Background:  Macrophages are key cells for HIV infection and spreading inside the organism. Macrophages cultured in vitro can be successfully infected after differentiation with cytokines, such as macrophage colony stimulating factor (M-CSF). In the monocyte to macrophage differentiation process with M-CSF, an up-regulation of av-integrins is produced concomitantly to the HIV capacity to replicate in monocyte-derived macrophages. We have evaluated the role of av-integrins in the replication of HIV-1 in macrophages.

Methods:  Primary monocytes from healthy donors were used to generate M-CSF-derived macrophages (MDM). HIV receptor and co-receptor expression and av-integrin expression were measured by flow cytometry. HIV replication in acutely and chronic MDM as measured by p24 antigen production and HIV entry by qPCR analysis were used to evaluated the effect  of av-integrin ligands in HIV infection.

Results:  We show that an anti-av antibody, 17E6, inhibited HIV-1 infection of primary macrophages. The effect of 17E6 on HIV-1_BaL replication in acutely infected macrophages was dose-dependent, with a 50% effective concentration (EC₅₀) of 17±2 μg/mL and without cytotoxic effects. Similarly, an anti-avb6 antibody, 14D9.F8, inhibited HIV-1_BaL replication in MDM; 17E6 reduced synthesis of HIV-1_BaL proviral DNA in acutely infected macrophages as long as 18 hours post-infection, but was completely ineffective against HIV-1_BaL production in chronically infected macrophages, suggesting that this antibody inhibited HIV infection at an early stage of the virus cycle. Consistently, preincubation of differentiating monocytes with 17E6 decreased cell surface density of CD4, CCR5, and CD14 about 20, 40, and 50%, respectively. Conversely to av-integrin agonists vitronectin and fibronectin, 17E6 did not induce the production of chemokines (CCL3, CCL4, or CCL5) affecting HIV infection. A small molecular weight antagonist of av-containing integrins effectively blocked HIV replication in MDM but not in lymphoid CD4⁺ cells.

Conclusions:  Our results provide evidence for a role of av-containing integrins in HIV replication in macrophages, and suggest that small molecular weight compounds may be developed to interfere with HIV replication in macrophages through interaction with av-integrins.