Nef-induced CCL2 Expression Contributes to HIV/SIV Brain Invasion and Neuronal Dysfunction

Abstract

C-C motif chemokine ligand 2 (CCL2) is a chemoattractant for leukocytes including monocytes, T cells, and natural killer cells and it plays an important role in maintaining the integrity and function of the brain. However, there is accumulating evidence that many neurological diseases are attributable to a dysregulation of CCL2 expression. Acquired immune deficiency syndrome (AIDS) encephalopathy is a severe and frequent complication in individuals infected with the human immunodeficiency virus (HIV) or the simian immunodeficiency virus (SIV). The HIV and SIV Nef protein, a progression factor in AIDS pathology, can be transferred by microvesicles including exosomes and tunneling nanotubes (TNT) within the host even to uninfected cells, and Nef can induce CCL2 expression. This review focuses on findings which collectively add new insights on how Nef-induced CCL2 expression contributes to neurotropism and neurovirulence of HIV and SIV and elucidates why adjuvant targeting of CCL2 could be a therapeutic option for HIV-infected persons.

Central Nervous System (CNS) Viral Seeding by Mature Monocytes and Potential Therapies To Reduce CNS Viral Reservoirs in the cART Era

“…Suppressive cART inhibits active viral replication and infection of additional cells. It efficiently reduces the number of cells productively infected with HIV but does not eliminate cells harboring virus ( 3 – 9 ), viral reservoirs ( 10 – 13 ), or the production of viral proteins ( 14 , 15 ). The cells with suppressed or latent virus may contribute to rebound of viral replication upon cessation of cART ( 16 – 18 ) and to the development of HIV-associated comorbidities in people living with HIV (PLWH), including HIV-Associated Neurocognitive Disorders (HAND), that persist in 15 to 40% of PLWH in the cART era ( 19 , 20 ).…”

“…Once within the CNS, monocytes may differentiate into perivascular macrophages that can constitute long-lived viral reservoirs or release infectious virus that infect additional CNS cells, including macrophages, microglia, and astrocytes, all of which can persist as reservoirs despite long-term viral suppression with cART. HIV-infected CNS cells produce host and viral factors, such as Tat and Nef, and activate other CNS cells, leading to the release of neurotoxic mediators and cytokines, resulting in low-level chronic neuroinflammation and neuronal damage ( 14 , 15 , 25 – 27 ). This chronic neuroinflammatory environment persists despite cART, mediating recruitment of additional uninfected and HIV-infected cells, contributing to replenishment of CNS viral reservoirs, and possibly enabling persistence of HAND.…”

Neuromodulation of BAG co-chaperones by HIV-1 viral proteins and H2O2: implications for HIV-associated neurological disorders

“…Current experiments provided further mechanistic insights for the biomolecular underpinnings of HIV neuropathogenesis, particularly regarding the consequences of viral proteins on homeostatic functioning in neurons 21 , 58 . Further investigations are necessary to validate the physiological relevance of these data in the context of recombinant Tat and Nef proteins.…”

“…Furthermore, the consequences of Tat on cellular homeostasis may be due to its capacity to significantly increase levels of oxidative stress 14 – 17 . In addition, Nef may promote neuronal dysfunction through several complementary processes in the brain, including impaired metabolic activity, elevated neuronal cell death, and increased levels of neuroinflammation 18 – 21 . Consistent with the effect of Tat, elevations in oxidative stress are observed in response to Nef 22 – 24 .…”

Alzheimer’s-Like Pathology at the Crossroads of HIV-Associated Neurological Disorders

“…Finally, HIV infection, HAND, and amyloid pathology are closely associated with neuroinflammation. HIV/AIDS is an autoimmune disease, directly infecting T cells, peripheral and central macrophages, and other glial cells, which release proinflammatory cytokines such as interleukin-1β, interferon-α, and TNFα [ 166 , 167 , 168 ]. HIV proteins, such as Nef, have also been linked to the downregulation of crucial scavenger proteins such as CD63 [ 167 ].…”