HIV-1 infection and AIDS: consequences for the central nervous system

Kaul, Marcus; Zheng, Jialin; Okamoto, Shu-ichi; Gendelman, Howard Eliot; Lipton, Stuart A.

doi:10.1038/sj.cdd.4401623

Cited by 328 publications

(365 citation statements)

References 190 publications

(274 reference statements)

Supporting

Mentioning

362

Contrasting

Unclassified

Order By: Relevance

“…However, increasing evidence suggests that inflammation is actively involved in the pathogenesis of HAD (7)(8)(9)(10). HIV encephalitis (HIVE), the pathologic correlate of HAD is characterized by the presence of unusually large numbers of HIV-infected macrophages in the brain, formation of multinucleated giant cells, activation of astrocytes and microglia, all accompanied by cytokine/ chemokine dysregulation, and neuronal degeneration (7,(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Roles of MCP-1 in development of HIV-dementia

Dhillon¹

2008

Front Biosci

View full text Add to dashboard Cite

The encephalopathy caused by HIV, known clinically as HIV-associated dementia (HAD) and pathologically as HIV encephalitis (HIVE), results from intense infiltration of mononuclear cells, productive replication of the virus in monocyte-derived macrophages/microglia, abortive replication in astrocytes and activation of macrophages/microglia and astrocytes leading to neuronal degeneration in the brains of infected persons. Recent findings have suggested that development of HAD is based more on the activation process than on direct evidence of virus replication in the brain. Since HAD is based on the encephalitic process, major studies have been directed to the mechanisms regulating the inflammatory process. Monocyte chemoattractant protein 1, MCP-1, is a chemokine that is implicated in this process and also in the development of activation in the brain. In this review, we have attempted to identify mechanisms that induce expression of MCP-1 in the brain and the role that it plays in recruitment of mononuclear cells from blood to brain and in the activation processes of inflammatory and neural cells that lead to development of degenerative changes in the neuronal population. KeywordsHIV-1; HAD; Neurons; Astrocytes; Macrophages; Blood Brain Barrier; Review INTRODUCTIONIn recent years the incidence of HIV-associated dementia (HAD) as an AIDS-defining illness has actually increased (1-4) with more prevalence of minor cognitive/motor disorder than frank dementia (5,6). Approximately 20% of AIDS patients develop neurological deficits severe enough to be diagnosed as dementia (1) and therefore, HAD still remains a significant independent risk factor for AIDS-related death.The CNS has been thought to be an immunologically privileged organ. However, increasing evidence suggests that inflammation is actively involved in the pathogenesis of HAD (7-10). HIV encephalitis (HIVE), the pathologic correlate of HAD is characterized by the presence of unusually large numbers of HIV-infected macrophages in the brain, formation of multinucleated giant cells, activation of astrocytes and microglia, all accompanied by cytokine/ chemokine dysregulation, and neuronal degeneration (7,(11)(12)(13)(14). The highly productive infection in macrophages in the brain is also accompanied by an abortive infection in astrocytes [15][16][17][18]. Although the primary cell types infected by HIV-1 in the brain are macrophages/ microglia, and to a lesser extent, astrocytes but not neurons, the low numbers of infected cells in the brain do not correlate with the severity of encephalopathy. Rather, the severity of HAD/ HIVE correlates with the presence of activated glial cells rather than with the presence and amount of HIV-infected cells in the brain and the current thinking about the disease is that CNS injury is mainly caused by the release of neurotoxic factors by immune-activated glial cells (7,13). The combined infection of macrophages/microglia and astrocytes leads to excessive production of viral gene products and host immune response fac...

show abstract

Section: Introductionmentioning

confidence: 99%

Roles of MCP-1 in development of HIV-dementia

Dhillon¹

2008

Front Biosci

View full text Add to dashboard Cite

show abstract

“…Both groups of receptors and their ligands are widely expressed in the brain throughout life and implicated in neuronal development and in neuroimmune responses (Law et al, 2000;Tran and Miller, 2003;Klein and Rubin, 2004;Cartier et al, 2005). Furthermore, chemokine receptors, namely CCR5 and CXCR4, mediate infection of target cells by human immunodeficiency virus (HIV)-1 and are directly involved in the neuronal injury/death caused by the HIV envelope protein gp120 (Miller and Meucci, 1999;Kaul et al, 2005). The natural CXCR4 ligand is SDF-1 (recently renamed CXCL12), one of the best-characterized chemokines in the central nervous system (CNS) that regulates neural migration, differentiation, and survival .…”

Section: Introductionmentioning

confidence: 99%

Modulation of neuronal CXCR4 by the μ-opioid agonist DAMGO

et al. 2006

View full text Add to dashboard Cite

The chemokine receptor CXCR4 regulates neuronal survival and differentiation and is involved in a number of pathologies, including cancer and human immunodeficiency virus (HIV). Recent data suggest that chemokines act in concert with neurotransmitters and neuropeptides, such as opioids. This study aimed to determine whether μ-opioid agonists alter the effect of CXCL12 (the specific CXCR4 ligand) on central neurons. Neuronal expression of CXCR4 and μ-opioid receptors (MORs) was analyzed by Western blot, immunostaining, and flow cytometry. Single-cell studies showed that all CXCR4-positive neurons coexpress MORs. Treatment of neuronal cultures with the selective MOR agonist DAMGO or the endogenous peptide endomorphin-1 inhibited intracellular signaling pathways (ERK1/2 and Akt) activated by CXCL12. Furthermore, DAMGO abolished the neuroprotective effect of CXCL12 in N-methyl-d-aspartate (NMDA) neurotoxicity studies. The effects of DAMGO and endomorphin-1 were inhibited by a general or a μ-specific opioid receptor antagonist, and not caused by changes in neuronal CXCR4 levels. DAMGO did not affect CXCL12-induced internalization of CXCR4. The authors propose that interactions between MOR and CXCR4 signaling can modulate the action of CXCL12 on neuronal survival-which may have important implications to neuroAIDS as well as other neuroinflammatory disorders.

show abstract

“…HIV also targets monocytes and macrophages early during infection, which enable HIV to establish viral reservoirs in the lymphoid tissue and the CNS (Gendelman, Lipton et al 1994;GonzalezScarano and Martin-Garcia 2005;Kaul, Zheng et al 2005). In fact, extensive in vitro and in vivo studies support the "Trojan Horse" model of HIV infection in the CNS (Liu, Lossinsky et al 2002).…”

Section: Neuropathology Of Handmentioning

confidence: 97%

“…Once in the CNS, infected monocytes differentiate into macrophages, which then constitute viral reservoirs in the brain. A small number of neurons and glia may also become infected; however, such infection is not productive (Gendelman, Lipton et al 1994;Kaul, Zheng et al 2005). Two major mechanisms of neuronal damage have been proposed: 1) Direct neurotoxicity by viral proteins such as HIV envelope glycoprotein (gp120) and HIV transactivator of transcription (Tat) protein, and, 2) Indirect neurotoxicity induced by soluble factors released by infected and/or activated macrophages including, but not limited to, quinolinic acid, TNF-, reactive oxygen species (ROS), and cytokines such as CXCL12 (stromal cell-derived factor-1, SDF-1), CCL2 (monocyte chemotactic protein-1, MCP-1), and interleukin-6 (IL-6) (Price, Brew et al 1988;Giulian, Yu et al 1996;Soontornniyomkij, Nieto-Rodriguez et al 1998;Lindl, Marks et al 2010).…”

Section: Neuropathology Of Handmentioning

confidence: 99%