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The V3 loop-mimicking pseudopeptide 5[Kpsi(CH2N)PR]-TASP inhibits HIV infection in primary macrophage cultures
1Unité de Virologie et Immunologie Cellulaire, ERS 572 CNRS, Institut Pasteur, Paris, France.
Abstract:
The V3 loop-mimicking pseudopeptide 5[Kpsi(CH2N)PR]-TASP [psi(CH2N) representing a reduced peptide bond], which presents pentavalently the tripeptide Kpsi(CH2N)PR, is a potent inhibitor of HIV entry. By its capacity to bind specifically protein components on the cell surface, 5[Kpsi(CH2N)PR]-TASP blocks the attachment of virus particles to permissive CD4+ cells. Here, the inhibitory effect of 5[Kpsi(CH2N)PR]-TASP was investigated in monocyte-derived macrophages (MDMs) infected by the monocytotropic HIV-1(Ba-L) isolate. We show that 5[Kpsi(CH2N)PR]-TASP inhibits HIV-1(Ba-L) infection in a dose-dependent manner, with more than 90% inhibition at 2 microM concentration. On the other hand, the control 5[QPQ]-TASP construct and the monovalent Kpsi(CH2N)PR tripeptide have no effect even at high concentrations. Under such experimental conditions, the biotin-labeled 5[Kpsi(CH2N)PR]-TASP, but not the Kpsi(CH2N)PR construct, binds specifically to the surface of MDMs and forms a stable complex with the cell surface-expressed nucleolin, as has been demonstrated to be the case in peripheral blood mononuclear cells. Infection of MDMs by HIV-1(Ba-L) could also be inhibited by beta-chemokines RANTES and MIP-1beta. Interestingly, association of low concentrations of 5[Kpsi(CH2N)PR]-TASP and beta-chemokines results in a synergistic inhibitory effect on HIV infection compared with the effect observed with each reagent alone. The inhibitory effect of 5[Kpsi(CH2N)PR]-TASP in primary macrophage cultures point out its potential as an anti-HIV drug in cells, which are the natural viral targets.
Insights
The pseudopeptide 5[Kpsi(CH2N)PR]-TASP effectively inhibits HIV-1 entry into macrophages by binding to cell surface proteins. This potent HIV inhibitor shows synergistic effects with beta-chemokines, highlighting its therapeutic potential.
Area of Science:
- Virology
- Immunology
- Drug Discovery
Background:
- Human Immunodeficiency Virus (HIV) entry into host cells is a critical step in viral pathogenesis.
- Monocyte-derived macrophages (MDMs) are primary targets for HIV infection.
- The V3 loop-mimicking pseudopeptide 5[Kpsi(CH2N)PR]-TASP is a known inhibitor of HIV entry.
Purpose of the Study:
- To investigate the inhibitory effect of 5[Kpsi(CH2N)PR]-TASP on HIV-1 infection in MDMs.
- To determine the mechanism of action of 5[Kpsi(CH2N)PR]-TASP in macrophages.
- To evaluate the potential synergistic effect of 5[Kpsi(CH2N)PR]-TASP with beta-chemokines.
Main Methods:
- Infection of MDMs with the monocytotropic HIV-1(Ba-L) isolate.
- Dose-dependent assessment of 5[Kpsi(CH2N)PR]-TASP's inhibitory activity.
- Biotin-labeled 5[Kpsi(CH2N)PR]-TASP binding assays to MDMs and nucleolin.
- Co-administration of 5[Kpsi(CH2N)PR]-TASP with beta-chemokines (RANTES, MIP-1beta).
Main Results:
- 5[Kpsi(CH2N)PR]-TASP demonstrated dose-dependent inhibition of HIV-1(Ba-L) infection in MDMs, achieving over 90% inhibition at 2 microM.
- Control constructs (5[QPQ]-TASP and monovalent Kpsi(CH2N)PR) showed no inhibitory effect.
- Biotin-labeled 5[Kpsi(CH2N)PR]-TASP specifically bound to MDM surfaces and formed a stable complex with cell surface-expressed nucleolin.
- A synergistic inhibitory effect on HIV infection was observed when 5[Kpsi(CH2N)PR]-TASP was combined with beta-chemokines.
Conclusions:
- 5[Kpsi(CH2N)PR]-TASP is a potent inhibitor of HIV-1 infection in primary macrophages.
- The mechanism involves binding to cell surface nucleolin, blocking viral attachment.
- The synergistic effect with beta-chemokines suggests a promising therapeutic strategy for HIV treatment in macrophages.