AEGiS-15IAC: Cell penetrating peptides binding Rev inhibit HIV replication in human PBMC and macrophages.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Cell penetrating peptides binding Rev inhibit HIV replication in human PBMC and macrophages.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. WeOrA1311)

Dereuddre-Bosquet N, Roisin A, Robin JP, Vitte AL, Dormont D, Clayette P, Jalinot P
LBMC, UMR5161-CNRS, ENS Lyon, Lyon, France

BACKGROUND: Tat and Rev proteins are necessary to HIV-1 replication. We have developed a rational strategy to identify small peptide sequences capable of penetrating within cells via the Tat basic domain and of binding to these essential HIV-1 regulatory proteins.

METHODS: Peptides were associated with a stabilizing domain consisting of human SUMO-1, allowing the generation of small proteins named SHPT and SHPR for those binding Tat and Rev, respectively. These proteins were stable and efficiently penetrated within primary lymphocytes. SHPRs bind the nuclear export sequence of Rev. Anti-HIV activities were evaluated using PHA-P-activated peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages, infected with HIV-1-LAI and HIV-1/Ba-L, respectively.

RESULTS: One SHPR inhibited HIV replication in both PBMC and macrophages, with ED50 of 615 and 850 nM, respectively and ED99 of 2 muM, in the absence of any cytotoxicity. One SHPT exhibited a slight activity in macrophages. To optimize the different parts of these fusion proteins, various mutations have been introduced in the anchor peptide, as well as in the Tat protein transduction domain. The effect of these inhibitors on the intracellular localization of Rev is also being analyzed.

CONCLUSIONS: These hybrid proteins may constitute prototypes of a new class of anti-HIV molecules targeting crucial functions exerted by viral regulatory factors. They could also allow structural studies to precise molecular interactions between Rev and active SHPR in order to design chemical inhibitors of Rev export. It is dedicated to the memory of Dr. D. Dormont.

Keywords: AEGIS, HIV, Acquired Immunodeficiency Syndrome, HIV Seropositivity, Gene Products, rev, Virus Replication, HIV-1, Gene Products, tat, Hominidae, Peptides, Anti-HIV Agents, Genes, tat, HIV Infections, Humans, Animal, metabolism, pharmacokinetics, virology, genetics

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