HIV-1/AIDS susceptibility and copy number variation in &lt;i&gt;CCL3L1&lt;/i&gt;, a gene encoding a natural ligand for HIV-1 co-receptor CCR5

Nakajima, Toshiaki; Kaur, Gurvinder; Mehra, N. K.; Kimura, Akinori

doi:10.1159/000184703

Cited by 29 publications

(31 citation statements)

References 40 publications

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“…The length and the amino acid composition of the N-terminal tail of CCR5-binding chemo-kines affect their binding and signaling properties as well as their anti-HIV potency (37,38). Moreover, different classes of N-terminal-modified CCL5 analogs displaying improved anti-HIV properties have different pharmacological profiles (23), suggesting that they may stabilize different conformations of CCR5.…”

Section: Discussionmentioning

confidence: 99%

Targeting Spare CC Chemokine Receptor 5 (CCR5) as a Principle to Inhibit HIV-1 Entry

Jin

Colin

Staropoli

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Targeting Spare CC Chemokine Receptor 5 (CCR5) as a Principle to Inhibit HIV-1 Entry

Jin

Colin

Staropoli

et al. 2014

Journal of Biological Chemistry

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“…Significant associations of CNVs with human disease are numerous as CNVs are thought to be able to influence gene expression and may also play a role in affecting metabolic traits. These include susceptibility to HIV1 [45], a role in auto immune disease and lupus glomerulonephritis [46]. CNVs are strongly correlated with gene, repeat and segmental duplication content [47] and play a significant role in the development of complex traits.…”

Section: Introductionmentioning

confidence: 99%

Genome wide analysis reveals single nucleotide polymorphisms associated with fatness and putative novel copy number variants in three pig breeds

et al. 2013

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BackgroundObesity, excess fat tissue in the body, can underlie a variety of medical complaints including heart disease, stroke and cancer. The pig is an excellent model organism for the study of various human disorders, including obesity, as well as being the foremost agricultural species. In order to identify genetic variants associated with fatness, we used a selective genomic approach sampling DNA from animals at the extreme ends of the fat and lean spectrum using estimated breeding values derived from a total population size of over 70,000 animals. DNA from 3 breeds (Sire Line Large White, Duroc and a white Pietrain composite line (Titan)) was used to interrogate the Illumina Porcine SNP60 Genotyping Beadchip in order to identify significant associations in terms of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs).ResultsBy sampling animals at each end of the fat/lean EBV (estimate breeding value) spectrum the whole population could be assessed using less than 300 animals, without losing statistical power. Indeed, several significant SNPs (at the 5% genome wide significance level) were discovered, 4 of these linked to genes with ontologies that had previously been correlated with fatness (NTS, FABP6, SST and NR3C2). Quantitative analysis of the data identified putative CNV regions containing genes whose ontology suggested fatness related functions (MCHR1, PPARα, SLC5A1 and SLC5A4).ConclusionsSelective genotyping of EBVs at either end of the phenotypic spectrum proved to be a cost effective means of identifying SNPs and CNVs associated with fatness and with estimated major effects in a large population of animals.

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“…They are secreted by a number of cell types and in particular immune cells including R5 HIV-1 target cells (6,8,9). The potential role of native CCR5 chemokines in blocking HIV-1 transmission and progression has been extensively studied (9)(10)(11)(12), but their efficacy as protective factors remains a matter of debate (13,14). A major paradox relates to the observation that native CCR5 chemokines show lower antiviral potencies than would be expected based on their CCR5 binding affinity constants (15)(16)(17)(18), which are in the subnanomolar range (2,19,20), much lower than the corresponding value for the HIV-1 envelope glycoprotein gp120, which is ∼10 nM (19,21).…”

mentioning

confidence: 99%

HIV-1 exploits CCR5 conformational heterogeneity to escape inhibition by chemokines

Colin

Benureau

Staropoli

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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CC chemokine receptor 5 (CCR5) is a receptor for chemokines and the coreceptor for R5 HIV-1 entry into CD4(+) T lymphocytes. Chemokines exert anti-HIV-1 activity in vitro, both by displacing the viral envelope glycoprotein gp120 from binding to CCR5 and by promoting CCR5 endocytosis, suggesting that they play a protective role in HIV infection. However, we showed here that different CCR5 conformations at the cell surface are differentially engaged by chemokines and gp120, making chemokines weaker inhibitors of HIV infection than would be expected from their binding affinity constants for CCR5. These distinct CCR5 conformations rely on CCR5 coupling to nucleotide-free G proteins ((NF)G proteins). Whereas native CCR5 chemokines bind with subnanomolar affinity to (NF)G protein-coupled CCR5, gp120/HIV-1 does not discriminate between (NF)G protein-coupled and uncoupled CCR5. Interestingly, the antiviral activity of chemokines is G protein independent, suggesting that "low-chemokine affinity" (NF)G protein-uncoupled conformations of CCR5 represent a portal for viral entry. Furthermore, chemokines are weak inducers of CCR5 endocytosis, as is revealed by EC50 values for chemokine-mediated endocytosis reflecting their low-affinity constant value for (NF)G protein-uncoupled CCR5. Abolishing CCR5 interaction with (NF)G proteins eliminates high-affinity binding of CCR5 chemokines but preserves receptor endocytosis, indicating that chemokines preferentially endocytose low-affinity receptors. Finally, we evidenced that chemokine analogs achieve highly potent HIV-1 inhibition due to high-affinity interactions with internalizing and/or gp120-binding receptors. These data are consistent with HIV-1 evading chemokine inhibition by exploiting CCR5 conformational heterogeneity, shed light into the inhibitory mechanisms of anti-HIV-1 chemokine analogs, and provide insights for the development of unique anti-HIV molecules

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HIV-1/AIDS susceptibility and copy number variation in <i>CCL3L1</i>, a gene encoding a natural ligand for HIV-1 co-receptor CCR5

Cited by 29 publications

References 40 publications

Targeting Spare CC Chemokine Receptor 5 (CCR5) as a Principle to Inhibit HIV-1 Entry

Targeting Spare CC Chemokine Receptor 5 (CCR5) as a Principle to Inhibit HIV-1 Entry

Genome wide analysis reveals single nucleotide polymorphisms associated with fatness and putative novel copy number variants in three pig breeds

HIV-1 exploits CCR5 conformational heterogeneity to escape inhibition by chemokines

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