Increased Human Immunodeficiency Virus (HIV) Type 1 DNA Content and Quinolinic Acid Concentration in Brain Tissues from Patients with HIV Encephalopathy

Abstract

Levels of human immunodeficiency virus type 1 (HIV-1) DNA and quinolinic acid were examined in areas of the central nervous system (CNS) and lymphoid organs (LN) from 5 AIDS patients with no clinically apparent CNS compromise (group I), 7 with CNS opportunistic diseases (group II), and 8 with HIV encephalopathy (group III). The brains from patients with HIV encephalopathy not only contained higher levels of HIV-1 DNA (cerebrum, P < .01; cerebellum, P < .05) as assessed by quantitative polymerase chain reaction but also showed a higher rate of viral pol region mutations suggestive of zidovudine or didanosine resistance than brains from patients in group I or II (P < .01). CNS quinolinic acid concentrations were significantly higher in group II and III patients than in group I (P = .03), even though quinolinic acid levels in LN were comparable among the 3 groups. These data suggest that CNS inflammatory changes associated with HIV encephalopathy may be triggered by a local productive HIV-1 infection within the CNS.

Induction of Indolamine 2,3-Dioxygenase in Primary Human Macrophages by Human Immunodeficiency Virus Type 1 Is Strain Dependent

“…Elevated levels of quinolinic acid, in particular, have been consistently observed in vivo in the cerebrospinal fluid and brain parenchyma of patients with ADC (1,19,36). The severity of neurological symptoms has been correlated with the increase in quinolinic acid levels in the brain in the simian immunodeficiency virus model of ADC (21).…”

“…Macrophages activated with HIV-1 or HIV-1 envelope glycoprotein (gp120) contribute to the production of a number of putative neurotoxins including glutamate (8), arachidonic acid metabolites (12,13), nitric oxide (12), platelet-activating factor (13), tumor necrosis factor alpha (12,13,38), and quinolinic acid (30,36). Elevated levels of quinolinic acid, in particular, have been consistently observed in vivo in the cerebrospinal fluid and brain parenchyma of patients with ADC (1,19,36).…”

“…Activated macrophages and microglia are apparently the only cells capable of catabolizing tryptophan to quinolinic acid in the CNS (20,25). Low levels of quinolinic acid production from HIV-1-infected macrophages have been observed (30,36); however, neither the mechanism of quinolinic acid synthesis (i.e., IDO induction) nor the effect of different viral strains on the induction of IDO has been previously investigated. Although the role of strain variability in the development of ADC is unknown, it has been suggested that conservation of key amino acids in the third hypervariable region (V3) of gp120 in brain-derived HIV-1 isolates correlates with their ability to infect brain microglia/macrophages (26,32).…”

The SIV-infected rhesus monkey model for HIV-associated dementia and implications for neurological diseases

“…The difficulty of measuring QUIN in CNS tissues has hampered our ability to examine this question more directly. However, direct measurement of QUIN in CNS tissues from HIV-infected humans at autopsy revealed higher levels in the CNS of patients with HIV encephalopathy or opportunistic infections than in patients with no clinically apparent CNS dysfunction [49]. A recent in vitro study found QUIN to be produced by HIVinfected monocytes at significantly higher levels on immune activation with lipopolysaccharide or interferon-␥, suggesting that viral infection, as well as immune activation, are key determinants of QUIN production [50].…”

Inhibition of murine embryonic growth by human immunodeficiency virus envelope protein and its prevention by vasoactive intestinal peptide and activity-dependent neurotrophic factor.

“…A recent study has shown that VIP can also prevent a similar NMDA-induced, nitric oxide-dependent injury in lung tissue (63). Elevated levels of quinolinate (64,65) and toxic products (including cytokines) released from macrophages/microglia have also been associated with increased levels of gp120 and may play a role in gp120 toxicity (55,59,60,66,67).…”