Review
HIV-1 neuroimmunity in the era of antiretroviral therapy

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Abstract

Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) can affect up to 50% of infected people during the disease course. While antiretroviral therapies have substantively increased the quality of life and reduced HIV-1-associated dementia, less severe minor cognitive and motor deficits continue. Trafficking of HIV-1 into the central nervous system (CNS), peripheral immune activation, dysregulated glial immunity, and diminished homeostatic responses are the disease-linked pathobiologic events. Monocyte–macrophage passage into the CNS remains an underlying force for disease severity. Monocyte phenotypes may change at an early stage of cell maturation and immune activation of hematopoietic stem cells. Activated monocytes are pulled into the brain in response to chemokines made as a result of glial inflammatory processes, which in turn, cause secondary functional deficits in neurons. Current therapeutic approaches are focused on adjunctive and brain-penetrating antiretroviral therapies. These may attenuate virus-associated neuroinflammatory activities thereby decreasing the severity and frequency of HAND.

Introduction

Human immunodeficiency virus-1 (HIV-1) targets CD4+ cells that include a subset of lymphocytes and a broad range of mononuclear phagocytes (MP; monocytes, dendritic cells, tissue macrophages, and microglia). Over time, this leads to profound immunodeficiency and an increased host susceptibility to a broad range of opportunistic infections (Ong, 2008). Moreover, continuous viral replication can directly impact end-organ dysfunction, particularly in the lung and central nervous system (CNS) (Everall, 2009, Hull, 2008). The advent of antiretroviral therapy (ART), however, has significantly changed the landscape of HIV neuropathogenesis (Cysique and Brew, 2009). Disease is no longer a result of continuous productive virus infection and activation of brain MP but rather a result of more limited infection and neuroinflammation. Although widespread ART usage in resource available settings has increased life expectancy for virus-infected individuals with a concomitant decrease in disease morbidities (Achmat and Simcock, 2007, Aracena-Genao, 2008), neurological complications continue to persist. This may be attributed to viral mutation and ART resistance; failure of drugs to access viral sanctuaries and toxicities or poor compliance to complex ART regimens (Battegay and Elzi, 2009, Blankson, 2006, Kiertiburanakul and Sungkanuparph, 2009, Krusi, 2009). Illicit drug usage (Cabral, 2006) and lack of ART availability (Cohen, 2007) may also influence neurological disease manifestations. Of these, the most feared long-term complication of HIV-1 disease is cognitive dysfunction.

During the disease course, it is estimated that the prevalence of disease may be as many as 50% of HIV-1-infected individuals will suffer from some form of impairment if asymptomatic neurocognitive disorder is included (McArthur et al., 2005). Although the incidence of HIV-1-associated dementia (HAD), the most severe form of CNS impairment, has been reduced significantly, now affecting < 7% of infected people following ART, a concomitant increase in minor cognitive impairments is emerging (Fischer-Smith and Rappaport, 2005). The spectrum of such neurocognitive impairment, now termed HIV-1-associated neurocognitive disorders (HAND), includes asymptomatic neurocognitive impairment and varying degrees of HIV-associated mild neurocognitive disorders (Antinori et al., 2007). HAND is associated with immune suppression. Chronic neuroinflammation causes a metabolic encephalopathy that is fueled by MP viral infection and immune activation (Langford, 2003, Yadav and Collman, 2009, Zheng and Gendelman, 1997). In the pre-ART era, this often paralleled the development of HIV-1 encephalitis (HIVE), a pathological correlate of HAD. Neuropathologically, HIVE is characterized by the formation of multinucleated giant cells (Sharer et al., 1985), myelin pallor (Petito et al., 1986), formation of microglial nodules, astrogliosis, productive viral replication, and neuronal dropout (Masliah, 1996, Ances and Ellis, 2007). While incidence of HIVE is now quite rare in the setting of ART, more subtle neuropathological alterations are common. These include blood-borne monocyte brain infiltration and limited gliosis (Everall et al., 2005). Indeed, it is uncertain whether or not ongoing viral replication in the brain is required for the development of milder forms of HAND. Limited histopathologic aberrations in the brain characterize mild cognitive dysfunction, leading to the speculation that glial activation may be a key determinant driving the process (Everall et al., 2005).

ART can also lead to a reversal of severe cognitive dysfunction (Gendelman et al., 1998). Nonetheless, and despite changes in disease severity, viral reservoirs within the CNS remain common and significant (Kramer-Hammerle et al., 2005). Virus can enter the brain as cell-free progeny, in monocyte–macrophages or in T cells (Banks et al., 2004). Restricted HIV-1 infection continues in circulating monocytes and resting CD4+ lymphocytes (Lambotte et al., 2003). Furthermore, both cell types can productively replicate virus following cell differentiation and activation (Alexaki et al., 2008) and, in this way, enable viable cellular reservoirs for HIV-1 to ensue and evade ART (McGee et al., 2006). Intriguingly, HIV-1 can cross the blood–brain barrier (BBB) through blood-borne monocytes, thereby escaping immune surveillance (Nottet, 1996, Persidsky, 1997). The specific mechanism(s) by which inflammatory cells are recruited into the CNS revolves around peripheral immune activation (push) and an established chemokine gradient (pull) established within the CNS as a result of viral infection and glial immune activation (Dhillon, 2008, Persidsky, 1999, Shacklett, 2004). There exists a carefully orchestrated cooperation between chemokine release from the CNS and chemotaxis and differentiation of monocyte progenitor cells from the bone marrow (Hasegawa, 2009, Soulas, 2009, Westhorpe, 2009). This cooperation, in turn, ultimately culminates into neuroimmune inflammatory responses and neuronal impairments (Coleman and Wu, 2009).

Section snippets

Crosstalk between the peripheral and CNS immunity

A Trojan horse cell model can explain how HIV-1-infected monocytes escape immune surveillance (Gendelman, 1985, Haase, 1986). The “pull” for viral entry is through CNS-produced chemokines, such as monocyte chemoattractant protein (MCP)-1 and the IFN-γ-inducible peptide, CXCL10, while the “push” is initiated by peripheral immune activation (Asensio, 2001, Fischer-Smith, 2008a, Yadav and Collman, 2009) (Fig. 1).

Once in the brain, HIV-1-infected blood-borne macrophages secrete proinflammatory

Blood–brain barrier (BBB)

The BBB plays a central role in the development of HAD serving as the conduit by which free virus and infected immune cells enter the brain from the circulatory system (Banks, 2000, Nottet, 1996, Persidsky, 1997). A number of laboratory animal models and human studies demonstrated BBB breakdown as a consequence of progressive HIV infection and immune compromise (Dallasta, 1999, Kanmogne, 2002, Persidsky, 2000). BBB dysfunction is more frequent in AIDS patients with dementia, as compared with

Adaptive neuroimmunity

CD8+ cytotoxic T cells (CTLs) can elicit the death of virus-infected cells (Yamamoto and Matano, 2008). Most CTLs express T-cell receptors that can recognize a specific antigenic peptide bound to class I major histocompatibility complex (MHC) molecules (Bangham, 2009). The affinity between CD8 and the MHC molecule keeps the CTL and the target cell bound closely during antigen-specific activation (Gulzar and Copeland, 2004). More recently, regulatory T cells (Treg) have been shown to exert cell

Chemokines

Monocyte and leukocyte passage into the CNS would not occur without the complex chemokine gradient that is established during HIV-1 infection. Chemokine involvement in HIV-1 neuropathogenesis is well-recognized because of their abilities to: (i) recruit HIV-1-infected immune cells into the brain, (ii) serve as mediators for inflammatory responses, and (iii) serve as ligands for HIV-1 coreceptors, specifically CXCR4 and CCR5 (Hesselgesser et al., 1998). Chemokines recruit monocytes/macrophages

Harnessing MP function for therapeutic benefit

Drug penetration past the BBB into the CNS has long been an obstacle in treating HIV-1. HIV-1 protease inhibitors are known to have poor CNS penetration, while other HIV-1 therapies such as zidovudine (AZT) have very efficient BBB penetration (Letendre, 2008, Varatharajan and Thomas, 2009). This being said, BBB permeability is only beneficial for controlling CNS HIV-1 infection if HIV-1 therapies themselves are not neurotoxic.

More recently, efforts are being made to develop

Conclusions

CNS complications of HIV-1 infection have evolved considerably since the widespread use of ART. Reduced severity of disease has paralleled lowered viral replication and reduced overt neuropathology. What remains are neuroinflammatory responses heralded by low levels of viral replication, disordered glial crosstalk and monocyte transmigration into the CNS. With antiretroviral treatments that specifically target the CNS and adjunctive therapies now becoming available, eliminating virus (and

Acknowledgments

We thank Ms. Robin Taylor for outstanding administrative and computer support. This work was supported by National Institutes of Health grants P01 NS43985, P20RR15635, R37 NS36126, PO1 NS31492, and R01NS034239.

References (126)

  • GrutersR.A.

    The advantage of early recognition of HIV-infected cells by cytotoxic T-lymphocytes

    Vaccine

    (2002)
  • HuangX.

    CD 4+ T cells in the pathobiology of neurodegenerative disorders

    J. Neuroimmunol.

    (2009)
  • HullM.W.

    Changing global epidemiology of pulmonary manifestations of HIV/AIDS

    Chest

    (2008)
  • KimW.K.

    CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood

    Am. J. Pathol.

    (2006)
  • KolbS.A.

    Identification of a T cell chemotactic factor in the cerebrospinal fluid of HIV-1-infected individuals as interferon-gamma inducible protein 10

    J. Neuroimmunol.

    (1999)
  • Kramer-HammerleS.

    Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus

    Virus Res.

    (2005)
  • Kraft-TerryS.D.

    A coat of many colors: neuroimmune crosstalk in human immunodeficiency virus infection

    Neuron

    (2009)
  • MankowskiJ.L.

    Cerebrospinal fluid markers that predict SIV CNS disease

    J. Neuroimmunol.

    (2004)
  • McArthurJ.C.

    Neurological complications of HIV infection

    Lancet. Neurol.

    (2005)
  • Melik-ParsadaniantzS. et al.

    Chemokines and neuromodulation

    J. Neuroimmunol.

    (2008)
  • MillerR.J. et al.

    AIDS and the brain: is there a chemokine connection?

    Trends Neurosci.

    (1999)
  • Monteiro de AlmeidaS.

    Dynamics of monocyte chemoattractant protein type one (MCP-1) and HIV viral load in human cerebrospinal fluid and plasma

    J. Neuroimmunol.

    (2005)
  • Monteiro de AlmeidaS.

    Relationship of CSF leukocytosis to compartmentalized changes in MCP-1/CCL2 in the CSF of HIV-infected patients undergoing interruption of antiretroviral therapy

    J. Neuroimmunol.

    (2006)
  • NottetH.S. et al.

    Unraveling the neuroimmune mechanisms for the HIV-1-associated cognitive/motor complex

    Immunol. Today

    (1995)
  • PersidskyY.

    Microglial and astrocyte chemokines regulate monocyte migration through the blood–brain barrier in human immunodeficiency virus-1 encephalitis

    Am. J. Pathol.

    (1999)
  • AchmatZ. et al.

    Combining prevention, treatment and care: lessons from South Africa

    Aids

    (2007)
  • AlexakiA.

    Cellular reservoirs of HIV-1 and their role in viral persistence

    Curr. HIV Res.

    (2008)
  • AncesB.M. et al.

    Dementia and neurocognitive disorders due to HIV-1 infection

    Semin. Neurol.

    (2007)
  • AndersonE.R.

    Memantine protects hippocampal neuronal function in murine human immunodeficiency virus type 1 encephalitis

    J. Neurosci.

    (2004)
  • AndrasI.E.

    Signaling mechanisms of HIV-1 Tat-induced alterations of claudin-5 expression in brain endothelial cells

    J. Cereb. Blood Flow. Metab.

    (2005)
  • AntinoriA.

    Updated research nosology for HIV-associated neurocognitive disorders

    Neurology

    (2007)
  • Aracena-GenaoB.

    Costs and benefits of HAART for patients with HIV in a public hospital in Mexico

    AIDS

    (2008)
  • AsensioV.C.

    Interferon-independent, human immunodeficiency virus type 1 gp120-mediated induction of CXCL10/IP-10 gene expression by astrocytes in vivo and in vitro

    J. Virol.

    (2001)
  • BanghamC.R.

    CTL quality and the control of human retroviral infections

    Eur. J. Immunol.

    (2009)
  • BanksW.A.

    Partial saturation and regional variation in the blood-to-brain transport of leptin in normal weight mice

    Am. J. Physiol. Endocrinol. Metab.

    (2000)
  • BattegayM. et al.

    Morbidity and mortality in HIV-infected individuals—a shift towards comorbidities

    Swiss Med. Wkly.

    (2009)
  • BeduneauA.

    Facilitated monocyte–macrophage uptake and tissue distribution of superparmagnetic iron-oxide nanoparticles

    PLoS ONE

    (2009)
  • BellizziM.J.

    Synaptic activity becomes excitotoxic in neurons exposed to elevated levels of platelet-activating factor

    J. Clin. Invest.

    (2005)
  • BerryC.C.

    Intracellular delivery of nanoparticles via the HIV-1 tat peptide

    Nanomed

    (2008)
  • BlanksonJ.N.

    Viral reservoirs and HIV-specific immunity

    Curr. Opin. HIV AIDS

    (2006)
  • BrabersN.A. et al.

    Role of the pro-inflammatory cytokines TNF-alpha and IL-1beta in HIV-associated dementia

    Eur. J. Clin. Invest.

    (2006)
  • CabralG.A.

    Drugs of abuse, immune modulation, and AIDS

    J. Neuroimmune. Pharmacol.

    (2006)
  • CaoW.

    Regulatory T cell expansion and immune activation during untreated HIV type 1 infection are associated with disease progression

    AIDS Res. Hum. Retroviruses

    (2009)
  • CardC.M.

    Decreased immune activation in resistance to HIV-1 infection is associated with an elevated frequency of CD4(+)CD25(+)FOXP3(+) regulatory T cells

    J. Infect. Dis.

    (2009)
  • CohenG.M.

    Access to diagnostics in support of HIV/AIDS and tuberculosis treatment in developing countries

    Aids

    (2007)
  • ColemanC.M. et al.

    HIV interactions with monocytes and dendritic cells: viral latency and reservoirs

    Retrovirology

    (2009)
  • ConantK.

    Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • CrewsL.

    Molecular pathology of neuro-AIDS (CNS-HIV)

    Int. J. Mol. Sci.

    (2009)
  • CysiqueL.A. et al.

    Neuropsychological functioning and antiretroviral treatment in HIV/AIDS: a review

    Neuropsychol. Rev.

    (2009)
  • CysiqueL.A.

    Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy

    Neurology

    (2009)
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