AEGiS-12IAC: Generation of recombinant analogues of the C-C chemokine RANTES with enhanced HIV-suppressive and reduced pro-inflammatory activity.

12th International AIDS Conference


Geneva, Switzerland - June 28-July 3, 1998

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Generation of recombinant analogues of the C-C chemokine RANTES with enhanced HIV-suppressive and reduced pro-inflammatory activity.

Int Conf AIDS 1998 Jun 28-Jul 3; 12:3 (abstract no. 11101)

Lusso P, Polo S, Nardese V, Prosperini E, De Santis C, Rizzi M, Bolognesi M
P2/P3 Laboratories-Dibit-San Raffaele, Scientific Inst., Milano, Italy.

OBJECTIVES: To generate analogues of the HIV-suppressive C-C chemokine RANTES with reduced pro-inflammatory side-effects and enhanced antiviral activity for potential therapeutic use in HIV-infected patients.

METHODS: The human RANTES cDNA was cloned from PHA-activated PBMC by PCR using primers that amplify the entire coding region of the chemokine. Different mutations were introduced into the wild-type (WT) gene by a modification of the overlap extension technique. A baculovirus expression system was used for the in vitro production of mature WT RANTES and analogues in soluble form. All the molecules were tested for their ability to: a) induce calcium mobilization in CCR5-expressing cells; b) chemoattract primary human lymphocytes and monocytes; c) inhibit infection in PBMC and macrophages by different laboratory-passaged and primary HIV-1 isolates characterized for viral coreceptor usage; d) induce CCR5 down-regulation in IL-2-expanded T cells; e) compete with radiolabeled WT RANTES for CCR5 binding in CCR5-expressing cells.

RESULTS: Two RANTES analogues, R15 and R17, demonstrated a markedly enhanced antiviral activity, compared to the WT, but failed to trigger CCR5-mediated calcium mobilization. The mechanism(s) responsible for the increased HIV-blocking effect of these mutants is currently under investigation. Other analogues showed a dramatic loss of antiviral potency, which generally correlated with a diminished pro-inflammatory activity.

CONCLUSIONS: By virtue of their unique biological characteristics, R15 and R17 represent suitable candidates for chemokine-based therapeutic approaches in HIV infection.

Keywords: AEGIS, RANTES, Chemokines, HIV Infections, HIV-1, HIV Seropositivity, Macrophages, T-Lymphocytes, Human, In Vitro, ICA12KWDaegis,rantes,chemokines,hivinfections,hiv-1,hivseropositivity,macrophages,t-lymphocytes,human,invitro,ica12
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Copyright © 1998 - International AIDS Society (IAS). Reproduction of this abstract (other than one copy for personal reference) must be cleared through the IAS.