Rational Engineering of a Sub-Picomolar HIV-1 Blocker

Massimiliano Secchi; Luca Vangelista

doi:10.3390/v14112415

Rational Engineering of a Sub-Picomolar HIV-1 Blocker

Viruses. 2022 Oct 31;14(11):2415. doi: 10.3390/v14112415.

Authors

Massimiliano Secchi^{1

2}, Luca Vangelista^{1

3}

Affiliations

¹ Protein Engineering and Therapeutics Group, Department of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, 20132 Milan, Italy.
² DNA Enzymology and Molecular Virology Unit, Institute of Molecular Genetics, National Research Council, 27100 Pavia, Italy.
³ Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan.

Abstract

With the aim of rationally devising a refined and potent HIV-1 blocker, the cDNA of CCL5 5p12 5m, an extremely potent CCR5 antagonist, was fused to that of C37, a gp41-targeted fusion inhibitor. The resulting CCL5 5p12 5m-C37 fusion protein was expressed in E. coli and proved to be capable of inhibiting R5 HIV-1 strains with low to sub-picomolar IC₅₀, maintaining its antagonism toward CCR5. In addition, CCL5 5p12 5m-C37 inhibits R5/X4 and X4 HIV-1 strains in the picomolar concentration range. The combination of CCL5 5p12 5m-C37 with tenofovir (TDF) exhibited a synergic effect, promoting this antiviral cocktail. Interestingly, a CCR5-targeted combination of maraviroc (MVC) with CCL5 5p12 5m-C37 led to a synergic effect that could be explained by an extensive engagement of different CCR5 conformational populations. Within the mechanism of HIV-1 entry, the CCL5 5p12 5m-C37 chimera may fit as a powerful blocker in several instances. In its possible consideration for systemic therapy or pre-exposure prophylaxis, this protein design represents an interesting lead in the combat of HIV-1 infection.

Keywords: CCL5; CCR5; HIV-1; drug combination; entry inhibitor; protein engineering.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CCR5 Receptor Antagonists / pharmacology
CCR5 Receptor Antagonists / therapeutic use
Escherichia coli / metabolism
HIV Infections* / metabolism
HIV Seropositivity*
HIV-1*
Humans
Maraviroc / pharmacology
Maraviroc / therapeutic use
Receptors, CCR5 / genetics
Receptors, CCR5 / metabolism

Substances

Receptors, CCR5
Maraviroc
CCR5 Receptor Antagonists

Grants and funding

This research was funded by a European Union’s Framework Program 7 grant to L.V. (242135) “Combined Highly Active Anti-Retroviral Microbicides, CHAARM consortium” and by a Nazarbayev University grant to L.V. (021220FD2551) “Expanding the therapeutic landscape of CCR5 blockade and CCL5 engineering”.