Migration of monocytes from the bloodstream across vascular endothelium is required for routine immunological surveillance of tissues and their entry into inflamed sites. Transendothelial migration of monocytes initially involves tethering of cells to the endothelium, followed by loose rolling along the vascular surface, firm adhesion to the endothelium and diapedesis between the tightly apposing endothelial cells. A number of adhesion molecules are involved in this process. Monocyte rolling can be mediated by selectins and their ligands, or alpha(4)beta(1) integrin interacting with endothelial VCAM-1. On the apical surface of the endothelial cell, bound chemokines (eg. MCP-1, MIP-1alpha/beta) can activate leukocyte beta(2) integrins for tight adhesion to ICAM-1 and -2. Diapedesis by monocytes occurs through interaction between PECAM-1 on both the monocyte and the endothelial cells, followed by similar homophilic adhesion via CD99. After penetration of the endothelial basement membrane, monocytes migrate through the extracellular matrix of the tissues where they may differentiate into tissue macrophages and/or migrate to sites of inflammation. Additionally, monocytes in the tissues may traffic to the lymphatics or back into the bloodstream, both of which involve basal to apical (reverse) transendothelial migration, possibly mediated by tissue factor and p-glycoprotein. Monocyte trafficking is of current interest in studies of the pathogenesis of HIV-infection, including establishment of viral reservoirs in tissues and sanctuary sites and the development of HIV-related dementia. This review provides insights into the most recent studies on the process of monocyte migration across the vascular endothelium, and changes in migration that can occur during HIV-infection.

Monocyte phenotype and function were measured in whole blood sampled from a current cohort of human immunodeficiency virus (HIV)-infected individuals attending a large, metropolitan, university-affiliated hospital. There was no significant difference in the prevalence of CD16+ monocytes or the capacity of monocytes to ingest heat-killed Mycobacterium avium complex between these individuals and HIV-uninfected control subjects, regardless of viral load, current CD4+ T cell count, nadir CD4+ T cell count, or time since diagnosis of HIV infection. CD16+ monocyte prevalence was, however, elevated in patients not currently receiving antiretroviral therapy. We conclude that HIV type 1 infection in the setting of highly active antiretroviral therapy is associated with normal monocyte function and phenotype.

Defective function of monocyte-derived macrophages contributes to HIV-1 pathogenesis. We found that phagocytosis of the opportunistic pathogens Mycobacterium avium complex and Toxoplasma gondii was impaired in monocytes obtained from individuals infected with wild-type strains of HIV-1 but generally not in monocytes collected over a 6-year period from Sydney Blood Bank Cohort (SBBC) members infected with nef/long terminal repeats (LTR) region-defective strains of HIV-1. However, longitudinal analysis of phagocytosis in 1 SBBC member, C54, showed the development of defective engulfment of opportunistic pathogens at the most recent time points, coincident with the development of further molecular deletions in the nef/LTR region. Another SBBC member, C98, underwent bronchoscopy, which provided material to examine phagocytic signaling in alveolar macrophages. In contrast to normal phagocytic efficiency of C98's monocytes (over a 6-year period), defective signaling events during FcgammaR-mediated phagocytosis by C98's alveolar macrophages were observed. High basal phosphorylation within HIV-infected macrophages correlated with colocalization of tyrosine-phosphorylated proteins with HIV-1 p24 antigen rather than around the phagocytic targets as observed in uninfected cells. Thus, although phagocytic efficiency appears to be generally unimpaired in monocytes from SBBC members, evidence of impairment in recent samples from 1 SBBC member, coincident with further genetic changes within the virus, and abnormal phagocytic signaling in alveolar macrophages from another SBBC member may herald loss of attenuation of those strains.