scholarly journals The Expression Level of HIV-1 Vif Is Optimized by Nucleotide Changes in the Genomic SA1D2prox Region during the Viral Adaptation Process

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2079
Author(s):  
Takaaki Koma ◽  
Naoya Doi ◽  
Mai Takemoto ◽  
Kyosuke Watanabe ◽  
Hideki Yamamoto ◽  
...  
Keyword(s):  
Viral Genome ◽  
Expression Level ◽  
Restriction Factors ◽  
Single Nucleotide ◽  
Expression Levels ◽  
Naturally Occurring ◽  
Viral Adaptation ◽  
Splicing Pattern ◽  
Apobec3 Proteins ◽  
Hiv 1

HIV-1 Vif plays an essential role in viral replication by antagonizing anti-viral cellular restriction factors, a family of APOBEC3 proteins. We have previously shown that naturally-occurring single-nucleotide mutations in the SA1D2prox region, which surrounds the splicing acceptor 1 and splicing donor 2 sites of the HIV-1 genome, dramatically alter the Vif expression level, resulting in variants with low or excessive Vif expression. In this study, we investigated how these HIV-1 variants with poor replication ability adapt and evolve under the pressure of APOBEC3 proteins. Adapted clones obtained through adaptation experiments exhibited an altered replication ability and Vif expression level compared to each parental clone. While various mutations were present throughout the viral genome, all replication-competent adapted clones with altered Vif expression levels were found to bear them within SA1D2prox, without exception. Indeed, the mutations identified within SA1D2prox were responsible for changes in the Vif expression levels and altered the splicing pattern. Moreover, for samples collected from HIV-1-infected patients, we showed that the nucleotide sequences of SA1D2prox can be chronologically changed and concomitantly affect the Vif expression levels. Taken together, these results demonstrated the importance of the SA1D2prox nucleotide sequence for modulating the Vif expression level during HIV-1 replication and adaptation.

scholarly journals Natural Single-Nucleotide Variations in the HIV-1 Genomic SA1prox Region Can Alter Viral Replication Ability by Regulating Vif Expression Levels

2016 ◽  
Vol 90 (9) ◽  
pp. 4563-4578 ◽  
Author(s):  
Masako Nomaguchi ◽  
Naoya Doi ◽  
Yosuke Sakai ◽  
Hirotaka Ode ◽  
Yasumasa Iwatani ◽  
...  
Keyword(s):  
Viral Replication ◽  
Mrna Expression ◽  
Expression Pattern ◽  
Proximal Region ◽  
Restriction Factors ◽  
Single Nucleotide ◽  
Expression Levels ◽  
Mrna Expression Pattern ◽  
Single Nucleotide Variations ◽  
Hiv 1

ABSTRACTWe previously found that natural single-nucleotide variations located within a proximal region of splicing acceptor 1 (SA1prox) in the HIV-1 genome could alter the viral replication potential and mRNA expression pattern, especially thevifmRNA level. Here, we studied the virological and molecular basis of nucleotide sequence variations in SA1prox for alterations of viral replication ability. Consistent with our previous findings, variant clones indeed expressed Vif at different levels and grew distinctively in cells with various APOBEC3G expression levels. Similar effects were observed for natural variations found in HIV-2 SA1prox, suggesting the importance of the SA1prox sequence. To define nucleotides critical for the regulation of HIV-1 Vif expression, effects of natural SA1prox variations newly found in the HIV Sequence Compendium database onvifmRNA/Vif protein levels were examined. Seven out of nine variations were found to produce Vif at lower, higher, or more excessive levels than wild-type NL4-3. Combination experiments of variations giving distinct Vif levels suggested that the variations mutually affectedviftranscript production. While low and high producers of Vif grew in an APOBEC3G-dependent manner, excessive expressers always showed an impeded growth phenotype due to defects in single-cycle infectivity and/or virion production levels. The phenotype of excessive expressers was not due primarily to inadequate expression of Tat or Rev, although SA1prox variations altered the overall HIV-1 mRNA expression pattern. Collectively, our results demonstrate that HIV SA1prox regulates Vif expression levels and suggest a relationship between SA1prox and viral adaptation/evolution given that variations occurred naturally.IMPORTANCEWhile human cells possess restriction factors to inhibit HIV-1 replication, HIV-1 encodes antagonists to overcome these barriers. Conflicts between host restriction factors and viral counterparts are critical driving forces behind mutual evolution. The interplay of cellular APOBEC3G and viral Vif proteins is a typical example. Here, we demonstrate that naturally occurring single-nucleotide variations in the proximal region of splicing acceptor 1 (SA1prox) of the HIV-1 genome frequently alter Vif expression levels, thereby modulating viral replication potential in cells with various ABOBEC3G levels. The results of the present study reveal a previously unidentified and important way for HIV-1 to compete with APOBEC3G restriction by regulating its Vif expression levels. We propose that SA1prox plays a regulatory role in Vif counteraction against APOBEC3G in order to contribute to HIV-1 replication and evolution, and this may be applicable to other primate lentiviruses.

scholarly journals Interactions of host APOBEC3 restriction factors with HIV-1 in vivo: implications for therapeutics

2010 ◽  
Vol 12 ◽  
Author(s):  
John S. Albin ◽  
Reuben S. Harris
Keyword(s):  
Restriction Factors ◽  
Cytidine Deaminases ◽  
Virion Infectivity Factor ◽  
Viral Particles ◽  
Viral Cdna ◽  
Basic Biology ◽  
Apobec3 Proteins ◽  
In Vivo Effects ◽  
Hiv 1

Restriction factors are natural cellular proteins that defend individual cells from viral infection. These factors include the APOBEC3 family of DNA cytidine deaminases, which restrict the infectivity of HIV-1 by hypermutating viral cDNA and inhibiting reverse transcription and integration. HIV-1 thwarts this restriction activity through its accessory protein virion infectivity factor (Vif), which uses multiple mechanisms to prevent APOBEC3 proteins such as APOBEC3G and APOBEC3F from entering viral particles. Here, we review the basic biology of the interactions between human APOBEC3 proteins and HIV-1 Vif. We also summarise, for the first time, current clinical data on the in vivo effects of APOBEC3 proteins, and survey strategies and progress towards developing therapeutics aimed at the APOBEC3–Vif axis.

scholarly journals Naturally Occurring Compounds Elicit HIV-1 Replication in Chronically Infected Promonocytic Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Andrea Alejandra Barquero ◽  
María Eugenia Dávola ◽  
Diego Ariel Riva ◽  
Susana Esther Mersich ◽  
Laura Edith Alché
Keyword(s):  
Viral Genome ◽  
Nordihydroguaiaretic Acid ◽  
Hiv Replication ◽  
Viral Reservoirs ◽  
Naturally Occurring ◽  
Latently Infected ◽  
Infected Cells ◽  
P24 Antigen ◽  
Hiv 1 ◽  
Promonocytic Cells

Since antiretroviral therapy suppresses but does not eradicate HIV-1 infection, methods to purge viral reservoirs are required. Many strategies involve the reactivation of chronically HIV infected cells to induce the expression of integrated viral genome. In this study, five bioactive compounds, the plant derivatives 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM), nordihydroguaiaretic acid (NDGA), and curcumin (Cur) and the synthetic stigmasterol analogs (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound1) and (22S,23S)-3β-bromo-5α,22,23-trihydroxystigmastan-6-one (compound2), were evaluated for their ability to elicit HIV replication in promonocytic (U1) and lymphocytic (H9+) HIV-1 chronically infected cells. The results revealed that natural compounds CDM, NDGA, and Cur were able to increase HIV-1 p24 antigen, determined by ELISA, only in latently infected promonocytic cells. CDM would reactivate HIV from latency by modulating the release of IL-6 and TNF-α, since the amount of both cytokines measured through ELISA significantly increased in U1 treated cells. Besides, NDGA increased ROS production, which might be related to the increase on p24 level observed in NDGA treated U1. These findings suggest that CDM, NDGA, and Cur might be candidates for further studies on latency-reversing therapeutics to eliminate latently HIV-1 reservoirs.

scholarly journals A novel HIV-1 inhibitor that blocks viral replication and rescues APOBEC3s by interrupting vif/CBFβ interaction

2020 ◽  
Vol 295 (43) ◽  
pp. 14592-14605
Author(s):  
Sizhu Duan ◽  
Shiqi Wang ◽  
Yanan Song ◽  
Nan Gao ◽  
Lina Meng ◽  
...  
Keyword(s):  
Drug Targets ◽  
Cytidine Deaminase ◽  
Family Members ◽  
Restriction Factors ◽  
Host Restriction ◽  
Development Of Resistance ◽  
Cytidine Deaminase Activity ◽  
Important Host ◽  
Apobec3 Proteins ◽  
Hiv 1

HIV remains a health challenge worldwide, partly because of the continued development of resistance to drugs. Therefore, it is urgent to find new HIV inhibitors and targets. Apolipoprotein B mRNA-editing catalytic polypeptide-like 3 family members (APOBEC3) are important host restriction factors that inhibit HIV-1 replication by their cytidine deaminase activity. HIV-1 viral infectivity factor (Vif) promotes proteasomal degradation of APOBEC3 proteins by recruiting the E3 ubiquitin ligase complex, in which core-binding factor β (CBFβ) is a necessary molecular chaperone. Interrupting the interaction between Vif and CBFβ can release APOBEC3 proteins to inhibit HIV-1 replication and may be useful for developing new drug targets for HIV-1. In this study, we identified a potent small molecule inhibitor CBFβ/Vif-3 (CV-3) of HIV-1 replication by employing structure-based virtual screening using the crystal structure of Vif and CBFβ (PDB: 4N9F) and validated CV-3's antiviral activity. We found that CV-3 specifically inhibited HIV-1 replication (IC50 = 8.16 µm; 50% cytotoxic concentration >100 µm) in nonpermissive lymphocytes. Furthermore, CV-3 treatment rescued APOBEC3 family members (human APOBEC3G (hA3G), hA3C, and hA3F) in the presence of Vif and enabled hA3G packaging into HIV-1 virions, which resulted in Gly-to-Ala hypermutations in viral genomes. Finally, we used FRET to demonstrate that CV-3 inhibited the interaction between Vif and CBFβ by simultaneously forming hydrogen bonds with residues Gln-67, Ile-102, and Arg-131 of CBFβ. These findings demonstrate that CV-3 can effectively inhibit HIV-1 by blocking the interaction between Vif and CBFβ and that this interaction can serve as a new target for developing HIV-1 inhibitors.

scholarly journals Bone marrow stromal antigen 2 (BST-2) genetic variants influence expression levels and disease outcome in HIV-1 chronically infected patients

2021 ◽  
Author(s):  
Hlelolwenkosi Mlimi ◽  
Kewreshini K. Naidoo ◽  
Jenniffer Mabuka ◽  
Thumbi Ndung’u ◽  
Paradise Madlala
Keyword(s):  
Viral Load ◽  
Mrna Expression ◽  
Genetic Variants ◽  
Disease Outcome ◽  
Mrna Levels ◽  
Single Nucleotide ◽  
Cd4 Counts ◽  
Expression Levels ◽  
Hiv 1 ◽  
Mrna Expression Levels

Abstract BackgroundBone marrow stromal antigen 2 (BST-2) also known as Tetherin (CD317/HM1.24), is a host restriction factor that blocks the release of HIV-1 virions from infected cells. Previous studies reported that BST-2 genetic variants or single nucleotide polymorphims (SNPs) have a preventative role during HIV-1 infection. However, the influence of BST-2 SNPs on expression levels remains unknown. In this study, we investigated the inffluence of BST-2 SNPs on expression levels and disease outcome in HIV-1 subtype C chronically infected antiretroviral therapy naïve individuals.ResultsWe quantified BST-2 mRNA levels in peripheral blood mononuclear cells (PBMCs), determined BST-2 protein expression on the surface of CD4 + T cells using flow cytometry and genotyped single nucleotide polymorphisms (SNPs) rs919267, rs919266 and rs9576 using TaqMan assays from HIV-1 uninfected and infected participants. Determined the ability of plasma antibody levels to meadiate andibodydependenet cellular phagocytosis (ADCP) using gp120 consensus C and p24 subtype B/C protein. Fc receptor-mediated NK cell degranulation was evaluated as a surrogate for ADCC activity using plasma from HIV-1 positive participants. BST-2 mRNA expression levels in PBMCs and protein levels on CD4 + T cells were lower in HIV-1 infected compared to uninfected participants (p=0.075 and p=0.005, respectively). rs919267CT (p=0.042) and rs919267TT (p=0.045) were associated with lower BST-2 mRNA expression levels compared to rs919267CC in HIV-1 uninfected participants. In HIV-1 infected participants, rs919267CT associated with lower CD4 count, (p=0.003), gp120-IgG1 (p=0.040), gp120-IgG3 (p=0.016) levels and but higher viral load (p=0.001) while rs919267TT was associated with lower BST-2 mRNA levels (p=0.046), CD4 counts (p=0.001), gp120-IgG1 levels (p=0.033) but higher plasma viral load (p=0.007). Conversely, rs9576CA was associated with higher BST-2 mRNA expression levels (p=0.027), CD4 counts (p=0.079), gp120-IgG1 (p=0.009), -IgG3 (p=0.039) levels and but with lower viral load (p=0.037). However, there was not correlation between BST-2 SNPs, p24-IgG subclass, ADCC and ADCP activity. ConclusionOur findings show that bst- 2 SNPs mediate BST-2 expression and disease outcome, correlate with gp120-IgG1, gp120-IgG3 levels but p24-IgG levels, ADCC and ADCP activity. Future studies should investigate the role of BST-2 polymorphic variants on improving myeloid dentritic cell (DC) activation and MHC class II antigene presentation.

scholarly journals Naturally Occurring Mutations in HIV-1 CRF01_AE Capsid Affect Viral Sensitivity to Restriction Factors

2018 ◽  
Vol 34 (4) ◽  
pp. 382-392 ◽  
Author(s):  
Emi E. Nakayama ◽  
Akatsuki Saito ◽  
Tahmina Sultana ◽  
Zhuan Jin ◽  
Kyotaro Nohata ◽  
...  
Keyword(s):  
Restriction Factors ◽  
Naturally Occurring ◽  
Hiv 1

scholarly journals Evolutionary rate shifts suggest species-specific adaptation events in HIV-1 and SIV

2017 ◽  
Author(s):  
Maoz Gelbart ◽  
Adi Stern
Keyword(s):  
Evolutionary Rate ◽  
Virus Transmission ◽  
Restriction Factors ◽  
Species Barrier ◽  
New Host ◽  
Major Barrier ◽  
Viral Adaptation ◽  
Rate Deceleration ◽  
Species Specific ◽  
Hiv 1

AbstractThe process of molecular adaptation following a cross-species virus transmission event is currently poorly understood. Here, we identified 137 protein sites that experienced deceleration in their rate of evolution along the HIV-1/SIV phylogeny, likely indicating gain-of-function and consequent adaptation. The majority of such events occurred in parallel to cross-species transmission events and varied between HIV-1 groups, indicating independent adaptation strategies. The evolutionary rate decelerations we found were particularly prominent in accessory proteins that counteract host antiviral restriction factors, suggesting that these factors are a major barrier to viral adaptation to a new host. Surprisingly, we observed that the non-pandemic HIV-1 group O, derived from gorillas, exhibited more rate deceleration events than the pandemic group M, derived from chimpanzees. We suggest that the species barrier is higher when the genetic distance of the hosts increases. Our approach paves the way for subsequent studies on cross-species transfers in other major pathogens.

Electroacupuncture ameliorates CUMS-induced depression-like behavior: involvement of the glutamatergic system and apoptosis in rats

2020 ◽  
Vol 23 ◽  
Author(s):  
Qin Guo ◽  
Xian-Ming Lin ◽  
Zhong Di ◽  
Quan-Ai Zhang ◽  
Shuo Jiang
Keyword(s):  
Nmda Receptor ◽  
Caspase 3 ◽  
B Cell Lymphoma ◽  
Sucrose Preference ◽  
Expression Level ◽  
Receptor Subunit ◽  
Glutamatergic System ◽  
Ionotropic Receptor ◽  
Nmda Receptor Subunit ◽  
Expression Levels

Background: Converging evidence indicates that glutamatergic system and glia are directly implicated in the pathophysiology of depression. Clinical studies indicate that electroacupuncture (EA) has antidepressant-like effect with low side effects for depression. However, the underlying antidepressant mechanism of acupuncture remains obscure. Methods: Chronic unpredictable mild stress (CUMS)-induced depressive rats were used to induce depressive-like behavior, and evaluated by the weight change, open field test, sucrose preference test, and novelty suppressed feeding test. EA, NMDA receptor subunit 2A antagonist (NR2A RA) or NMDA receptor subunit 2B antagonist (NR2B RA) was used for comparison. High performance liquid chromatography (HPLC) was performed to detect the content of hippocampal glutamate, while western blot for the hippocampal protein expression levels of calcium/calmodulin-dependent protein kinase II (CaMKII), Bax, caspase 3 and B-cell lymphoma-2 (Bcl-2). The distribution of glutamate ionotropic receptor NMDA type subunit 2A (NR2A), neuronal nuclear protein (NeuN), glutamate ionotropic receptor NMDA type subunit 2B (NR2B) and glial fibrillary acidic protein (GFAP) were detected by immunofluorescence. Results: Significant depression behavior (reduced body weight and sucrose preference, increased feeding and immobility time) was produced in CUMS-induced depressive rats, which was reversed significantly by EA. EA decreased hippocampal glutamate level. EA led to a significant decrease in expression levels of Bax, caspase 3 and CaMKⅡ accompanied by increased Bcl-2 expression level. Furthermore, EA significantly increased NR2A expression level as well as decreased NR2B expression level in hippocampus. Conclusion: EA ameliorated depression-like behavior in CUMS rats, which might be mediated, at least in part, by regulating the glutamate, NMDA receptors and apoptosis in the hippocampus.

Restriction Factors in HIV-1 Disease Progression

2015 ◽  
Vol 13 (6) ◽  
pp. 448-461 ◽  
Author(s):  
Natacha Merindol ◽  
Lionel Berthoux
Keyword(s):  
Disease Progression ◽  
Restriction Factors ◽  
Hiv 1

scholarly journals PCIP-seq: simultaneous sequencing of integrated viral genomes and their insertion sites with long reads

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Maria Artesi ◽  
Vincent Hahaut ◽  
Basiel Cole ◽  
Laurens Lambrechts ◽  
Fereshteh Ashrafi ◽  
...  
Keyword(s):  
Viral Genome ◽  
Clonal Expansion ◽  
Endogenous Retroviruses ◽  
Viral Genomes ◽  
Short Read Sequencing ◽  
Long Reads ◽  
Infected Cells ◽  
Insertion Sites ◽  
Viral Insertion ◽  
Hiv 1

AbstractThe integration of a viral genome into the host genome has a major impact on the trajectory of the infected cell. Integration location and variation within the associated viral genome can influence both clonal expansion and persistence of infected cells. Methods based on short-read sequencing can identify viral insertion sites, but the sequence of the viral genomes within remains unobserved. We develop PCIP-seq, a method that leverages long reads to identify insertion sites and sequence their associated viral genome. We apply the technique to exogenous retroviruses HTLV-1, BLV, and HIV-1, endogenous retroviruses, and human papillomavirus.

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