Humoral Immune Pressure Selects for HIV-1 CXC-chemokine Receptor 4-using Variants

Lin, Nina; González, Óscar; Registre, Ludy; Becerril, Carlos; Etemad, Behzad; Liang, Hong; Wu, Xueling; Lockman, Shahin; Essex, Myron; Moyo, Sikhulile; Kuritzkes, Daniel R.; Sagar, Manish

doi:10.1016/j.ebiom.2016.04.040

Cited by 24 publications

(32 citation statements)

References 83 publications

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“…Our results would not seem in line with in vivo evidence of the emergence of the more aggressive sincytium-inducing (SI) CXCR4- tropic strains in the terminal phases of HIV-1 disease associated with rapid decline of CD4+ and CD8+ T cells [28,85] but this phenomenon almost represents an effect of the breakdown of the immune system and the onset of AIDS [86]. We speculate that CXCR4- tropic strains play a minor role in disease progression because dying CXCR4 virus infected reservoirs, cannot provide virus nor continue to directly contribute to the depletion of immune cell system.…”

Section: Discussionmentioning

confidence: 68%

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: 68%

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

et al. 2019

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“…X4-R5 reversions have already been reported in HIV-1-infected patients after immune reconstitution [51–54]. Because recent findings indicate that X4-capable HIV-1 viruses are less susceptible to neutralization by autologous antibodies than R5-using viruses from the same host [55], X4-R5 reversions could result from the normalization of naïve T-cell turnover following immunological recovery [56], after which the infection of naïve T-cells by X4-capable variants may not be productive enough [51]. Since X4-capable HIV-2 also seem to be less susceptible to neutralization than CCR5-using strains [19], X4-R5 reversions in HIV-2 could be explained by the same mechanism.…”

Section: Discussionmentioning

confidence: 99%

A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support

et al. 2016

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BackgroundCCR5-coreceptor antagonists can be used for treating HIV-2 infected individuals. Before initiating treatment with coreceptor antagonists, viral coreceptor usage should be determined to ensure that the virus can use only the CCR5 coreceptor (R5) and cannot evade the drug by using the CXCR4 coreceptor (X4-capable). However, until now, no online tool for the genotypic identification of HIV-2 coreceptor usage had been available. Furthermore, there is a lack of knowledge on the determinants of HIV-2 coreceptor usage. Therefore, we developed a data-driven web service for the prediction of HIV-2 coreceptor usage from the V3 loop of the HIV-2 glycoprotein and used the tool to identify novel discriminatory features of X4-capable variants.ResultsUsing 10 runs of tenfold cross validation, we selected a linear support vector machine (SVM) as the model for geno2pheno[coreceptor-hiv2], because it outperformed the other SVMs with an area under the ROC curve (AUC) of 0.95. We found that SVMs were highly accurate in identifying HIV-2 coreceptor usage, attaining sensitivities of 73.5% and specificities of 96% during tenfold nested cross validation. The predictive performance of SVMs was not significantly different (p value 0.37) from an existing rules-based approach. Moreover, geno2pheno[coreceptor-hiv2] achieved a predictive accuracy of 100% and outperformed the existing approach on an independent data set containing nine new isolates with corresponding phenotypic measurements of coreceptor usage. geno2pheno[coreceptor-hiv2] could not only reproduce the established markers of CXCR4-usage, but also revealed novel markers: the substitutions 27K, 15G, and 8S were significantly predictive of CXCR4 usage. Furthermore, SVMs trained on the amino-acid sequences of the V1 and V2 loops were also quite accurate in predicting coreceptor usage (AUCs of 0.84 and 0.65, respectively).ConclusionsIn this study, we developed geno2pheno[coreceptor-hiv2], the first online tool for the prediction of HIV-2 coreceptor usage from the V3 loop. Using our method, we identified novel amino-acid markers of X4-capable variants in the V3 loop and found that HIV-2 coreceptor usage is also influenced by the V1/V2 region. The tool can aid clinicians in deciding whether coreceptor antagonists such as maraviroc are a treatment option and enables epidemiological studies investigating HIV-2 coreceptor usage. geno2pheno[coreceptor-hiv2] is freely available at http://coreceptor-hiv2.geno2pheno.org.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0320-7) contains supplementary material, which is available to authorized users.

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“…This hypothesis is supported by data indicating infected individuals heterozygous for a 32 base-pair deletion in the CCR5 gene, which results in lower expression of CCR5, have a higher incidence of X4 viruses when compared to infected individuals with normal CCR5 expression levels [71, 72]. Alternatively, a 2016 study provides evidence for host humoral immune pressure selecting against CCR5 variants facilitating the emergence of CXCR4 utilizing virus [73]. Although the mechanisms of tropism switch may not be clear, the switch in receptor usage has demonstrable clinical implications and the emergence of X4 strains have been linked to more severe illness and a more rapid progression to AIDS [74].…”

Section: Hiv Gp-120mentioning

confidence: 94%

“…Immunohistochemistry and flow cytometry have been used to demonstrate expression of CCR5 receptors on neurons of macaques and humans and in particular, on hippocampal neurons of patients with AIDS [72, 73]. Notably, neuronal expression of the receptor was decreased in the brains of AIDS patients with HIV encephalitis as compared to AIDS patients without HAND [79, 80].…”

Section: Hiv Gp-120mentioning

confidence: 99%

HIV Associated Neurodegenerative Disorders: A New Perspective on the Role of Lipid Rafts in Gp120-Mediated Neurotoxicity

Smith

Kühn

Chen

et al. 2019

CHR

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The implementation of combination antiretroviral therapy (cART) as the primary means of treatment for HIV infection has achieved a dramatic decline in deaths attributed to AIDS and the reduced incidence of severe forms of HIV-associated neurocognitive disorders (HAND) in infected individuals. Despite these advances, milder forms of HAND persist and prevalence of these forms of neurocognitive impairment are rising with the aging population of HIV infected individuals. HIV enters the CNS early in the pathophysiology establishing persistent infection in resident macrophages and glial cells. These infected cells, in turn, secrete neurotoxic viral proteins, inflammatory cytokines, and small metabolites thought to contribute to neurodegenerative processes. The viral envelope protein gp120 has been identified as a potent neurotoxin affecting neurodegeneration via indirect and direct mechanisms involving interactions with chemokine co-receptors CCR5 and CXCR4. This short review focuses on gp120 neurotropism and associated mechanisms of neurotoxicity linked to chemokine receptors CCR5 and CXCR4 with a new perspective on plasma membrane lipid rafts as an active participant in gp120-mediated neurodegeneration underlying HIV induced CNS pathology.

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Humoral Immune Pressure Selects for HIV-1 CXC-chemokine Receptor 4-using Variants

Cited by 24 publications

References 83 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

A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support

HIV Associated Neurodegenerative Disorders: A New Perspective on the Role of Lipid Rafts in Gp120-Mediated Neurotoxicity

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