Current HIV/AIDS Reports

, Volume 12, Issue 1, pp 16–24 | Cite as

Neuropathogenesis of HIV: From Initial Neuroinvasion to HIV-Associated Neurocognitive Disorder (HAND)

  • Zaina Zayyad
  • Serena SpudichEmail author
HIV Pathogenesis and Treatment (AL Landay, Section Editor)
Part of the following topical collections:
  1. Topical Collection on HIV Pathogenesis and Treatment


Early in the HIV epidemic, the central nervous system (CNS) was recognized as a target of infection and injury in the advanced stages of disease. Though the most severe forms of HIV-associated neurocognitive disorder (HAND) related to severe immunosuppression are rare in the current era of widespread combination antiretroviral therapy (cART), evidence now supports pathological involvement of the CNS throughout the course of infection. Recent work suggests that the stage for HIV neuropathogenesis may be set with initial viral entry into the CNS, followed by initiation of pathogenetic processes including neuroinflammation and neurotoxicity, and establishment of local, compartmentalized HIV replication that may reflect a tissue reservoir for HIV. Key questions still exist as to when HIV establishes local infection in the CNS, which CNS cells are the primary targets of HIV, and what mechanistic processes underlie the injury to neurons that produce clinical symptoms of HAND. Advances in these areas will provide opportunities for improved treatment of patients with established HAND, prevention of neurological disease in those with early stage infection, and understanding of HIV tissue reservoirs that will aid efforts at HIV eradication.


HIV AIDS HIV-associated neurocognitive disorder (HAND) Asymptomatic neurocognitive impairment (ANI) Mild neurocognitive disorder (MND) HIV-associated dementia (HAD) AIDS dementia complex Cerebrospinal fluid (CSF) Central nervous system (CNS) Combination antiretroviral therapy (cART) Neopterin Neurofilament light chain (NFL) Magnetic resonance spectroscopy (MRS) Neuroinflammation CSF escape Neurotoxicity 


Compliance with Ethics Guidelines

Conflict of Interest

Zaina Zayyad and Serena Spudich declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Levy RM, Bredesen DE, Rosenblum ML. Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): experience at UCSF and review of the literature. J Neurosurg. 1985;62(4):475–95.CrossRefPubMedGoogle Scholar
  2. 2.
    Navia BA, Price RW. The acquired immunodeficiency syndrome dementia complex as the presenting or sole manifestation of human immunodeficiency virus infection. Arch Neurol. 1987;44(1):65–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS. Nat Rev Immunol. 2005;5(1):69–81.CrossRefPubMedGoogle Scholar
  4. 4.
    Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, Wu J, et al. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS. 2007;21(14):1915–21.CrossRefPubMedGoogle Scholar
  5. 5.
    Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789–99.CrossRefPubMedGoogle Scholar
  6. 6.
    Heaton RK, Clifford DB, Franklin Jr DR, Woods SP, Ake C, Vaida F, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75(23):2087–96.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Cysique LA, Brew BJ. Prevalence of non-confounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression. J Neurovirol. 2011;17(2):176–83.CrossRefPubMedGoogle Scholar
  8. 8.
    Navia BA, Cho ES, Petito CK, Price RW. The AIDS dementia complex: II. Neuropathology. Ann Neurol. 1986;19(6):525–35.CrossRefPubMedGoogle Scholar
  9. 9.
    Gyorkey F, Melnick JL, Gyorkey P. Human immunodeficiency virus in brain biopsies of patients with AIDS and progressive encephalopathy. J Infect Dis. 1987;155(5):870–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Enting RH, Prins JM, Jurriaans S, Brinkman K, Portegies P, Lange JM. Concentrations of human immunodeficiency virus type 1 (HIV-1) RNA in cerebrospinal fluid after antiretroviral treatment initiated during primary HIV-1 infection. Clin Infect Dis. 2001;32(7):1095–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Spudich S, Gisslen M, Hagberg L, Lee E, Liegler T, Brew B, et al. Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. J Infect Dis. 2011;204(5):753–60.CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Ho DD, Sarngadharan MG, Resnick L, Dimarzoveronese F, Rota TR, Hirsch MS. Primary human T-lymphotropic virus type III infection. Ann Intern Med. 1985;103(6 (Pt 1)):880–3.CrossRefPubMedGoogle Scholar
  13. 13.
    Scarpini E, Sacilotto G, Lazzarin A, Geremia L, Doronzo R, Scarlato G. Acute ataxia coincident with seroconversion for anti-HIV. J Neurol. 1991;238(6):356–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Davis LE, Hjelle BL, Miller VE, Palmer DL, Llewellyn AL, Merlin TL, et al. Early viral brain invasion in iatrogenic human immunodeficiency virus infection. Neurology. 1992;42(9):1736–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Valcour V, Chalermchai T, Sailasuta N, Marovich M, Lerdlum S, Suttichom D, et al. Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis. 2012;206(2):275–82.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Liu Y, Tang XP, McArthur JC, Scott J, Gartner S. Analysis of human immunodeficiency virus type 1 gp160 sequences from a patient with HIV dementia: evidence for monocyte trafficking into brain. J Neurovirol. 2000;6 Suppl 1:S70–81.PubMedGoogle Scholar
  17. 17.
    Spudich S, González-Scarano F. HIV-1-related central nervous system disease: current issues in pathogenesis, diagnosis, and treatment. Cold Spring Harb Perspect Med. 2012;2(6):a007120.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Andras IE, Pu H, Deli MA, Nath A, Hennig B, Toborek M. HIV-1 Tat protein alters tight junction protein expression and distribution in cultured brain endothelial cells. J Neurosci Res. 2003;74(2):255–65.CrossRefPubMedGoogle Scholar
  19. 19.
    Xu R, Feng X, Xie X, Zhang J, Wu D, Xu L. HIV-1 Tat protein increases the permeability of brain endothelial cells by both inhibiting occludin expression and cleaving occludin via matrix metalloproteinase-9. Brain Res. 2012;1436:13–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Awan FM, Anjum S, Obaid A, Ali A, Paracha RZ, Janjua HA. In-silico analysis of claudin-5 reveals novel putative sites for post-translational modifications: insights into potential molecular determinants of blood-brain barrier breach during HIV-1 infiltration. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis. 2014;27:355–65.CrossRefGoogle Scholar
  21. 21.
    Woollard SM, Bhargavan B, Yu F, Kanmogne GD. Differential effects of Tat proteins derived from HIV-1 subtypes B and recombinant CRF02_AG on human brain microvascular endothelial cells: implications for blood-brain barrier dysfunction. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2014;34(6):1047–59.CrossRefGoogle Scholar
  22. 22.
    Campbell J, Autissier P, MacLean AG, Burdo T, Westmoreland S, Gonzalez G, et al. VLA-4 treatment blocks virus traffic to the gut and brain early, and stabilizes CNS injury late in infection. 20th Conference for Retroviruses and Opportunistic Infections; Atlanta, GA 2013.Google Scholar
  23. 23.
    Lentz MR, Kim WK, Kim H, Soulas C, Lee V, Venna N, et al. Alterations in brain metabolism during the first year of HIV infection. J Neurovirol. 2011;17(3):220–9.CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Sailasuta N, Ross W, Ananworanich J, Chalermchai T, DeGruttola V, Lerdlum S, et al. Change in brain magnetic resonance spectroscopy after treatment during acute HIV infection. PLoS One. 2012;7(11):e49272.CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Suh J, Sinclair E, Peterson J, Lee E, Kyriakides TC, Li FY, et al. Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection. J Neuroinflammation. 2014;11(1):199.CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.•
    Young AC, Yiannoutsos CT, Hegde M, Lee E, Peterson J, Walter R, et al. Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection. Neurology. 2014;83(18):1592–600. This study uses longitudinal brain magnetic spectroscopy in individuals identified during primary HIV infection to demonstrate that neuroinflammation progressively increases during the early stages of infection prior to the initiation of antiretroviral therapy. CrossRefPubMedGoogle Scholar
  27. 27.
    Schnell G, Price RW, Swanstrom R, Spudich S. Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol. 2010;84(5):2395–407.CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Marcondes MC, Morsey B, Emanuel K, Lamberty BG, Flynn CT, Fox HS. CD8+ T cells maintain suppression of simian immunodeficiency virus in the central nervous system. J Inf Dis. 2015;211(1):40-4.Google Scholar
  29. 29.
    Schmitz JE, Simon MA, Kuroda MJ, Lifton MA, Ollert MW, Vogel CW, et al. A nonhuman primate model for the selective elimination of CD8+ lymphocytes using a mouse-human chimeric monoclonal antibody. Am J Pathol. 1999;154(6):1923–32.CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Strickland SL, Rife BD, Lamers SL, Nolan DJ, Veras NM, Prosperi MC, et al. Spatiotemporal dynamics of simian immunodeficiency virus brain infection in CD8+ lymphocyte-depleted rhesus macaques with neuroAIDS. J Gen Virol. 2014;95(Pt 12):2784–95.CrossRefPubMedGoogle Scholar
  31. 31.
    Wong JK, Ignacio CC, Torriani F, Havlir D, Fitch NJ, Richman DD. In vivo compartmentalization of human immunodeficiency virus: evidence from the examination of pol sequences from autopsy tissues. J Virol. 1997;71(3):2059–71.PubMedCentralPubMedGoogle Scholar
  32. 32.
    Ritola K, Robertson K, Fiscus SA, Hall C, Swanstrom R. Increased human immunodeficiency virus type 1 (HIV-1) env compartmentalization in the presence of HIV-1-associated dementia. J Virol. 2005;79(16):10830–4.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Pillai SK, Pond SL, Liu Y, Good BM, Strain MC, Ellis RJ, et al. Genetic attributes of cerebrospinal fluid-derived HIV-1 env. Brain. 2006;129(Pt 7):1872–83.CrossRefPubMedGoogle Scholar
  34. 34.
    Schnell G, Joseph S, Spudich S, Price RW, Swanstrom R. HIV-1 replication in the central nervous system occurs in two distinct cell types. PLoS Pathog. 2011;7(10):e1002286.CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.•
    Dahl V, Gisslen M, Hagberg L, Peterson J, Shao W, Spudich S, et al. An example of genetically distinct HIV type 1 variants in cerebrospinal fluid and plasma during suppressive therapy. J Infect Dis. 2014;209(10):1618–22. This study employed single genome sequencing methods to sequence HIV RNA from paired cerebrospinal fluid and plasma samples of patients on cART, demonstrating that in the setting of suppressive treatment, unique HIV sequences could be identified in the CSF as compared to blood compartments. CrossRefPubMedGoogle Scholar
  36. 36.
    Clements JE, Babas T, Mankowski JL, Suryanarayana K, Piatak Jr M, Tarwater PM, et al. The central nervous system as a reservoir for simian immunodeficiency virus (SIV): steady-state levels of SIV DNA in brain from acute through asymptomatic infection. J Infect Dis. 2002;186(7):905–13.CrossRefPubMedGoogle Scholar
  37. 37.
    Barber SA, Gama L, Dudaronek JM, Voelker T, Tarwater PM, Clements JE. Mechanism for the establishment of transcriptional HIV latency in the brain in a simian immunodeficiency virus–macaque model. J Infect Dis. 2006;193(7):963–70.CrossRefPubMedGoogle Scholar
  38. 38.
    Zink MC, Brice AK, Kelly KM, Queen SE, Gama L, Li M, et al. Simian immunodeficiency virus-infected macaques treated with highly active antiretroviral therapy have reduced central nervous system viral replication and inflammation but persistence of viral DNA. J Infect Dis. 2010;202(1):161–70.CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.••
    Canestri A, Lescure FX, Jaureguiberry S, Moulignier A, Amiel C, Marcelin AG, et al. Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin Infect Dis. 2010;50(5):773–8. In this paper, the investigators describe a phenomenon of symptomatic CSF escape, wherein during cART, patients with marked neurologic symptoms have HIV RNA detected in the CSF either at higher levels than in the plasma, or in the absence of plasma HIV RNA detection, providing proof-of-concept evidence that the CNS may serve as an autonomous source of ongoing viral replication despite systemically active cART. CrossRefPubMedGoogle Scholar
  40. 40.
    Peluso MJ, Ferretti F, Peterson J, Lee E, Fuchs D, Boschini A, et al. Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well-controlled plasma viral load. AIDS. 2012.Google Scholar
  41. 41.
    An SF, Groves M, Gray F, Scaravilli F. Early entry and widespread cellular involvement of HIV-1 DNA in brains of HIV-1 positive asymptomatic individuals. J Neuropathol Exp Neurol. 1999;58(11):1156–62.CrossRefPubMedGoogle Scholar
  42. 42.
    Bissel SJ, Wang G, Trichel AM, Murphey-Corb M, Wiley CA. Longitudinal analysis of monocyte/macrophage infection in simian immunodeficiency virus-infected, CD8+ T-cell-depleted macaques that develop lentiviral encephalitis. Am J Pathol. 2006;168(5):1553–69.CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.••
    Thompson KA, Cherry CL, Bell JE, McLean CA. Brain cell reservoirs of latent virus in presymptomatic HIV-infected individuals. Am J Pathol. 2011;179(4):1623–9. Extensive pathologic studies of patients who died of non-HIV related causes during neuroasymptomatic infection reveal HIV DNA in cells of the CNS as well as widespread microglial activation, confirming that HIV infection and immune activation is present prior to development of encephalitis in human HIV infection. CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Shikuma CM, Nakamoto B, Shiramizu B, Liang CY, DeGruttola V, Bennett K, et al. Antiretroviral monocyte efficacy score linked to cognitive impairment in HIV. Antivir Ther. 2012;17(7):1233–42.CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841–5.CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38(4):792–804.CrossRefPubMedGoogle Scholar
  47. 47.
    Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 2009;27:119–45.CrossRefPubMedGoogle Scholar
  48. 48.
    Henrich TJ, Hanhauser E, Marty FM, Sirignano MN, Keating S, Lee TH, et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med. 2014;161(5):319–27.CrossRefPubMedGoogle Scholar
  49. 49.
    Ellis RJ, Gamst AC, Capparelli E, Spector SA, Hsia K, Wolfson T, et al. Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources. Neurology. 2000;54(4):927–36.CrossRefPubMedGoogle Scholar
  50. 50.
    Churchill MJ, Wesselingh SL, Cowley D, Pardo CA, McArthur JC, Brew BJ, et al. Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia. Ann Neurol. 2009;66(2):253–8.CrossRefPubMedGoogle Scholar
  51. 51.•
    Zhuang K, Leda AR, Tsai L, Knight H, Harbison C, Gettie A, et al. Emergence of CD4 independence envelopes and astrocyte infection in R5 simian-human immunodeficiency virus model of encephalitis. J Virol. 2014;88(15):8407–20. The authors highlight the emergence of CD4-independent viral envelopes in a SHIVE model of HIV and link this to astrocyte infection in the model. This HIV consistent model of astrocyte infection may shed light on glial infection and neurodegeneration in HIV. CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Strazza M, Pirrone V, Wigdahl B, Nonnemacher MR. Breaking down the barrier: the effects of HIV-1 on the blood-brain barrier. Brain Res. 2011;1399:96–115.CrossRefPubMedCentralPubMedGoogle Scholar
  53. 53.
    Peluso MJ, Meyerhoff DJ, Price RW, Peterson J, Lee E, Young AC, et al. Cerebrospinal fluid and neuroimaging biomarker abnormalities suggest early neurological injury in a subset of individuals during primary HIV infection. J Infect Dis. 2013;207(11):1703–12.CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Lentz MR, Kim WK, Lee V, Bazner S, Halpern EF, Venna N, et al. Changes in MRS neuronal markers and T cell phenotypes observed during early HIV infection. Neurology. 2009;72(17):1465–72.CrossRefPubMedCentralPubMedGoogle Scholar
  55. 55.
    Kaul D, Ahlawat A, Gupta SD. HIV-1 genome-encoded hiv1-mir-H1 impairs cellular responses to infection. Mol Cell Biochem. 2009;323(1–2):143–8.CrossRefPubMedGoogle Scholar
  56. 56.
    Hagberg L, Cinque P, Gisslen M, Brew BJ, Spudich S, Bestetti A, et al. Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection. AIDS Res Ther. 2010;7:15.CrossRefPubMedCentralPubMedGoogle Scholar
  57. 57.
    Kamat A, Lyons JL, Misra V, Uno H, Morgello S, Singer EJ, et al. Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection. J Acquir Immune Defic Syndr. 2012;60(3):234–43.CrossRefPubMedCentralPubMedGoogle Scholar
  58. 58.
    Airoldi M, Bandera A, Trabattoni D, Tagliabue B, Arosio B, Soria A, et al. Neurocognitive impairment in HIV-infected naive patients with advanced disease: the role of virus and intrathecal immune activation. Clin Dev Immunol. 2012;2012:467154.CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.
    Gill AJ, Kovacsics CE, Cross SA, Vance PJ, Kolson LL, Jordan-Sciutto KL, et al. Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders. J Clin Invest. 2014;124(10):4459–72.CrossRefPubMedCentralPubMedGoogle Scholar
  60. 60.
    Yilmaz A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslen M. Persistent intrathecal immune activation in HIV-1-infected individuals on antiretroviral therapy. J Acquir Immune Defic Syndr. 2008;47(2):168–73.CrossRefPubMedCentralPubMedGoogle Scholar
  61. 61.
    Peluso MJ, Spudich S. Treatment of HIV in the CNS: effects of antiretroviral therapy and the promise of non-antiretroviral therapeutics. Curr HIV/AIDS Rep. 2014;11(3):353–62.CrossRefPubMedGoogle Scholar
  62. 62.
    Romani B, Engelbrecht S, Glashoff RH. Functions of Tat: the versatile protein of human immunodeficiency virus type 1. J Gen Virol. 2010;91(Pt 1):1–12.CrossRefPubMedGoogle Scholar
  63. 63.
    Sagnier S, Daussy CF, Borel S, Robert-Hebmann V, Faure M, Blanchet FP, et al. Autophagy restricts HIV-1 infection by selectively degrading Tat in CD4+ T lymphocytes. J Virol. 2015;89(1):615-25.Google Scholar
  64. 64.
    Moran LM, Fitting S, Booze RM, Webb KM, Mactutus CF. Neonatal intrahippocampal HIV-1 protein Tat injection: neurobehavioral alterations in the absence of increased inflammatory cytokine activation. Int J Dev Neurosci Off J Int Soc Dev Neurosci. 2014;38C:195–203.CrossRefGoogle Scholar
  65. 65.•
    Meulendyke KA, Queen SE, Engle EL, Shirk EN, Liu J, Steiner JP, et al. Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease. J Neurovirol. 2014. This group administered fluconazole/paroxetine after the acute phase of infection in an SIV model and found that protection from neurodegeneration could be achieved despite continued neuroinflammation. Google Scholar
  66. 66.
    Tewari M, Monika, Varghese RK, Menon M, Seth P. Astrocytes mediate HIV-1 Tat-induced neuronal damage via ligand-gated ion channel P2X7R. J Neurochem. 2014. doi: 10.1111/jnc.12953
  67. 67.
    Bethel-Brown C, Yao H, Hu G, Buch S. Platelet-derived growth factor (PDGF)-BB-mediated induction of monocyte chemoattractant protein 1 in human astrocytes: implications for HIV-associated neuroinflammation. J Neuroinflammation. 2012;9:262.CrossRefPubMedCentralPubMedGoogle Scholar
  68. 68.•
    Eugenin EA, Berman JW. Cytochrome C dysregulation induced by HIV infection of astrocytes results in bystander apoptosis of uninfected astrocytes by an IP3 and calcium-dependent mechanism. J Neurochem. 2013;127(5):644–51. This study describes a cellular mechanism for bystander astrocyte apoptosis, neuroprotective effects of HIV on infected astrocytes, and the combination of these effects in the generation of a CNS HIV reservoir. CrossRefPubMedCentralPubMedGoogle Scholar
  69. 69.
    Shin AH, Kim HJ, Thayer SA. Subtype selective NMDA receptor antagonists induce recovery of synapses lost following exposure to HIV-1 Tat. Br J Pharmacol. 2012;166(3):1002–17.CrossRefPubMedCentralPubMedGoogle Scholar
  70. 70.
    Chauhan A, Tikoo A, Patel J, Abdullah AM. HIV-1 endocytosis in astrocytes: a kiss of death or survival of the fittest? Neurosci Res. 2014;88C:16–22.CrossRefGoogle Scholar
  71. 71.
    Lee KM, Chiu KB, Renner NA, Sansing HA, Didier PJ, MacLean AG. Form follows function: astrocyte morphology and immune dysfunction in SIV neuroAIDS. J Neurovirol. 2014;20(5):474–84.PubMedGoogle Scholar
  72. 72.
    Wang S, Rong L. Stochastic population switch may explain the latent reservoir stability and intermittent viral blips in HIV patients on suppressive therapy. J Theor Biol. 2014;360:137–48.CrossRefPubMedGoogle Scholar
  73. 73.
    Eden A, Fuchs D, Hagberg L, Nilsson S, Spudich S, Svennerholm B, et al. HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J Infect Dis. 2010;202(12):1819–25.CrossRefPubMedCentralPubMedGoogle Scholar
  74. 74.
    Gisslen M, Hagberg L, Rosengren L, Brew BJ, Cinque P, Spudich S, et al. Defining and evaluating HIV-related neurodegenerative disease and its treatment targets: a combinatorial approach to use of cerebrospinal fluid molecular biomarkers. J Neuroimmune Pharm. 2007;2(1):112–9.CrossRefGoogle Scholar
  75. 75.•
    Jessen Krut J, Mellberg T, Price RW, Hagberg L, Fuchs D, Rosengren L, et al. Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients. PloS one. 2014;9(2):e88591. This paper describes elevated levels of cerebrospinal fluid (CSF) neurofilament light chain (NFL), a marker of active axonal injury, in neuroasymptomatic HIV-infected subjects on suppressive antiretroviral therapy, suggesting ongoing neural injury despite systemically successful treatment. CrossRefPubMedCentralPubMedGoogle Scholar
  76. 76.
    Dahl V, Peterson J, Fuchs D, Gisslen M, Palmer S, Price RW. Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation. AIDS. 2014;28(15):2251–8.CrossRefPubMedGoogle Scholar
  77. 77.
    Ances BM, Hammoud DA. Neuroimaging of HIV-associated neurocognitive disorders (HAND). Curr Opin HIV AIDS. 2014;9(6):545–51. doi: 10.1097/COH.0000000000000112.CrossRefPubMedGoogle Scholar
  78. 78.
    Hudson CL, Zemlin AE, Ipp H. The cardiovascular risk marker asymmetric dimethylarginine is elevated in asymptomatic, untreated HIV-1 infection and correlates with markers of immune activation and disease progression. Ann Clin Biochem. 2014;51(Pt 5):568–75.CrossRefPubMedGoogle Scholar
  79. 79.
    Langford D, Marquie-Beck J, de Almeida S, Lazzaretto D, Letendre S, Grant I, et al. Relationship of antiretroviral treatment to postmortem brain tissue viral load in human immunodeficiency virus-infected patients. J Neurovirol. 2006;12(2):100–7.CrossRefPubMedGoogle Scholar
  80. 80.
    Yilmaz A, Gisslen M. Treatment of HIV in the central nervous system. Semin Neurol. 2014;34(1):14–20.CrossRefPubMedGoogle Scholar
  81. 81.
    O’Brien M, Montenont E, Hu L, Nardi MA, Valdes V, Merolla M, et al. Aspirin attenuates platelet activation and immune activation in HIV-1-infected subjects on antiretroviral therapy: a pilot study. J Acquir Immune Defic Syndr. 2013;63(3):280–8.CrossRefPubMedCentralPubMedGoogle Scholar
  82. 82.
    Rodrigo R, Cauli O, Gomez-Pinedo U, Agusti A, Hernandez-Rabaza V, Garcia-Verdugo JM, et al. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology. 2010;139(2):675–84.CrossRefPubMedGoogle Scholar
  83. 83.
    Gaskill PJ, Yano HH, Kalpana GV, Javitch JA, Berman JW. Dopamine receptor activation increases HIV entry into primary human macrophages. PLoS One. 2014;9(9):e108232.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of NeurologyYale University School of MedicineNew HavenUSA

Personalised recommendations