Two Mechanisms for Human Immunodeficiency Virus Type 1 Inhibition by N-Terminal Modifications of RANTES

Pastore, Cristina; Picchio, Gastón; Galimi, Francesco; Fish, Richard E.; Hartley, Oliver; Offord, Robin E.; Mosier, Donald E.

doi:10.1128/aac.47.2.509-517.2003

Cited by 71 publications

(75 citation statements)

References 47 publications

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“…During infection, increased production of CCR5 ligands, such as RANTES, MIP-1a, and MIP-1b, may drive this evolution. 40,49 The presence of these chemokines decreases CCR5 receptor expression on target cells, 50 which potentially forces viruses to acquire an ability to infect cells that have low CCR5 densities. The ability to replicate in cells with low CCR5 expression correlates with inhibition by CCR5 blockers, which is further related to T-20 susceptibility and fusion capacity.…”

Section: Discussionmentioning

confidence: 99%

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Sensitivity Changes over the Course of Infection Increases the Likelihood of Resistance Against Fusion but Not CCR5 Receptor Blockers

Chatziandreou

Araúz

Freitas

et al. 2012

AIDS Research and Human Retroviruses

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As HIV-1 evolves over the course of infection, resistance against antiretrovirals may arise in the absence of drug pressure, especially against receptor and fusion blockers because of the extensive changes observed in the envelope glycoprotein. Here we show that viruses from the chronic phase of disease are significantly less sensitive to CCR5 receptor and fusion blockers compared to early infection variants. Differences in susceptibility to CCR5 antagonists were observed in spite of no demonstrable CXCR4 receptor utilization. No significant sensitivity differences were observed to another entry blocker, soluble CD4, or to reverse transcriptase, protease, or integrase inhibitors. Chronic as compared to early phase variants demonstrated greater replication when passaged in the presence of subinhibitory concentrations of fusion but not CCR5 receptor inhibitors. Fusion antagonist resistance, however, emerged from only one chronic phase virus culture. Because sensitivity to receptor and fusion antagonists is correlated with receptor affinity and fusion capacity, respectively, changes that occur in the envelope glycoprotein over the course of infection confer greater ability to use the CCR5 receptor and increased fusion ability. Our in vitro passage studies suggest that these evolving phenotypes increase the likelihood of resistance against fusion but not CCR5 receptor blockers.

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Section: Discussionmentioning

confidence: 99%

“…2A). In addition, viruses with the chronic (median 5.3 nM, range 4.3-13.1 nM) as compared to early (median 1.8 nM, range 0.9-5.1 nM, p = 0.03) infection envelopes had significantly lower IC 50 to another CCR5 inhibitor, maraviroc (Fig. 2B).…”

Section: Generation Of Replication-competent Recombinant Virusesmentioning

confidence: 96%

Sensitivity Changes over the Course of Infection Increases the Likelihood of Resistance Against Fusion but Not CCR5 Receptor Blockers

Chatziandreou

Araúz

Freitas

et al. 2012

AIDS Research and Human Retroviruses

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“…Both receptor occupancy and receptor sequestration can contribute to the inhibitory activity of both chemokines and chemokine analogs (13,23), and we next tested the hypothesis that potent nonsequestering molecules like 5P12-RANTES owe their enhanced anti-HIV activity to increased binding affinity for CCR5. We performed CCR5 binding affinity studies on 5P12-RANTES and a range of other structurally related chemokine analogs (Fig.…”

Section: Inhibitory Mechanism Of 5p12-rantes-increased Ccr5 Binding Amentioning

confidence: 99%

“…PSC-RANTES acts via an unusual mechanism involving the induction of long-term intracellular sequestration of CCR5 (10,13). This may be helpful for topical HIV prevention (14) because of prolonged protection of target cells after a single dose and setting a high barrier against the development of resistant viruses.…”

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confidence: 99%

Highly potent, fully recombinant anti-HIV chemokines: Reengineering a low-cost microbicide

Gaertner

Cerini

Escola

et al. 2008

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

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130

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New prevention strategies for use in developing countries are urgently needed to curb the worldwide HIV/AIDS epidemic. The N-terminally modified chemokine PSC-RANTES is a highly potent entry inhibitor against R5-tropic HIV-1 strains, with an inhibitory mechanism involving long-term intracellular sequestration of the HIV coreceptor, CCR5. PSC-RANTES is fully protective when applied topically in a macaque model of vaginal HIV transmission, but it has 2 potential disadvantages related to further development: the requirement for chemical synthesis adds to production costs, and its strong CCR5 agonist activity might induce local inflammation. It would thus be preferable to find a recombinant analogue that retained the high potency of PSC-RANTES but lacked its agonist activity. Using a strategy based on phage display, we set out to discover PSC-RANTES analogs that contain only natural amino acids. We sought molecules that retain the potency and inhibitory mechanism of PSC-RANTES, while trying to reduce CCR5 signaling to as low a level as possible. We identified 3 analogues, all of which exhibit in vitro potency against HIV-1 comparable to that of PSC-RANTES. The first, 6P4-RANTES, resembles PSC-RANTES in that it is a strong agonist that induces prolonged intracellular sequestration of CCR5. The second, 5P12-RANTES, has no detectable G protein-linked signaling activity and does not bring about receptor sequestration. The third, 5P14-RANTES, induces significant levels of CCR5 internalization without detectable G protein-linked signaling activity. These 3 molecules represent promising candidates for further development as topical HIV prevention strategies.HIV/AIDS ͉ phage display ͉ CCR5 ͉ PSC-RANTES

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“…One of these peptides, T-20, has been approved for clinical use (10 -12). Another strategy to inhibit HIV infection involves binding the co-receptor on the human cell surface, particularly CCR5 (1,(13)(14)(15)(16)(17)(18)(19)(20). Natural ligands for CCR5, namely chemokines MIP-1␤, MIP-1␣, and RANTES, 3 were found to be able to block HIV infection (21).…”

mentioning

confidence: 99%

Highly Potent Chimeric Inhibitors Targeting Two Steps of HIV Cell Entry

Zhao

Mankowski

Snyder

et al. 2011

Journal of Biological Chemistry

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Blocking HIV-1 cell entry has long been a major goal of anti-HIV drug development. Here, we report a successful design of two highly potent chimeric HIV entry inhibitors composed of one CCR5-targeting RANTES (regulated on activation normal T cell expressed and secreted) variant (5P12-RANTES or 5P14-RANTES (Gaertner, H., Cerini, F., Escola, J. M., Kuenzi, G., Melotti, A., Offord, R., Rossitto-Borlat, I., Nedellec, R., Salkowitz, J., Gorochov, G., Mosier, D., and Hartley, O. (2008) Proc. Natl. Acad. Sci. U.S.A. 105, 17706 -17711)) linked to a gp41 fusion inhibitor, C37. Chimeric inhibitors 5P12-linker-C37 and 5P14-linker-C37 showed extremely high antiviral potency in single cycle and replication-competent viral assays against R5-tropic viruses, with IC 50 values as low as 0.004 nM. This inhibition was somewhat strain-dependent and was up to 100-fold better than the RANTES variant alone or in combination with unlinked C37. The chimeric inhibitors also fully retained the antiviral activity of C37 against X4-tropic viruses, and this inhibition can be further enhanced significantly if the target cell co-expresses CCR5 receptor. On human peripheral blood mononuclear cells, the inhibitors showed very strong inhibition against R5-tropic Ba-L strain and X4-tropic IIIB strain, with IC 50 values as low as 0.015 and 0.44 nM, which are 45-and 16-fold better than the parent inhibitors, respectively. A clear delivery mechanism requiring a covalent linkage between the two segments of the chimera was observed and characterized. Furthermore, the two chimeric inhibitors are fully recombinant and are easily produced at low cost. These attributes make them excellent candidates for anti-HIV microbicides. The results of this study also suggest a potent approach for optimizing existing HIV entry inhibitors or designing new inhibitors.Approximately 33 million people are living with HIV, and millions more are infected each year.2 There is currently no vaccine, and treatments usually involve inhibiting viral activity post-infection by inhibiting the HIV protease or reverse transcriptase. More recently, therapies that target other parts of the viral life cycle have been approved, including an HIV integrase inhibitor (3).One of the most promising areas in the fight against HIV/ AIDS has been the development of entry inhibitors, which generally bind to either the viral surface or the human cell surface to stop HIV before it can enter a cell. The HIV surface protein gp120 first makes contact with the human cell surface protein CD4, which causes a conformational rearrangement in gp120, allowing the protein to then bind its co-receptor on the cell surface (either the chemokine receptor CCR5 or CXCR4). During this process, the HIV protein gp41 is exposed, and its fusion peptide enters the cell surface. Toward the end of the infection process, the C-terminal helical trimer folds over to contact the N-terminal trimer of gp41, forming a 6-helix bundle that likely pulls the membranes of the two entities in closer proximity to assist fusion of the vir...

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Two Mechanisms for Human Immunodeficiency Virus Type 1 Inhibition by N-Terminal Modifications of RANTES

Cited by 71 publications

References 47 publications

Sensitivity Changes over the Course of Infection Increases the Likelihood of Resistance Against Fusion but Not CCR5 Receptor Blockers

Sensitivity Changes over the Course of Infection Increases the Likelihood of Resistance Against Fusion but Not CCR5 Receptor Blockers

Highly potent, fully recombinant anti-HIV chemokines: Reengineering a low-cost microbicide

Highly Potent Chimeric Inhibitors Targeting Two Steps of HIV Cell Entry

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