Molecular Mechanisms of HIV Entry

Wilen, Craig B.; Tilton, John C.; Doms, Robert W.

doi:10.1007/978-1-4614-0980-9_10

Cited by 195 publications

(170 citation statements)

References 131 publications

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“…CXCR4 is also a major co-receptor for HIV infection of human CD4 T cells [2]. During viral entry, the virus glycoprotein gp120 binds to CD4 and the co-receptor CXCR4/CCR5 to mediate viral fusion [3] and intracellular signal transduction [4] necessary for viral entry and post-entry migration in blood CD4 T cells [5][6][7][8][9][10]. Clinically, the viral switch from the usage of CCR5 to CXCR4 is also associated with rapid depletion of blood CD4 T cells and disease progression towards AIDS [11][12][13].…”

Section: Resultsmentioning

confidence: 99%

Effects of Tadalafil and Sildenafil on HIV Infection in vitro

Liang¹,

Toro²,

Wu³

et al. 2015

JHVRV

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Background: Tadala�il (Cialis, Lilly ICOS) and Sildena�il citrate (Viagra, P�izer) are by far the most popular and widely used drugs for enhancing male erectile function. Recent studies have suggested that Tadala�il administration increases the expression of CXCR4 in human endothelial progenitor cells (EPC). CXCR4 is also a major co-receptor for HIV (Human Immunode�iciency Virus) infection of human CD4 T cells. In addition, the viral tropism switch to CXCR4 is associated with rapid disease progression in patients. Findings:We investigated whether Tadala�il and Sildena�il increased CXCR4 expression on human CD4 T cells, which may potentially facilitate HIV infection and transmission. We found that both drugs transiently increase CXCR4 expression on CD4 T cells. We further used an HIV-1 Rev-dependent reporter cell (Rev-CEM-Luc-GFP) to evaluate possible drug enhancement of viral replication in vitro. We also found that no signi�icant impact of viral replication was observed, when cells were transiently exposed to these drugs. In contrast, both drugs inhibited HIV-1 infection when cells were treated for extended periods of time, likely resulting from interference with intracellular signaling environment involved in HIV-1 infection. Conclusion:These results suggest that although both drugs enhance CXCR4 expression, they may not enhance HIV replication and increase HIV transmission. KeywordsHIV-1; Tadala�il; Sildena�il; Rev-CEM-Luc-GFP; PBMC We further tested the effects of these drugs on promoting HIV infection. We used an HIV-1 Rev-dependent indicator CD4 T cell line, Rev-CEM-Luc-GFP [18,19], which expresses luciferase and GFP only after HIV infection. To measure the effects of Tadala�il and Sildena�il, we �irst performed transient treatment of Rev-CEM-Luc-GFP cells with these drugs. Cells were pre-treated for 1 hour with Tadala�il or Sildena�il, and then infected with HIV-1 for two hours in the presence of the drug. Following infection, cells were washed and then cultured in fresh medium for 72 hours without the drug being added back. GFP expression was measured at 72 hours by �low cytometry. Infected cells were also stained for apoptosis with propidium iodide (P.I.) during cytometry to exclude drug cytotoxicity. GFP expression was measured only in the viable cell population (low P.I. staining). As shown in (Figure 2A), HIV-1 infection led to the GFP expression in 2.12% cells, whereas brief treatment of cells with Tadala�il in a range of dosages (from 10 nM to 10 μM) during infection did not enhance viral replication. We performed a similar infection experiment in Sildena�il-treated cells. As shown in (Figure 2B), HIV-1 infection led to the GFP expression in 1.58% cells, whereas brief treatment of cells with Sildena�il in a range of dosages (from 10 nM to 10 μM) during infection did not lead to signi�icant enhancement of viral replication (GFP+ cells, 1.89-2.20%). Similar results were observed when concentrated high titer viruses (2500ng p24) were used for infection (Figure 3).We also investigated the dru...

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Section: Resultsmentioning

confidence: 99%

Effects of Tadalafil and Sildenafil on HIV Infection in vitro

Liang¹,

Toro²,

Wu³

et al. 2015

JHVRV

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“…In addition to conformational changes in cell surface receptors, coreceptors of HIV (CD4, CCR5, and CXCR4) and viral envelope proteins (gp120, gp41), redox changes in these proteins are also required for successful HIV entry [21][22][23][24][25][26][27][28]. Specifically, (1) the reduction of the second domain of CD4 was reported to be an obligatory step in CD4-dependent fusion [25]; (2) two of the nine disulfide bonds of gp120 must be reduced in order to promote the successful HIV entry [23,28].…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, (1) the reduction of the second domain of CD4 was reported to be an obligatory step in CD4-dependent fusion [25]; (2) two of the nine disulfide bonds of gp120 must be reduced in order to promote the successful HIV entry [23,28]. UD29 is chemically a thiolated nucleotide, in which the enol form of the compound (Fig.…”

Section: Discussionmentioning

confidence: 99%

Antiretroviral effect of 4-thio-uridylate against human immunodeficiency virus type 1

Kanizsai

Ghidán

Ongrádi

et al. 2012

Acta Microbiologica Et Immunologica Hungarica

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Antiretroviral effect of thiolated nucleotide 4-thio-uridylate (S 4 UMP, designated as UD29) against human immunodeficiency virus type 1 (HIV-1) have been quantitatively determined in cell-based viral infectivity assays. In syntitium inhibition assay on MT-2 human T-cell line UD29 prevented cell fusion and formation of syntitia induced by HIV-1 IIIB with IC 50 values of 11.7 µg/ml. In a single-cycle viral infection assay (MAGI assay) UD29 proved to have a potent inhibitory effect against HIV-1 IIIB on HeLaCD4-LTR/b-gal cells, which was dose dependent with IC 50 values of 4.75 µg/ml and IC 90 of 39.7 µg/ml. UD29 showed a most prominent antiviral effect when administered 30 min prior HIV-1 infection. As HIV entry requires thiol/disulfide exchange process, results suggest that reactive -SH group of enol-form of the thiolated nucleotide may interfere with the function of cell surface proteins. UD29 cannot penetrate into cells and may have an interactive role in redox processes active in viral entry.

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“…Conformationally masked by carbohydrate structures and variable amino acid loops that enable it to evade the humoral immune response, the envelope glycoprotein (Env) on virions is organized into trimers of noncovalently associated surface gp120 and transmembrane gp41 heterodimers (reviewed in [34]). The interaction of HIV with host cell surface receptors trigger the fusogenic potential of Env and allow the virus to enter into its target cells by fusion, presumably at the plasma membrane [35].…”

Section: The Coreceptors In Hiv Entrymentioning

confidence: 99%

Chemokine Receptors as Therapeutic Targets in HIV Infection

Anastassopoulou¹

2012

Immunodeficiency

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Molecular Mechanisms of HIV Entry

Cited by 195 publications

References 131 publications

Effects of Tadalafil and Sildenafil on HIV Infection in vitro

Effects of Tadalafil and Sildenafil on HIV Infection in vitro

Antiretroviral effect of 4-thio-uridylate against human immunodeficiency virus type 1

Chemokine Receptors as Therapeutic Targets in HIV Infection

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