 + T cell counts were noted to be associated with PYxE insertion in HIV-1C patients compared to patients with wild type HIV-1C from East Africa (17). Furthermore, we observed that increased replication fitness in PYQE inserted HIV-1C viruses was polymerase independent (17).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, lower pre-therapy CD4 + T cell counts, higher plasma viral loads, and reduced increase in CD4 + T cell counts were noted to be associated with PYxE insertion in HIV-1C patients compared to patients with wild type HIV-1C from East Africa (17). Furthermore, we observed that increased replication fitness in PYQE inserted HIV-1C viruses was polymerase independent (17). A more recent study also claimed that gag-protease is the major determinant of subtype differences in disease progression among HIV-1 subtypes (18).…”

Section: Introductionmentioning

confidence: 99%

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HIV-1 subtype C with PYxE insertion has enhanced binding of Gag-p6 to host cell protein ALIX and increased replication fitness

Domselaar

Njenda

Rao

et al. 2018

Preprint

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Human immunodeficiency virus type 1 subtype C (HIV-1C) has a natural deletion of a YPxL motif in its Gag-p6 late domain. This domain mediates the binding of Gag to host cell protein ALIX and subsequently facilitates viral budding. In a subset of HIV-1C infected individuals, the tetrapeptide insertion PYxE has been identified at the deleted YPxL motif site. Here, we report the consequences of PYxE insertion on the interaction with ALIX and the relevance regarding replication fitness and drug sensitivity. In our three HIV-1C cohorts, PYKE and PYQE were most prevalent among PYxE variants. Through in silico predictions and in vitro experiments, we showed that HIV-1C Gag has an increased binding to ALIX when PYxE motif is present. To go more into the clinical relevance of the PYxE insertion, we obtained patient-derived gag-pol sequences from HIV-1C PYxEi viruses and inserted them in a reference HIV-1. Viral growth was increased, and the sensitivity to protease inhibitor (PI) lopinavir (LPV) and nucleoside reverse transcriptase inhibitor tenofovir alafenamide (TAF) was decreased for some of the HIV-1C PYxE variants compared to wild-type variants. Our data suggest that PYxE insertion in Gag restores the ability of Gag to bind ALIX and correlates with enhanced viral fitness in the absence or presence of LPV and TAF. The high prevalence and increased replication fitness of the HIV-1C virus with PYxE insertion could indicate the clinical importance of these viral variants.

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Section: Resultssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HIV-1 subtype C with PYxE insertion has enhanced binding of Gag-p6 to host cell protein ALIX and increased replication fitness

Domselaar

Njenda

Rao

et al. 2018

Preprint

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“…It is also of interest that an unusual mutant with deletion at residues 482 and 483, shown to disrupt Alix binding (68), was previously associated with nonprogressive HIV-1 infection (69), indicating that the ability to bind Alix may influence disease progression. Furthermore, it was recently described that a PYxE insertion (at the same position as the LY motif) in some East African subtype C isolates enhanced the replication capacity and virulence of these isolates compared to subtype C isolates without the insertion (70).…”

Section: Discussionmentioning

confidence: 99%

Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression

Kiguoya

Mann

Chopera

et al. 2017

J Virol

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There are marked differences in the spread and prevalence of HIV-1 subtypes worldwide, and differences in clinical progression have been reported. However, the biological reasons underlying these differences are unknown. Gag-protease is essential for HIV-1 replication, and Gag-protease-driven replication capacity has previously been correlated with disease progression. We show that Gag-protease replication capacity correlates significantly with that of whole isolates (r ϭ 0.51; P ϭ 0.04), indicating that Gag-protease is a significant contributor to viral replication capacity. Furthermore, we investigated subtype-specific differences in Gag-proteasedriven replication capacity using large well-characterized cohorts in Africa and the Americas. Patient-derived Gag-protease sequences were inserted into an HIV-1 NL4-3 backbone, and the replication capacities of the resulting recombinant viruses were measured in an HIV-1-inducible reporter T cell line by flow cytometry. Recombinant viruses expressing subtype C Gag-proteases exhibited substantially lower replication capacities than those expressing subtype B Gag-proteases (P Ͻ 0.0001); this observation remained consistent when representative Gag-protease sequences were engineered into an HIV-1 subtype C backbone. We identified Gag residues 483 and 484, located within the Alix-binding motif involved in virus budding, as major contributors to subtype-specific replicative differences. In East African cohorts, we observed a hierarchy of Gag-protease-driven replication capacities, i.e., subtypes A/C Ͻ D Ͻ intersubtype recombinants (P Ͻ 0.0029), which is consistent with reported intersubtype differences in disease progression. We thus hypothesize that the lower Gagprotease-driven replication capacity of subtypes A and C slows disease progression in individuals infected with these subtypes, which in turn leads to greater opportunity for transmission and thus increased prevalence of these subtypes.IMPORTANCE HIV-1 subtypes are unevenly distributed globally, and there are reported differences in their rates of disease progression and epidemic spread. The biological determinants underlying these differences have not been fully elucidated. Here, we show that HIV-1 Gag-protease-driven replication capacity correlates with Citation Kiguoya MW, Mann JK, Chopera D, Gounder K, Lee GQ, Hunt PW, Martin JN, Ball TB, Kimani J, Brumme ZL, Brockman MA, Ndung'u T. 2017. Subtype-specific differences in Gagprotease-driven replication capacity are consistent with intersubtype differences in HIV-1 disease progression. J Virol 91:e00253-17.

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“…For example, it has been hypothesized that HIV-1 subtype C isolates, which comprise more than >50% of infections worldwide (Hemelaar, 2012), may be inherently more transmissible - possibly because of subtype-specific motifs within Env-gp120 that modulate interactions with host cell entry receptors (Walter et al, 2009) - though this remains controversial (Kahle et al, 2014). Subtype-specific differences in HIV-1 entry efficiency (Marozsan et al, 2005), replication capacity (Aralaguppe et al, 2016; Konings et al, 2006), and the function of viral accessory proteins Vif (Binka et al, 2012; Iwabu et al, 2010) and Nef (Mann et al, 2013) have also been described. Methods to assess the function of other HIV-1 proteins encoded by natural sequences are thus warranted.…”

Section: Introductionmentioning

confidence: 99%

In vitro functional assessment of natural HIV-1 group M Vpu sequences using a universal priming approach

Rahimi

Anmole

Soto-Nava³

et al. 2017

Journal of Virological Methods

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The HIV-1 accessory protein Vpu exhibits high inter- and intra- subtype genetic diversity that may influence Vpu function and possibly contribute to HIV-1 pathogenesis. However, scalable methods to evaluate genotype/phenotype relationships in natural Vpu sequences are limited, particularly those expressing the protein in CD4+ T-cells, the natural target of HIV-1 infection. A major impediment to assay scalability is the extensive genetic diversity within, and immediately upstream of, Vpu's initial 5' coding region, which has necessitated the design of oligonucleotide primers specific for each individual HIV-1 isolate (or subtype). To address this, we developed two universal forward primers, located in relatively conserved regions 38 and 90 bases upstream of Vpu, and a single universal reverse primer downstream of Vpu, which are predicted to cover the vast majority of global HIV-1 group M sequence diversity. We show that inclusion of up to 90 upstream bases of HIV-1 genomic sequence does not significantly influence in vitro Vpu expression or function when a Rev/Rev Response Element (RRE)-dependent expression system is used. We further assess the function of four diverse HIV-1 Vpu sequences, revealing reproducible and significant differences between them. Our approach represents a scalable option to measure the in vitro function of genetically diverse natural Vpu isolates in a CD4+ T-cell line.

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Increased replication capacity following evolution of PYxE insertion in Gag‐p6 is associated with enhanced virulence in HIV‐1 subtype C from East Africa

Abstract: This is the first evidence of polymerase independent increased virulence and RC in HIV-1C following PYxE-insertion that is associated with suboptimal CD4 T-cell gain following therapy initiation. J. Med. Virol. 89:106-111, 2017. © 2016 Wiley Periodicals, Inc.

Cited by 12 publications

References 16 publications

HIV-1 subtype C with PYxE insertion has enhanced binding of Gag-p6 to host cell protein ALIX and increased replication fitness

HIV-1 subtype C with PYxE insertion has enhanced binding of Gag-p6 to host cell protein ALIX and increased replication fitness

Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression

In vitro functional assessment of natural HIV-1 group M Vpu sequences using a universal priming approach

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