Monocytes mediate HIV neuropathogenesis: mechanisms that contribute to HIV associated neurocognitive disorders

Abstract

HIV infected people are living longer due to the success of combined antiretroviral therapy (cART). However, greater than 40-70% of HIV infected individuals develop HIV associated neurocognitive disorders (HAND) that continues to be a major public health issue. While cART reduces peripheral virus, it does not limit the low level, chronic neuroinflammation that is ongoing during the neuropathogenesis of HIV. Monocyte transmigration across the blood brain barrier (BBB), specifically that of the mature CD14(+)CD16(+) population that is highly susceptible to HIV infection, is critical to the establishment of HAND as these cells bring virus into the brain and mediate the neuroinflammation that persists, even if at low levels, despite antiretroviral therapy. CD14(+)CD16(+) monocytes preferentially migrate into the CNS early during peripheral HIV infection in response to chemotactic signals, including those from CCL2 and CXCL12. Once within the brain, monocytes differentiate into macrophages and elaborate inflammatory mediators. Monocytes/macrophages constitute a viral reservoir within the CNS and these latently infected cells may perpetuate the neuropathogenesis of HIV. This review will discuss mechanisms that mediate transmigration of CD14(+)CD16(+) monocytes across the BBB in the context of HIV infection, the contribution of these cells to the neuropathogenesis of HIV, and potential monocyte/macrophage biomarkers to identify HAND and monitor its progression.

Figure 1. Schematic Representation of Mechanisms of CNS HIV Infection and Damage

CD14⁺CD16⁺ monocytes, which were infected with HIV while in the peripheral circulation, transmigrate across the BBB and enter the brain parenchyma in response to baseline levels of chemokine. Infectious virus is released as the mature monocytes enter the CNS and also as they differentiates into macrophages. This virus can then infect macrophages, microglia, and a small percent of astrocytes. Viral proteins, such as tat and gp120, and inflammatory mediators are released from these infected cells which activate the surrounding resident CNS cells. The activated cells produce cytokines, including TNF-α, IL-1β, and IL-6 and chemokines, including CCL2 and CXCL12. The elevated levels of CCL2 and CXCL12 promote additional influx of uninfected and HIV infected monocytes into the brain. Small molecules, such as arachidonic acid and quinolinic acid, are also produced. The elaboration of chemotactic, inflammatory, and neurotoxic factors perpetuates the cycle of chronic inflammation within the CNS and ultimately result in the neuronal damage and loss associated with HAND.

Figure 2. CXCL12 and CCL2 Promote Transmigration of CD14⁺CD16⁺ Monocytes Across a Tissue Culture Model of the Human BBB

Monocytes from 4 independent donors were cultured nonadherently for 3 days in our system and then added to the top of our in vitro model of the human BBB and transmigrated in response to media alone, 25 ng/mL CXCL12, and 200 ng/mL CCL2 for 24 hours. Both chemokines promoted increased transmigration of CD14⁺CD16⁺ monocytes across the BBB as compared to media alone (*p<0.05, n=4). NS indicates no significant change.