Differential Vpu-Mediated CD4 and Tetherin Downregulation Functions among Major HIV-1 Group M Subtypes

Umviligihozo, Gisele; Cobarrubias, Kyle D.; Chandrarathna, Sandali; Jin, Steven; Reddy, Nicole; Byakwaga, Helen; Muzoora, Conrad; Bwana, Mwebesa; Lee, Guinevere Q.; Hunt, Peter W.; Martin, Jeff; Brumme, Chanson J.; Bangsberg, David R.; Karita, Etienne; Allen, Susan; Hunter, Eric; Ndung’u, Thumbi; Brumme, Zabrina L.; Brockman, Mark A.

doi:10.1128/jvi.00293-20

Cited by 6 publications

(10 citation statements)

References 55 publications

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“…Control plasma samples were obtained from participants of the Heterosexual Transmission [HT] study in Kigali, Rwanda. Previously-generated Vpu ( 27 ) and Nef ( 28 ) clones from participants of the Uganda AIDS Rural Treatment Outcomes [UARTO] study in Mbarara, Uganda were also included as controls. All participants provided written informed consent prior to enrolment.…”

Section: Methodsmentioning

confidence: 99%

“…HIV-1 RNA was extracted from plasma using the NucliSENS EasyMag system (bioMérieux). The nef and vpu coding regions were amplified by reverse transcription-polymerase chain reaction (RT-PCR) using the Superscript III one-step RT-PCR system with Platinum Taq HiFi (Invitrogen) as described previously for Nef ( 28 , 29 ) and Vpu ( 27 ). First-round amplicons were subjected to a nested second-round PCR reaction using the Expand High-Fidelity Plus PCR system (Roche) and primers containing AscI and SacII restriction enzyme sites to facilitate cloning.…”

Section: Methodsmentioning

confidence: 99%

“…Nef and vpu sequences from LTS and a subset of Nef controls have been submitted to GenBank accession numbers ON044919 - ON044988 . Control nef sequences with accession numbers KC906733-KC907077 ( 28 ) and control vpu sequences with accession numbers MT116441-MT116772 ( 27 ) were deposited in GenBank previously. All clone sequences are provided in the Supplementary Data File; Tables S1 and S2 .…”

Section: Methodsmentioning

confidence: 99%

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Attenuated HIV-1 Nef But Not Vpu Function in a Cohort of Rwandan Long-Term Survivors

Umviligihozo

Mann²,

Jin³

et al. 2022

Front. Virol.

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HIV-1 accessory proteins Nef and Vpu enhance viral pathogenesis through partially overlapping immune evasion activities. Attenuated Nef or Vpu functions have been reported in individuals who display slower disease progression, but few studies have assessed the relative impact of these proteins in non-B HIV-1 subtypes or examined paired proteins from the same individuals. Here, we examined the sequence and function of matched Nef and Vpu clones isolated from 29 long-term survivors (LTS) from Rwanda living with HIV-1 subtype A and compared our results to those of 104 Nef and 62 Vpu clones isolated from individuals living with chronic untreated HIV-1 subtype A from the same geographic area. Nef and vpu coding regions were amplified from plasma HIV RNA and cloned. The function of one intact, phylogenetically-validated Nef and Vpu clone per individual was then quantified by flow cytometry following transient expression in an immortalized CD4+ T-cell line. We measured the ability of each Nef clone to downregulate CD4 and HLA class I, and of each Vpu clone to downregulate CD4 and Tetherin, from the cell surface. Results were normalized to reference clones (Nef-SF2 and Vpu-NL4.3). We observed that Nef-mediated CD4 and HLA downregulation functions were lower in LTS compared to the control cohort (Mann-Whitney p=0.03 and p<0.0001, respectively). Moreover, we found a positive correlation between Nef-mediated CD4 downregulation function and plasma viral load in LTS and controls (Spearman ρ= 0.59, p=0.03 and ρ=0.30, p=0.005, respectively). In contrast, Vpu-mediated functions were similar between groups and did not correlate with clinical markers. Further analyses identified polymorphisms at Nef codon 184 and Vpu codons 60-62 that were associated with function, which were confirmed through mutagenesis. Overall, our results support attenuated function of Nef, but not Vpu, as a contributor to slower disease progression in this cohort of long-term survivors with HIV-1 subtype A.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Attenuated HIV-1 Nef But Not Vpu Function in a Cohort of Rwandan Long-Term Survivors

Umviligihozo

Mann²,

Jin³

et al. 2022

Front. Virol.

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“…This has been shown to be mediated by the HIV accessory proteins Vpu and Nef. [114][115][116] It is thought that downregulating CD4, and the co-receptors CXCR4 and CCR5, in the host cell will prevent superinfection and aid in incorporation of Env protein into the virions at the time of budding by preventing Env-CD4 interactions. 115,116 Downregulation of surface MHC class I is namely mediated by HIV protein Nef via endocytic vesicles and sequestration of molecules being transported to the surface.…”

Section: Key Receptors: Decisive Pointmentioning

confidence: 99%

SARS-CoV-2 and Human Immunodeficiency Virus: Pathogen Pincer Attack

Evans¹,

Martínez²,

Petrosillo³

et al. 2021

HIV

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Paramount efforts worldwide are seeking to increase understanding of the basic virology of SARS-CoV-2, characterize the spectrum of complications associated with COVID-19, and develop vaccines that can protect from new and recurrent infections with SARS-CoV-2. While we continue learning about this new virus, it is clear that 1) the virus is spread via the respiratory route, primarily by droplets and contact with contaminated surfaces and fomites, as well as by aerosol formation during invasive respiratory procedures; 2) the airborne route is still controversial; and 3) that those infected can spread the virus without necessarily developing asymptomatic). With the number of SARS-CoV-2 infections increasing globally, the possibility of co-infections and/or co-morbidities is becoming more concerning. Co-infection with Human Immunodeficiency Virus (HIV) is one such example of polyparasitism of interest. This military-themed comparative review of SARS-CoV-2 and HIV details their virology and describes them figuratively as separate enemy armies. HIV, an old enemy dug into trenches in individuals already infected, and SARS-CoV-2 the new army, attempting to attack and capture territories, tissues and organs, in order to provide resources for their expansion. This analogy serves to aid in discussion of three main areas of focus and draw attention to how these viruses may cooperate to gain the upper hand in securing a host. Here we compare their target, the key receptors found on those tissues, viral lifecycles and tactics for immune response surveillance. The last focus is on the immune response to infection, addressing similarities in cytokines released. While the majority of HIV cases can be successfully managed with antiretroviral therapy nowadays, treatments for SARS-CoV-2 are still undergoing research given the novelty of this army.

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“…Overall, the viral factors that may underlie variation in transmission efficiency and virulence are poorly understood. However, subtype-specific functional differences in various HIV-1 genetic loci are now well documented, suggesting that some of these may account for the distinct transmission patterns, epidemic spread, and rates of disease progression [ 27 – 34 ]. Gag-protease mediated VRC has been shown to differ between HIV-1 subtypes and correlates strongly with whole virus isolates, making it an important determinant of the rate of disease progression [ 35 – 38 ].…”

Section: Introductionmentioning

confidence: 99%

Subtype-specific differences in Gag-protease replication capacity of HIV-1 isolates from East and West Africa

et al. 2021

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Background The HIV-1 epidemic in sub-Saharan Africa is heterogeneous with diverse unevenly distributed subtypes and regional differences in prevalence. Subtype-specific differences in disease progression rate and transmission efficiency have been reported, but the underlying biological mechanisms have not been fully characterized. Here, we tested the hypothesis that the subtypes prevalent in the East Africa, where adult prevalence rate is higher, have lower viral replication capacity (VRC) than their West African counterparts where adult prevalence rates are lower. Results Gag-protease sequencing was performed on 213 and 160 antiretroviral-naïve chronically infected participants from West and East Africa respectively and bioinformatic tools were used to infer subtypes and recombination patterns. VRC of patient-derived gag-protease chimeric viruses from West (n = 178) and East (n = 114) Africa were determined using a green fluorescent protein reporter-based cell assay. Subtype and regional differences in VRC and amino acid variants impacting VRC were identified by statistical methods. CRF02_AG (65%, n = 139), other recombinants (14%, n = 30) and pure subtypes (21%, n = 44) were identified in West Africa. Subtypes A1 (64%, n = 103), D (22%, n = 35), or recombinants (14%, n = 22) were identified in East Africa. Viruses from West Africa had significantly higher VRC compared to those from East Africa (p < 0.0001), with subtype-specific differences found among strains within West and East Africa (p < 0.0001). Recombination patterns showed a preference for subtypes D, G or J rather than subtype A in the p6 region of gag, with evidence that subtype-specific differences in this region impact VRC. Furthermore, the Gag A83V polymorphism was associated with reduced VRC in CRF02_AG. HLA-A*23:01 (p = 0.0014) and HLA-C*07:01 (p = 0.002) were associated with lower VRC in subtype A infected individuals from East Africa. Conclusions Although prevalent viruses from West Africa displayed higher VRC than those from East Africa consistent with the hypothesis that lower VRC is associated with higher population prevalence, the predominant CRF02_AG strain in West Africa displayed higher VRC than other prevalent strains suggesting that VRC alone does not explain population prevalence. The study identified viral and host genetic determinants of virus replication capacity for HIV-1 CRF02_AG and subtype A respectively, which may have relevance for vaccine strategies.

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Differential Vpu-Mediated CD4 and Tetherin Downregulation Functions among Major HIV-1 Group M Subtypes

Cited by 6 publications

References 55 publications

Attenuated HIV-1 Nef But Not Vpu Function in a Cohort of Rwandan Long-Term Survivors

Attenuated HIV-1 Nef But Not Vpu Function in a Cohort of Rwandan Long-Term Survivors

SARS-CoV-2 and Human Immunodeficiency Virus: Pathogen Pincer Attack

Subtype-specific differences in Gag-protease replication capacity of HIV-1 isolates from East and West Africa

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