Figure 1.

Mechanistic model of HIV-1 neuroinvasion. (1) The physiological expression of chemokines by brain cells, among which are soluble fractalkine (Fkn) and CXCL12, supports a slow but continuous entry of monocytes and macrophages into the central nervous system. Due to their expression of CX₃CR1, CD16 positive, activated monocytes are the preferential targets for such attraction. These CD16 positive monocytes are the main reservoir of monocyte/macrophage-harbored virus and are thus likely to be the predominant cell type carrying HIV into the brain. (2) Infiltrated HIV-infected monocytes locally produce HIV and inflammatory mediators in perivascular areas. This activates neighbouring astrocytes as well as the blood brain barrier (BBB) endothelium. (3) In response, endothelial cells up-regulate adhesion molecules, enhancing monocyte recruitment. However, membrane-bound Fkn is also induced on endothelial cells and can arrest CD16 positive monocytes at the endothelium thus inhibiting their further infiltration. (4) CCL2 is overexpressed by infected, HIV-stimulated macrophages and activated astrocytes, attracting CD16 negative, CCR2 positive monocytes toward the perivascular area. (5) Both CXCL12 and nerve growth factor (NGF) are overexpressed in the inflamed brain. NGF increases CXCR4 expression and promotes uninfected monocyte attraction by CXCL12. At the same time it limits entry of infected monocytes into the brain. (6) Activated uninfected perivascular macrophages may be targets for de novo infection by locally produced HIV, amplifying the activation - attraction - infection cycle. (7) Local inflammation as well as HIV products induce tight junction disorganization and lead to breaches in the BBB. Toxic serum proteins and free virions may enter the brain, favouring more infection and further amplifying inflammation.