Integrating integrins into HIV pathogenesis

In this issue of Blood, Ballana and colleagues show that integrins that mediate macrophage adhesion are important for HIV replication and inhibition of these integrins suppresses HIV replication at the transcriptional level.

In the absence of integrins, every person would probably disintegrate into a pile of cells! These transmembrane proteins, together with other membrane receptors, mediate cell- to-cell interactions and cell binding to the extracellular matrix (ECM), supporting tissue structure. Nevertheless, if all that integrins did was to cement our tissues, one type would probably be enough. In reality, there are more than 20 different integrins (formed by α and β heterodimers), and their diversity reflects the complexity and diversity of the signals that they transmit into the cell. Integrins represent the cell's exploratory organ. Cell attachment, spreading, and locomotion, as well as other sophisticated cellular functions like growth, division, and apoptosis, are dependent on integrin-mediated signals.

It is not surprising that viruses exploit integrins for their own benefit. In recent years, integrins have emerged as attachment or entry receptors for a large number of viruses, including herpes-, rota-, adeno-, and flavi-viruses.¹  Obviously, HIV-1 did not lose the opportunity to use integrins as well. Recently, it was reported that the HIV-1 envelope binds and signals through α₄β₇ integrin, the homing receptor for gut lymphocytes, providing another explanation for the critical importance of gut tissue in HIV disease.² 

Here, Ballana et al present evidence that αV-containing integrins play an important role in HIV-1 infection of macrophages. The differentiation of monocytes into macrophages requires cell attachment and is accompanied by up-regulation of these integrins. However, blocking of αV integrins by a small molecule or suppression of their expression by siRNA not only decreases macrophages' attachment/spreading but also reduces HIV replication in these cells (see figure). The authors present evidence that this reduction is due to decreased activation of NF-κB.

What contribution do these results offer to the understanding of basic mechanisms of HIV infection and to the development of new anti-HIV therapies? Engagement of integrins with the ECM in the course of differentiation of circulating monocytes into tissue macrophages may enhance viral replication and thus facilitate HIV tissue dissemination. Inhibition of αV integrins suppresses HIV replication only partially, and, in spite of this inhibition, cells still remain partially attached. It is possible that molecules (other than the αV integrins targeted in this work) that are involved in cell adhesion can play a role in modulating HIV-1 replication by affecting macrophage attachment. In detached cells, other elements of cell machinery besides blockage of integrin-signaling pathways may become incompatible with HIV replication (eg, inappropriate actin polymerization, intracellular pH, calcium levels).

Unfortunately, the development of new anti-HIV therapies based on these results is not in sight. First, suppression of integrin expression inhibits HIV replication only by approximately 50%, too little for an efficient therapy. Second, the consequences of severing the adhesion of macrophages and probably other cells to the ECM would be too drastic for this process to be used as a therapeutic intervention. However, the history of science shows that it is often difficult to foresee practical applications of basic scientific discoveries. In this case, full understanding of the complicated and possibly redundant system of integrins may permit targeting of only those that are essential for HIV infection. This work by Ballana et al is a step toward understanding whether this will be possible.