Abstract

HIV-1 infection of cells of macrophage lineage impairs a number of effector functions performed by these cells, including phagocytosis of opsonized pathogens.

In this study we investigate the effects of HIV-1 on the mechanism of complement (C')-mediated phagocytosis by human monocyte-derived macrophages (MDM).

Using C'-opsonized sheep red blood cells (sRBC) as targets, we demonstrate that phagocytosis is inhibited by HIV-1 infection in vitro.

Inhibition is not due to downregulation of surface C' receptors ® or altered binding of C'-opsonized targets to HIV-1-infected MDM, suggesting a postreceptor-mediated mechanism of suppression.

Having shown that increased levels of intracellular cAMP in uninfected MDM inhibit phagocytosis, we demonstrate that HIV-1 infection of MDM is associated with increased intracellular cAMP.

Using the adenylate cyclase inhibitors 2',5'-dideoxyadenosine and MDL-12,330A, we show that phagocytosis by HIV-1- infected MDM can be restored by inhibition of cAMP production.

Defective phagocytosis by HIV-1-infected MDM did not correlate with prostaglandin secretion, and was less in uninfected MDM within the HIV-1-infected cell culture suggesting a minimal bystander effect.

Inhibition required viral entry but not active viral replication, as shown by use of the antiretroviral drug lamivudine.

Hence, our study suggests that HIV-1 impairs C'R-mediated phagocytosis in MDM by elevating intracellular cAMP levels, independent of prostaglandin secretion, and contributes to our understanding of how HIV-1 impairs cell-mediated immunity.