A killer mimotope with therapeutic activity against AIDS-related opportunistic micro-organisms inhibits ex-vivo HIV-1 replication.
OBJECTIVE
To verify whether a synthetic therapeutic killer decapeptide (KP), a functional mimotope of a yeast killer toxin with wide-spectrum microbicidal activity, inclusive of AIDS-related opportunistic micro-organisms, through interaction with beta-glucan receptors, which has been found to possess sequence homology with critical segments in gp160 V1/V2 and V3 loops, may also be inhibiting HIV-1 replication.


METHODS
Primary peripheral blood mononuclear cells (PBMCs) cultures established from HIV-1-infected patients were treated with KP in comparison with zidovudine and supernatants and cells were harvested for analysis of HIV RNA and proviral contents, respectively. Virus production in exogenous in-vitro PBMCs infection with lymphocytotropic and monocytotropic HIV-1 strains was also assessed in presence of KP by enzyme-linked immunosorbent assay HIV p24 gag antigen detection. The binding affinity of KP to CD4, CCR5 and CXCR4 was evaluated on CD4-CCR5 or CD4-CXCR4 transfected astroglioma cell lines.


RESULTS
KP was shown to be devoid of cytotoxicity on PBMCs and to inhibit HIV-1 replication in PBMCs of a patient in the acute phase of infection. The antiretroviral activity of KP, which proved to be more potent than zidovudine at micromolar concentrations, is abolished by beta 1,3-glucan but not by beta 1,6-glucan. Down-regulation of CCR5 co-receptor, and/or physical block of the gp120-receptor interaction are possible mechanisms of KP activity.


CONCLUSIONS
KP appears to be the first antibody-derived short peptide displaying an inhibitory activity against HIV-1 and related opportunistic micro-organisms by different mechanisms of action.
Casoli
Claudio
C
Department of Clinical Medicine, Nephrology and Health Sciences, University of Parma, Viale Antonio Gramsci 14, 43100 Parma, Italy.
Pilotti
Elisabetta
E
Perno
Carlo Federico
CF
Balestra
Emanuela
E
Polverini
Eugenia
E
Cassone
Antonio
A
Conti
Stefania
S
Magliani
Walter
W
Polonelli
Luciano
L
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D019380:Anti-HIV Agents / Q000276:immunology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D019302:HIV Envelope Protein gp160 / Q000737:chemistry; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D018716:Molecular Mimicry / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D012367:RNA, Viral / Q000032:analysis; D019713:Receptors, CCR5 / Q000276:immunology; D019718:Receptors, CXCR4 / Q000276:immunology; D016415:Sequence Alignment; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology*; D015215:Zidovudine / Q000276:immunology / Q000627:therapeutic use
D019380:Anti-HIV Agents; D019302:HIV Envelope Protein gp160; D010455:Peptides; D012367:RNA, Viral; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015215:Zidovudine