Top

Published in:

01-06-2015 | Review

Eradication of human immunodeficiency virus from brain reservoirs

Author: Avindra Nath

Published in: Journal of NeuroVirology | Issue 3/2015

Abstract

Isolated cases in which human immunodeficiency virus (HIV) infection was claimed to have been eradicated generated renewed interest in HIV reservoirs in the brain particularly since attempts to reproduce the findings using genetically engineered stem cells and immune- or myeloablation have failed. A clear understanding of the cell types in which the virus resides in the brain, the mechanism of viral persistence, restricted replication and latency, and the turnover rate of the infected cells is critical for us to develop ways to control or get rid of the virus in the brain. The brain has several unique features compared to other reservoirs. There are no resident T cells in the brain; the virus resides in macrophages and astrocytes where the viral infection is non-cytopathic. The virus evolves in the brain and since the turnover rate of these cells is low, the virus has the potential to reside in these cells for several decades and possibly for the life of the individual. This review discusses the HIV reservoirs in the brain, issues related to eradication of the virus from sanctuaries in the brain, and current challenges faced by neuroscientists in finding a cure.

Allers K, Hutter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E et al (2011) Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood 117(10):2791–2799PubMedCrossRef

Andras IE, Pu H, Deli MA, Nath A, Hennig B, Toborek M (2003) HIV-1 Tat protein alters tight junction protein expression and distribution in cultured brain endothelial cells. J Neurosci Res 74(2):255–265PubMedCrossRef

Bansal AK, Mactutus CF, Nath A, Maragos W, Hauser KF, Booze RM (2000) Neurotoxicity of HIV-1 proteins gp120 and Tat in the rat striatum. Brain Res 879(1–2):42–49PubMedCrossRef

Bechmann I, Priller J, Kovac A, Bontert M, Wehner T, Klett FF et al (2001) Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages. Eur J Neurosci 14(10):1651–1658PubMedCrossRef

Bechmann I, Goldmann J, Kovac AD, Kwidzinski E, Simburger E, Naftolin F et al (2005) Circulating monocytic cells infiltrate layers of anterograde axonal degeneration where they transform into microglia. FASEB J 19(6):647–649PubMed

Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H et al (1997) Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387(6629):183–188PubMedCrossRef

Churchill MJ, Gorry PR, Cowley D, Lal L, Sonza S, Purcell DF et al (2006) Use of laser capture microdissection to detect integrated HIV-1 DNA in macrophages and astrocytes from autopsy brain tissues. J Neurovirol 12(2):146–152PubMedCrossRef

Churchill MJ, Wesselingh SL, Cowley D, Pardo CA, McArthur JC, Brew BJ et al (2009) Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia. Ann Neurol 66(2):253–258PubMedCrossRef

Cohen J (2011) Understanding HIV, latency to undo it. Science 332(6031):786PubMedCrossRef

Cosenza MA, Zhao ML, Si Q, Lee SC (2002) Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis. Brain Pathol 12(4):442–455PubMedCrossRef

Cowley D, Gray LR, Wesselingh SL, Gorry PR, Churchill MJ (2011) Genetic and functional heterogeneity of CNS-derived tat alleles from patients with HIV-associated dementia. J Neurovirol 17(1):70–81PubMedCrossRef

Croteau D, Letendre S, Best BM, Ellis RJ, Breidinger S, Clifford D et al (2010) Total raltegravir concentrations in cerebrospinal fluid exceed the 50-percent inhibitory concentration for wild-type HIV-1. Antimicrob Agents Chemother 54(12):5156–5160PubMedCentralPubMedCrossRef

Dahl V, Lee E, Peterson J, Spudich SS, Leppla I, Sinclair E et al (2011) Raltegravir treatment intensification does not alter cerebrospinal fluid HIV-1 infection or immunoactivation in subjects on suppressive therapy. J Infect Dis 204(12):1936–1945PubMedCentralPubMedCrossRef

Davey RT Jr, Bhat N, Yoder C, Chun TW, Metcalf JA, Dewar R et al (1999) HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci U S A 96(26):15109–15114PubMedCentralPubMedCrossRef

Deeks SG, Wagner B, Anton PA, Mitsuyasu RT, Scadden DT, Huang C et al (2002) A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy. Mol Ther 5(6):788–797PubMedCrossRef

Dunfee RL, Thomas ER, Gorry PR, Wang J, Taylor J, Kunstman K et al (2006) The HIV Env variant N283 enhances macrophage tropism and is associated with brain infection and dementia. Proc Natl Acad Sci U S A 103(41):15160–15165PubMedCentralPubMedCrossRef

Ene L, Duiculescu D, Ruta SM (2011) How much do antiretroviral drugs penetrate into the central nervous system? J Med Life 4(4):432–439PubMedCentralPubMed

Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T et al (1999) Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 5(5):512–517PubMedCrossRef

Fischer-Smith T, Bell C, Croul S, Lewis M, Rappaport J (2008) Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: lessons from human and nonhuman primate studies. J Neurovirol 14(4):318–326PubMedCentralPubMedCrossRef

Fitting S, Xu R, Bull C, Buch SK, El-Hage N, Nath A et al (2010) Interactive comorbidity between opioid drug abuse and HIV-1 Tat: chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons. Am J Pathol 177(3):1397–1410PubMedCentralPubMedCrossRef

Fujimura RK, Goodkin K, Petito CK, Douyon R, Feaster DJ, Concha M et al (1997) HIV-1 proviral DNA load across neuroanatomic regions of individuals with evidence for HIV-1-associated dementia. J Acquir Immune Defic Syndr Hum Retrovirol 16(3):146–152PubMedCrossRef

Gonzalez-Perez MP, O’Connell O, Lin R, Sullivan WM, Bell J, Simmonds P et al (2012) Independent evolution of macrophage-tropism and increased charge between HIV-1 R5 envelopes present in brain and immune tissue. Retrovirology 9:20PubMedCentralPubMedCrossRef

Gonzalez-Scarano F, Martin-Garcia J (2005) The neuropathogenesis of AIDS. Nat Rev Immunol 5(1):69–81PubMedCrossRef

Gray LR, Gabuzda D, Cowley D, Ellett A, Chiavaroli L, Wesselingh SL et al (2011) CD4 and MHC class 1 down-modulation activities of nef alleles from brain- and lymphoid tissue-derived primary HIV-1 isolates. J Neurovirol 17(1):82–91PubMedCentralPubMedCrossRef

Gupta RK, Soni N, Kumar S, Khandelwal N (2012) Imaging of central nervous system viral diseases. J Magn Reson Imaging 35(3):477–491PubMedCrossRef

Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S et al (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 17(1):3–16PubMedCentralPubMedCrossRef

Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI et al (2013) Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155(3):540–551PubMedCentralPubMedCrossRef

Holman AG, Mefford ME, O’Connor N, Gabuzda D (2010) HIVBrainSeqDB: a database of annotated HIV envelope sequences from brain and other anatomical sites. AIDS Res Ther 7:43PubMedCentralPubMedCrossRef

Holt N, Wang J, Kim K, Friedman G, Wang X, Taupin V et al (2010) Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat Biotechnol 28(8):839–847PubMedCentralPubMedCrossRef

Hutter G, Ganepola S (2011) Eradication of HIV by transplantation of CCR5-deficient hematopoietic stem cells. Sci World J 11:1068–1076CrossRef

Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K et al (2009) Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 360(7):692–698PubMedCrossRef

Johnson T, Nath A (2011) Immune reconstitution inflammatory syndrome and the central nervous system. Curr Opin Neurol 24(3):284–290PubMedCrossRef

Johnson TP, Patel K, Johnson KR, Maric D, Calabresi PA, Hasbun R et al (2013) Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein. Proc Natl Acad Sci U S A 110(33):13588–13593PubMedCentralPubMedCrossRef

Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410(6831):988–994PubMedCrossRef

Kramer-Hammerle S, Rothenaigner I, Wolff H, Bell JE, Brack-Werner R (2005) Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res 111(2):194–213PubMedCrossRef

Lamers SL, Salemi M, Galligan DC, Morris A, Gray R, Fogel G et al (2010) Human immunodeficiency virus-1 evolutionary patterns associated with pathogenic processes in the brain. J Neurovirol 16(3):230–241PubMedCentralPubMedCrossRef

Lamers SL, Poon AF, McGrath MS (2011a) HIV-1 nef protein structures associated with brain infection and dementia pathogenesis. PLoS One 6(2):e16659PubMedCentralPubMedCrossRef

Lamers SL, Gray RR, Salemi M, Huysentruyt LC, McGrath MS (2011b) HIV-1 phylogenetic analysis shows HIV-1 transits through the meninges to brain and peripheral tissues. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis 11(1):31–37CrossRef

Lawrence DM, Durham LC, Schwartz L, Seth P, Maric D, Major EO (2004) Human immunodeficiency virus type 1 infection of human brain-derived progenitor cells. J Virol 78(14):7319–7328PubMedCentralPubMedCrossRef

Li W, Huang Y, Reid R, Steiner J, Malpica-Llanos T, Darden TA et al (2008) NMDA receptor activation by HIV-Tat protein is clade dependent. J Neurosci Off J Soc Neurosci 28(47):12190–12198CrossRef

Maldarelli F, Palmer S, King MS, Wiegand A, Polis MA, Mican J et al (2007) ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog 3(4):e46PubMedCentralPubMedCrossRef

Marra CM, Zhao Y, Clifford DB, Letendre S, Evans S, Henry K et al (2009) Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 23(11):1359–1366PubMedCentralPubMedCrossRef

McCarthy GF, Leblond CP (1988) Radioautographic evidence for slow astrocyte turnover and modest oligodendrocyte production in the corpus callosum of adult mice infused with 3H-thymidine. J Comp Neurol 271(4):589–603PubMedCrossRef

Mediouni S, Darque A, Baillat G, Ravaux I, Dhiver C, Tissot-Dupont H et al (2012) Antiretroviral therapy does not block the secretion of the human immunodeficiency virus tat protein. Infect Disord Drug Targets 12(1):81–86PubMedCrossRef

Mercier F, Kitasako JT, Hatton GI (2002) Anatomy of the brain neurogenic zones revisited: fractones and the fibroblast/macrophage network. J Comp Neurol 451(2):170–188PubMedCrossRef

Nath A (2002) Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J Infect Dis 186(Suppl 2):S193–S198PubMedCrossRef

Nath A, Hartloper V, Furer M, Fowke KR (1995) Infection of human fetal astrocytes with HIV-1: viral tropism and the role of cell to cell contact in viral transmission. J Neuropathol Exp Neurol 54(3):320–330PubMedCrossRef

Nath A, Haughey NJ, Jones M, Anderson C, Bell JE, Geiger JD (2000) Synergistic neurotoxicity by human immunodeficiency virus proteins Tat and gp120: protection by memantine. Ann Neurol 47(2):186–194PubMedCrossRef

O’Donnell LA, Agrawal A, Jordan-Sciutto KL, Dichter MA, Lynch DR, Kolson DL (2006) Human immunodeficiency virus (HIV)-induced neurotoxicity: roles for the NMDA receptor subtypes. J Neurosci 26(3):981–990PubMedCrossRef

Olivieri KC, Agopian KA, Mukerji J, Gabuzda D (2010) Evidence for adaptive evolution at the divergence between lymphoid and brain HIV-1 nef genes. AIDS Res Hum Retrovir 26(4):495–500PubMedCentralPubMedCrossRef

Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ, Brun SC et al (2008) Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A 105(10):3879–3884PubMedCentralPubMedCrossRef

Pang S, Koyanagi Y, Miles S, Wiley C, Vinters HV, Chen IS (1990) High levels of unintegrated HIV-1 DNA in brain tissue of AIDS dementia patients. Nature 343(6253):85–89PubMedCrossRef

Ranki A, Nyberg M, Ovod V, Haltia M, Elovaara I, Raininko R et al (1995) Abundant expression of HIV Nef and Rev proteins in brain astrocytes in vivo is associated with dementia. AIDS 9(9):1001–1008PubMedCrossRef

Sawchuk RJ, Yang Z (1999) Investigation of distribution, transport and uptake of anti-HIV drugs to the central nervous system. Adv Drug Deliv Rev 39(1–3):5–31PubMedCrossRef

Schnell G, Price RW, Swanstrom R, Spudich S (2010) Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol 84(5):2395–2407PubMedCentralPubMedCrossRef

Schwartz L, Major EO (2006) Neural progenitors and HIV-1-associated central nervous system disease in adults and children. Curr HIV Res 4(3):319–327PubMedCrossRef

Schwartz L, Civitello L, Dunn-Pirio A, Ryschkewitsch S, Berry E, Cavert W et al (2007) Evidence of human immunodeficiency virus type 1 infection of nestin-positive neural progenitors in archival pediatric brain tissue. J Neurovirol 13(3):274–283PubMedCrossRef

Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC et al (2012) Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 36(3):491–501PubMedCentralPubMedCrossRef

Singh IN, Goody RJ, Dean C, Ahmad NM, Lutz SE, Knapp PE et al (2004) Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: differential involvement of caspase-3 and endonuclease G. J Neurovirol 10(3):141–151PubMedCentralPubMedCrossRef

Stranford SA, Ong JC, Martinez-Marino B, Busch M, Hecht FM, Kahn J et al (2001) Reduction in CD8+ cell noncytotoxic anti-HIV activity in individuals receiving highly active antiretroviral therapy during primary infection. Proc Natl Acad Sci U S A 98(2):597–602PubMedCentralPubMedCrossRef

Takahashi K, Wesselingh SL, Griffin DE, McArthur JC, Johnson RT, Glass JD (1996) Localization of HIV-1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry. Ann Neurol 39(6):705–711PubMedCrossRef

Teo I, Veryard C, Barnes H, An SF, Jones M, Lantos PL et al (1997) Circular forms of unintegrated human immunodeficiency virus type 1 DNA and high levels of viral protein expression: association with dementia and multinucleated giant cells in the brains of patients with AIDS. J Virol 71(4):2928–2933PubMedCentralPubMed

Thompson KA, Churchill MJ, Gorry PR, Sterjovski J, Oelrichs RB, Wesselingh SL et al (2004) Astrocyte specific viral strains in HIV dementia. Ann Neurol 56(6):873–877PubMedCrossRef

Tornatore C, Nath A, Amemiya K, Major EO (1991) Persistent human immunodeficiency virus type 1 infection in human fetal glial cells reactivated by T-cell factor(s) or by the cytokines tumor necrosis factor alpha and interleukin-1 beta. J Virol 65(11):6094–6100PubMedCentralPubMed

Tornatore C, Chandra R, Berger JR, Major EO (1994) HIV-1 infection of subcortical astrocytes in the pediatric central nervous system. Neurology 44(3 Pt 1):481–487PubMedCrossRef

Trillo-Pazos G, Diamanturos A, Rislove L, Menza T, Chao W, Belem P et al (2003) Detection of HIV-1 DNA in microglia/macrophages, astrocytes and neurons isolated from brain tissue with HIV-1 encephalitis by laser capture microdissection. Brain Pathol 13(2):144–154PubMedCrossRef

Vissers M, Stelma FF, Koopmans PP (2010) Could differential virological characteristics account for ongoing viral replication and insidious damage of the brain during HIV 1 infection of the central nervous system? J Clin Virol Off Pub Pan Am Soc Clin Virol 49(4):231–238CrossRef

Wang Z, Trillo-Pazos G, Kim SY, Canki M, Morgello S, Sharer LR et al (2004) Effects of human immunodeficiency virus type 1 on astrocyte gene expression and function: potential role in neuropathogenesis. J Neurovirol 10(Suppl 1):25–32PubMedCrossRef

Wang T, Lee MH, Choi E, Pardo-Villamizar CA, Lee SB, Yang IH et al (2012) Granzyme B-induced neurotoxicity is mediated via activation of PAR-1 receptor and Kv1.3 channel. PLoS One 7(8):e43950PubMedCentralPubMedCrossRef

Wiley CA, Soontornniyomkij V, Radhakrishnan L, Masliah E, Mellors J, Hermann SA et al (1998) Distribution of brain HIV load in AIDS. Brain Pathol 8(2):277–284PubMedCrossRef

Williams KC, Hickey WF (2002) Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS. Annu Rev Neurosci 25:537–562PubMedCrossRef

Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H, de Bakker C et al (2001) Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS. J Exp Med 193(8):905–915PubMedCentralPubMedCrossRef

Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA et al (1997) Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278(5341):1291–1295PubMedCrossRef

Wu Y, Marsh JW (2001) Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science 293(5534):1503–1506PubMedCrossRef

Zhao L, Galligan DC, Lamers SL, Yu S, Shagrun L, Salemi M et al (2009) High level HIV-1 DNA concentrations in brain tissues differentiate patients with post-HAART AIDS dementia complex or cardiovascular disease from those with AIDS. Sci China Ser C Life Sci / Chin Acad Sci 52(7):651–656CrossRef

Title: Eradication of human immunodeficiency virus from brain reservoirs
Author: Avindra Nath
Publication date: 01-06-2015
Publisher: Springer US
Published in: Journal of NeuroVirology / Issue 3/2015
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-014-0291-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Eradication of human immunodeficiency virus from brain reservoirs

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2015

Role of the macrophage in HIV-associated neurocognitive disorders and other comorbidities in patients on effective antiretroviral treatment

Evidence for cFMS signaling in HIV production by brain macrophages and microglia

Eradication of HIV-1 from CNS reservoirs: current strategies and future priorities

Humanized mouse models for HIV-1 infection of the CNS

Genome editing strategies: potential tools for eradicating HIV-1/AIDS

Translational challenges in targeting latent HIV infection and the CNS reservoir problem