NeuroHIV is initiated by HIV crossing the blood brain

NeuroHIV is initiated by HIV crossing the blood–brain barrier (BBB) to enter the CNS. This is thought to occur primarily via the transmigration of infected CD14+CD16+ monocytes (Williams, 2014), using the monocytes as “Trojan Horses” (Peluso, 1985), although some studies suggest alternate routes of entry (Dohgu, 2012). These mature CD14+CD16+ monocytes, are enriched in people with HIV and are more susceptible to HIV infection (Williams, 2014, Ellery, 2007). The enrichment of this population is maintained in the presence of cART treatment (Castley, 2014), and is important to the development of HAND due to the disproportionate transmigration of CD14+CD16+ cells into the CNS (Williams, 2014, Fischer-Smith, 2001, Buckner, 2011). Within the CNS, infected monocytes differentiate into perivascular macrophages and shed new virions, which infect additional macrophages and microglia. In addition to being the primary target for HIV infection in the Kartogenin sale (Koenig, 1986, Navia, 1986, Williams and Hickey, 2002, Kraft-Terry, 2009, Rappaport and Volsky, 2015), myeloid cells are the primary reservoir for HIV in this compartment (Aquaro, 2002, Churchill and Nath, 2013). Astrocytes are infected at low levels (Eugenin and Berman, 2007, Churchill, 2009), and pericytes may also be infected (Cho, 2017), but the role of these cells in neuropathogenesis is unclear. Although T-cells are the primary focus of HIV in the periphery, in the CNS the primary cells involved in neuropathogenesis are myeloid cells. This is because relatively few T-cells are present in the CNS, and these mostly surveil brain regions outside the parenchyma (Wekerle, et al., 1986, Hickey et al., 1991, Ousman and Kubes, 2012). Increased T-cells, particularly CD8+T-cells, are found in the brains of HIV-infected drug abusers and those with CNS-immune reconstitution inflammatory syndrome (Gaskill, 2013). Polymorphonuclear neutrophils (PMNs) are the most abundant immune cells in the blood and can contribute to chronic immune activation during HIV infection (Yaseen, 2018). However, PMNs do not seem to be infected by HIV (Spear, 1990) and their role in HIV-neuropathogenesis is not clear. Because the cells primarily targeted by HIV are T-cells and macrophages, these cells will be the focus of the remainder of this review. In healthy individuals, CNS macrophages and microglia act as the primary immune response within the CNS, communicating with neurons by releasing a variety of cytokines and neurotrophic factors important to neuronal health and function (Kennedy and Silver, 2016, Colonna and Butovsky, 2017, London et al., 2013, Faraco, 2017). Infection of these cells dysregulates production and release of inflammatory cytokines and neurotoxic viral proteins, activating neighboring uninfected cells and inducing further production of factors that perpetuate the neuroinflammatory environment. Infected or activated myeloid populations are thought to be primary drivers of neuroinflammation, and prior to cART, development of dementia correlated with myeloid cell activation (Kraft-Terry, 2009, Rappaport and Volsky, 2015, Glass, 1995). Even with cART, immune activation is a critical component in the development of neurologic disease (Spudich, 2016). Infected brain tissue from cART-treated individuals shows upregulated CD68+expression, as well as CD16 and CD163 positivity, indicative of significant macrophage and microglia accumulation and activation (Tavazzi, 2014). Soluble factors of monocyte activation, CD14 and CD163, are increased in the plasma and cerebrospinal fluid (CSF) of HIV+individuals with neurocognitive impairment (Burdo, 2013, Kamat, 2012, Lyons, 2011, Kamat, 2012). Activated monocytes and macrophages produce a number of inflammatory factors including cytokines (IL-6, IL-1β, TNF-α, interferons), chemokines (CCL2, CXCL8, CXCL9, CXCL10), hydrolytic enzymes (matrix-metalloproteinases), and oxidative mediators (nitric oxide) (Arango Duque and Descoteaux, 2014, Laskin and Pendino, 1995). Production of these and other inflammatory and cytotoxic factors is thought to be central to the neuropathology of HIV infection in cART treated individuals (Saylor, 2016, Kraft-Terry, 2009, Burdo et al., 2013, Anthony and Bell, 2008, Anthony, 2005).