AEGiS-11IAC: Effect of MIP-1a, MIP-1beta and RANTES on suppression of HIV replication in T cell blasts and dendritic cell/CD4+ T cell cocultures.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

Effect of MIP-1a, MIP-1beta and RANTES on suppression of HIV replication in T cell blasts and dendritic cell/CD4+ T cell cocultures.

Int Conf AIDS 1996 Jul 7-12; 11:226 (abstract no. Tu.A.391)
Rubbert A, Weissman D, Daucher J, Pettrone K, Barker T, Combadiere C, Murphy PM, Fauci AS; National Institutes of Health, Bethesda, MD, USA.

OBJECTIVE: To analyze the effect of beta-chemokines in suppressing HIV replication in standard T cell blast and dendritic cell-T cell coculture systems.

METHODS: Dendritic cells (DC) are capable of activating CD4+ T cells in the absence of mitogen. In one system, we employed DC and CD4 cells from HIV-uninfected donors and the DC were pulsed with primary or laboratory isolates of HIV-1. In another system, DC and CD4+ T cells from HIV-infected donors were used. Chemokines, ranging from 0.1 to 1000ng/ml, were added at the initiation of culture and subsequently every second or third day.

RESULTS: Recently, MIP-1a, MIP-1beta and RANTES have been identified in supernatants of HTLV-1 transformed CD8+ T cell lines and from stimulated CD8+ T cells from HIV-infected individuals; these factors mediated suppressive effects on viral replication in the PM-1 CD4 cell clone or PHA-stimulated PBMC infected with various laboratory and primary isolates of HIV (Cocchi et al, Science 1995). We have recently described an in vitro model for studying HIV replication which mimics the cellular interactions that occur at the primary site of HIV replication, the lymphoid microenvironment. DC were cocultured with autologous CD4+ T-cells, which resulted in viral replication in the absence of exogenous stimulation. CD8+ T-cells from HIV-infected patients were able to inhibit viral replication in these systems. However, MIP-la, MIP-1beta and RANTES did not demonstrate any inhibitory effect on viral replication in the DC systems, while demonstrating efficient inhibition in T cell blasts. The addition of neutralizing anti-chemokine antibodies did not abrogate the CD8+ T-cell mediated suppressor effect. Using functional assays (calcium influx) of the expression and integrity of beta chemokine receptors in the two systems, we could not completely explain the discordance between T cell blasts and DC-CD4+ Tcell systems with regard to beta chemokine effects.

CONCLUSIONS: Our data indicate, that MIP-1a, MIP-1beta and RANTES are not responsible for the suppressive effect mediated by HIV-positive CD8+ cells in the DC/CD4 coculture system. Other mechanisms, in addition to receptor expression, appear to be important in the divergence in the effect observed between T cell blasts and DC-CD4+ T cell systems.

Keywords: AEGIS, Macrophage Inflammatory Protein-1, RANTES, HIV, Antigens, CD4, T-Lymphocytes, Virus Replication, Dendritic Cells, HIV-1, HIV Infections, Coculture, Antigens, CD8, Chemokines, Chemokines, CC, HIV Long Terminal Repeat, HIV Core Protein p24, Clone Cells, In Vitro, Human, virology, genetics, ICA11

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