Impact of cellular restriction gene (TRIM5α, BST‐2) polymorphisms on the acquisition of HIV‐1 and disease progression

Singh, HariOm; Samani, Dharmesh; Ghate, Manisha; Gangakhedkar, Raman

doi:10.1002/jgm.3004

Cited by 13 publications

(8 citation statements)

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“…On the other hand, there are many reasons to consider a role of CCR5 viruses and their host cells as target for therapeutic strategies: (i) the protective role of the 32-nucleotides (Δ32) deletion in CCR5 gene in homozygous condition against HIV-1 infection and the more benign pattern of disease progression associated with the deletion in one of the two alleles [87,88] (ii) a logarithmic correlation between CCR5 expression and viremia in patients with disease progression [89,90,91] (iii) the importance of CCR5-tropic isolates for dissemination outside peripheral blood in compartments considered as “sanctuaries” like the Central Nervous System where macrophages represent more than 90% of the HIV-1 infected cells [92,93,94,95] the capacity of R5 isolates harbored in macrophagic reservoirs to provoke the immune anergy through host-related factors (bystander effect) and the emergence of more virulent SI variants and the subsequent AIDS progression (iv) increase of viremia in later stages of HIV disease caused by macrophages during opportunistic infections [96,97] (v) increase of both CCR5 expression on CD4+ T cells and the frequency of memory CD4 T-cells (the target cells of CCR5 virus variants) over the course of infection [97,98].…”

Section: Discussionmentioning

confidence: 99%

Different Patterns of HIV-1 Replication in MACROPHAGES is Led by Co-Receptor Usage

et al. 2019

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Background and objectives: To enter the target cell, HIV-1 binds not only CD4 but also a co-receptor β-chemokine receptor 5 (CCR5) or α chemokine receptor 4 (CXCR4). Limited information is available on the impact of co-receptor usage on HIV-1 replication in monocyte-derived macrophages (MDM) and on the homeostasis of this important cellular reservoir. Materials and Methods: Replication (measured by p24 production) of the CCR5-tropic 81A strain increased up to 10 days post-infection and then reached a plateau. Conversely, the replication of the CXCR4-tropic NL4.3 strain (after an initial increase up to day 7) underwent a drastic decrease becoming almost undetectable after 10 days post-infection. The ability of CCR5-tropic and CXCR4-tropic strains to induce cell death in MDM was then evaluated. While for CCR5-tropic 81A the rate of apoptosis in MDM was comparable to uninfected MDM, the infection of CXCR4-tropic NL4.3 in MDM was associated with a rate of 14.3% of apoptotic cells at day 6 reaching a peak of 43.5% at day 10 post-infection. Results: This suggests that the decrease in CXCR4-tropic strain replication in MDM can be due to their ability to induce cell death in MDM. The increase in apoptosis was paralleled with a 2-fold increase in the phosphorylated form of p38 compared to WT. Furthermore, microarray analysis showed modulation of proapoptotic and cancer-related genes induced by CXCR4-tropic strains starting from 24 h after infection, whereas CCR5 viruses modulated the expression of genes not correlated with apoptotic-pathways. Conclusions: In conclusion, CXCR4-tropic strains can induce a remarkable depletion of MDM. Conversely, MDM can represent an important cellular reservoir for CCR5-tropic strains supporting the role of CCR5-usage in HIV-1 pathogenesis and as a pharmacological target to contribute to an HIV-1 cure.

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Section: Discussionmentioning

confidence: 99%

Different Patterns of HIV-1 Replication in MACROPHAGES is Led by Co-Receptor Usage

et al. 2019

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“…On the other hand, there are many reasons to consider a role of CCR5 viruses and their host cells as target for therapeutic strategies: (i) the protective role of the 32-nucleotides (Δ32) deletion in CCR5 gene in homozygous condition against HIV-1 infection and the more benign pattern of disease progression associated with the deletion in one of the two alleles [87,88] (ii) a logarithmic correlation between CCR5 expression and viremia in patients with disease progression [89][90][91] (iii) the importance of CCR5-tropic isolates for dissemination outside peripheral blood in compartments considered as "sanctuaries" like the Central Nervous System where macrophages represent more than 90% of the HIV-1 infected cells [92][93][94][95] the capacity of R5 isolates harbored in macrophagic reservoirs to provoke the immune anergy through host-related factors (bystander effect) and the emergence of more virulent SI variants and the subsequent AIDS progression (iv) increase of viremia in later stages of HIV disease caused by macrophages during opportunistic infections [96,97] (v) increase of both CCR5 expression on CD4+ T cells and the frequency of memory CD4 T-cells (the target cells of CCR5 virus variants) over the course of infection [97,98].…”

Section: Discussionmentioning

confidence: 99%

Features of Pathogenesis of Human Viral Infections and Antiviral Drugs

Aquaro¹

2021

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Among infectious diseases, viral infections are the leading cause of death worldwide, especially in the most low-income countries, particularly in young children. Most of the human viruses are all well characterized in terms of structure, life-cycle, tropism, and associated primary pathologies, but many of the pathogenetic mechanisms underlying their ability to cause acute infection, persist or reactivate in the host and cause chronic and/or degenerative damage, and still need to be fully clarified. At the same time, it seems necessary to develop novel therapeutic approaches and rationale, and possibly more potent antiviral compounds that are addressed to novel targets.

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“…DNA was extracted using the Qiagen Blood Genomic DNA Kit (QIAamp DNA kit; Qiagen, Inc., Valencia, California, USA) in accordance with the manufacturer's instructions as used in the previous studies [29]. 20 μl of Qiagen Protease was pipetted into the bottom of a 1.5 ml microcentrifuge tube, then 200 μl sample added.…”

Section: Dna Extractionmentioning

confidence: 99%

Variations in Trim5α and Cyclophilin A genes among HIV-1 elite controllers and non controllers in Uganda: a laboratory-based cross-sectional study

et al. 2020

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Background: Tripartite Motif Containing 5 alpha (TRIM5α), a restriction factor produced ubiquitously in cells and tissues of the body plays an important role in the immune response against HIV. TRIM5α targets the HIV capsid for proteosomal destruction. Cyclophilin A, an intracellular protein has also been reported to influence HIV infectivity in a cell-specific manner. Accordingly, variations in TRIM5α and Cyclophilin A genes have been documented to influence HIV-1 disease progression. However, these variations have not been documented among Elite controllers in Uganda and whether they play a role in viral suppression remains largely undocumented. Our study focused on identifying the variations in TRIM5α and Cyclophilin A genes among HIV-1 Elite controllers and non-controllers in Uganda. Results: From the sequence analysis, the rs10838525 G > A mutation in exon 2 of TRIM5α was only found among elite controllers (30%) while the rs3824949 in the 5′UTR was seen among 25% of the non-controllers. In the Cyclophilin A promoter, rs6850 was seen among 62.5% of the non-controllers and only among 10% elite controllers. Furthermore, rs17860048 in the Cyclophillin A promoter was predominantly seen among elite controllers (30%) and 12.5% noncontrollers. From gene expression analysis, we noted that the respective genes were generally elevated among elite controllers, however, this difference was not statistically significant (TRIM5α p = 0.6095; Cyclophilin A p = 0.6389). Conclusion: Variations in TRIM5α and Cyclophillin A promoter may influence HIV viral suppression. The rs10838525 SNP in TRIM5α may contribute to viral suppression among HIV-1 elite controllers. The rs6850 in the cyclophillin A gene may be responsible for HIV-1 rapid progression among HIV-1 non-controllers. These SNPs should be investigated mechanistically to determine their precise role in HIV-1 viral suppression.

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Impact of cellular restriction gene (TRIM5α, BST‐2) polymorphisms on the acquisition of HIV‐1 and disease progression

Abstract: TRIM5α haplotypes and the BST-2 i19 allele may significantly affect the modulation of HIV-1 acquisition and its progression. TRIM5α rs7127617 CC and BST-2 Δ19/i19 genotypes in alcohol-using HIV patients elevated the risk of HIV disease progression.

Cited by 13 publications

References 50 publications

Different Patterns of HIV-1 Replication in MACROPHAGES is Led by Co-Receptor Usage

Different Patterns of HIV-1 Replication in MACROPHAGES is Led by Co-Receptor Usage

Features of Pathogenesis of Human Viral Infections and Antiviral Drugs

Variations in Trim5α and Cyclophilin A genes among HIV-1 elite controllers and non controllers in Uganda: a laboratory-based cross-sectional study

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