Abstract
This review outlines the neuropathogenesis of HIV, from initial HIV entry into the central nervous system (CNS) to chronic infection, focusing on key advancements in the last 5 years. Discoveries regarding acute HIV infection reveal timing and mechanisms of early HIV entry and replication in the CNS, early inflammatory responses, and establishment of genetically distinct viral reservoirs in the brain. Recent studies additionally explore how chronic HIV infection is maintained in the CNS, examining how the virus remains in a latent “hidden” state in diverse cells in the brain, and how this leads to sustained pathological inflammatory responses. Despite viral suppression with antiretroviral therapy, HIV can persist and even replicate in the CNS, and associate with ongoing neuropathology including CD8 + T-lymphocyte mediated encephalitis. Crucial investigation to advance our understanding of the immune mechanisms that both control viral infection and lead to pathological consequences in the brain is necessary to develop treatments to optimize long-term neurologic health in people living with HIV.
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References
HIV Surveillance Report: (2020) Supplemental Report, Centers for Disease Control and Prevention
Estimated number of people (all ages) living with HIV (2020) World Health Organization
Zayyad Z, Spudich S (2015) Neuropathogenesis of HIV: from initial neuroinvasion to HIV-associated neurocognitive disorder (HAND). Curr HIV/AIDS Rep 12:16–24
Veenstra M, Leon-Rivera R, Li M, Gama L, Clements JE, Berman JW (2017) Mechanisms of CNS viral seeding by HIV(+) CD14(+) CD16(+) monocytes: establishment and reseeding of viral reservoirs contributing to HIV-associated neurocognitive disorders. mBio mBio 8(5):e01280-17
Fiebig EW, Wright DJ, Rawal BD, Garrett PE, Schumacher RT, Peddada L, Heldebrant C, Smith R, Conrad A, Kleinman SH, Busch MP (2003) Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS 17:1871–1879
Spudich S, Peterson J, Fuchs D, Price RW, Gisslen M (2019) Potential for early antiretroviral therapy to reduce central nervous system HIV-1 persistence. AIDS 33(Suppl 2):S135–S144
Valcour V, Chalermchai T, Sailasuta N, Marovich M, Lerdlum S, Suttichom D, Suwanwela NC, Jagodzinski L, Michael N, Spudich S, van Griensven F, de Souza M, Kim J, Ananworanich J, Group RSS (2012) Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis 206:275–282
Chan P, Patel P, Hellmuth J, Colby DJ, Kroon E, Sacdalan C, Pinyakorn S, Jagodzinski L, Krebs S, Ananworanich J, Valcour V, Spudich S, Team RSS (2018) Distribution of human immunodeficiency virus (HIV) ribonucleic acid in cerebrospinal fluid and blood is linked to CD4/CD8 ratio during acute HIV. J Infect Dis 218:937–945
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 74:255–265
Xu R, Feng X, **e X, Zhang J, Wu D, Xu L (2012) 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 1436:13–19
Rojas-Celis V, Valiente-Echeverria F, Soto-Rifo R, Toro-Ascuy D (2019) New challenges of HIV-1 infection: how HIV-1 attacks and resides in the central nervous system. Cells 8:1245
Banks WA, Kastin AJ, Akerstrom V (1997) HIV-1 protein gp120 crosses the blood-brain barrier: role of adsorptive endocytosis. Life Sci 61:PL119-25
Campbell JH, Ratai EM, Autissier P, Nolan DJ, Tse S, Miller AD, Gonzalez RG, Salemi M, Burdo TH, Williams KC (2014) Anti-alpha4 antibody treatment blocks virus traffic to the brain and gut early, and stabilizes CNS injury late in infection. PLoS Pathog 10:e1004533
Sturdevant CB, Joseph SB, Schnell G, Price RW, Swanstrom R, Spudich S (2015) Compartmentalized replication of R5 T cell-tropic HIV-1 in the central nervous system early in the course of infection. PLoS Pathog 11:e1004720
Lee CA, Beasley E, Sundar K, Smelkinson M, Vinton C, Deleage C, Matsuda K, Wu F, Estes JD, Lafont BAP, Brenchley JM, Hirsch VM (2020) Simian immunodeficiency virus-infected memory CD4(+) T cells infiltrate to the site of infected macrophages in the neuroparenchyma of a chronic macaque model of neurological complications of AIDS. mBio 11(2):e00602-20
Sharma V, Creegan M, Tokarev A, Hsu D, Slike BM, Sacdalan C, Chan P, Spudich S, Ananworanich J, Eller MA, Krebs SJ, Vasan S, Bolton DL, Rv254/Search, Teams RSS (2021) Cerebrospinal fluid CD4+ T cell infection in humans and macaques during acute HIV-1 and SHIV infection. PLoS Pathog 17:e1010105
Russell RA, Chojnacki J, Jones DM, Johnson E, Do T, Eggeling C, Padilla-Parra S, Sattentau QJ (2017) Astrocytes resist HIV-1 fusion but engulf infected macrophage material. Cell Rep 18:1473–1483
Carroll-Anzinger D, Al-Harthi L (2006) Gamma interferon primes productive human immunodeficiency virus infection in astrocytes. J Virol 80:541–544
Ash MK, Al-Harthi L, Schneider JR (2021) HIV in the brain: identifying viral reservoirs and addressing the challenges of an HIV cure. Vaccines (Basel) 9:867
Li GH, Maric D, Major EO, Nath A (2020) Productive HIV infection in astrocytes can be established via a nonclassical mechanism. AIDS 34:963–978
Bertin J, Jalaguier P, Barat C, Roy MA, Tremblay MJ (2014) Exposure of human astrocytes to leukotriene C4 promotes a CX3CL1/fractalkine-mediated transmigration of HIV-1-infected CD4(+) T cells across an in vitro blood-brain barrier model. Virology 454–455:128–138
Subra C, Trautmann L (2019) Role of T lymphocytes in HIV neuropathogenesis. Curr HIV/AIDS Rep 16(3):236–243
Lee KM, Chiu KB, Renner NA, Sansing HA, Didier PJ, MacLean AG (2014) Form follows function: astrocyte morphology and immune dysfunction in SIV neuroAIDS. J Neurovirol 20:474–484
Williams DW, Calderon TM, Lopez L, Carvallo-Torres L, Gaskill PJ, Eugenin EA, Morgello S, Berman JW (2013) Mechanisms of HIV entry into the CNS: increased sensitivity of HIV infected CD14+CD16+ monocytes to CCL2 and key roles of CCR2, JAM-A, and ALCAM in diapedesis. PLoS ONE 8:e69270
Nickoloff-Bybel EA, Calderon TM, Gaskill PJ, Berman JW (2020) HIV Neuropathogenesis in the presence of a disrupted dopamine system. J Neuroimmune Pharmacol 15:729–742
Calderon TM, Williams DW, Lopez L, Eugenin EA, Cheney L, Gaskill PJ, Veenstra M, Anastos K, Morgello S, Berman JW (2017) Dopamine Increases CD14(+)CD16(+) Monocyte transmigration across the blood brain barrier: implications for substance abuse and HIV neuropathogenesis. J Neuroimmune Pharmacol 12:353–370
Coley JS, Calderon TM, Gaskill PJ, Eugenin EA, Berman JW (2015) Dopamine increases CD14+CD16+ monocyte migration and adhesion in the context of substance abuse and HIV neuropathogenesis. PLoS ONE 10:e0117450
Carvallo L, Lopez L, Fajardo JE, Jaureguiberry-Bravo M, Fiser A, Berman JW (2017) HIV-Tat regulates macrophage gene expression in the context of neuroAIDS. PLoS ONE 12:e0179882
McRae M (2016) HIV and viral protein effects on the blood brain barrier. Tissue Barriers 4:e1143543
Williams ME, Zulu SS, Stein DJ, Joska JA, Naude PJW (2020) Signatures of HIV-1 subtype B and C Tat proteins and their effects in the neuropathogenesis of HIV-associated neurocognitive impairments. Neurobiol Dis 136:104701
Rao VR, Sas AR, Eugenin EA, Siddappa NB, Bimonte-Nelson H, Berman JW, Ranga U, Tyor WR, Prasad VR (2008) HIV-1 clade-specific differences in the induction of neuropathogenesis. J Neurosci 28:10010–10016
Sonti S, Sharma AL, Tyagi M (2021) HIV-1 persistence in the CNS: mechanisms of latency, pathogenesis and an update on eradication strategies. Virus Res 303:198523
Bethel-Brown C, Yao H, Hu G, Buch S (2012) Platelet-derived growth factor (PDGF)-BB-mediated induction of monocyte chemoattractant protein 1 in human astrocytes: implications for HIV-associated neuroinflammation. J Neuroinflammation 9:262
Spudich SS (2016) Immune activation in the central nervous system throughout the course of HIV infection. Curr Opin HIV AIDS 11:226–233
Thangaraj A, Periyasamy P, Liao K, Bendi VS, Callen S, Pendyala G, Buch S (2018) HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy. Autophagy 14:1596–1619
Samikkannu T, Atluri VS, Arias AY, Rao KV, Mulet CT, Jayant RD, Nair MP (2014) HIV-1 subtypes B and C Tat differentially impact synaptic plasticity expression and implicates HIV-associated neurocognitive disorders. Curr HIV Res 12:397–405
Haughey NJ, Nath A, Mattson MP, Slevin JT, Geiger JD (2001) HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity. J Neurochem 78:457–467
Hu XT (2016) HIV-1 Tat-mediated calcium dysregulation and neuronal dysfunction in vulnerable brain regions. Curr Drug Targets 17:4–14
Var SR, Day TR, Vitomirov A, Smith DM, Soontornniyomkij V, Moore DJ, Achim CL, Mehta SR, Perez-Santiago J (2016) Mitochondrial injury and cognitive function in HIV infection and methamphetamine use. AIDS 30:839–848
Kessing CF, Spudich S, Valcour V, Cartwright P, Chalermchai T, Fletcher JL, Takata H, Nichols C, Josey BJ, Slike B, Krebs SJ, Sailsuta N, Lerdlum S, Jagodzinski L, Tipsuk S, Suttichom D, Rattanamanee S, Zetterberg H, Hellmuth J, Phanuphak N, Robb ML, Michael NL, Ananworanich J, Trautmann L (2017) High number of activated CD8+ T cells targeting HIV antigens are present in cerebrospinal fluid in acute HIV infection. J Acquir Immune Defic Syndr 75:108–117
Valcour VG, Spudich SS, Sailasuta N, Phanuphak N, Lerdlum S, Fletcher JL, Kroon ED, Jagodzinski LL, Allen IE, Adams CL, Prueksakaew P, Slike BM, Hellmuth JM, Kim JH, Ananworanich J, Group SRS (2015) Neurological response to cART vs. cART plus integrase inhibitor and CCR5 antagonist initiated during acute HIV. PLoS One 10:e0142600
Ho EL, Ronquillo R, Altmeppen H, Spudich SS, Price RW, Sinclair E (2013) Cellular composition of cerebrospinal fluid in HIV-1 infected and uninfected subjects. PLoS ONE 8:e66188
Subra CFF, Buranapraditkun S , Chan P , Sacdalan C, Tangnaree K, Rolland M, Krebs S, Sailasuta N, Tovanabutra S, Paul R, Michael NL, Robb M, Ananworanich J, Spudich S, Trautmann L (2019) CSF HIV specific T cells persist during ART and associate with lower CNS inflammation. Presented at CROI, Seattle, WA
Ananworanich J, Sacdalan CP, Pinyakorn S, Chomont N, de Souza M, Luekasemsuk T, Schuetz A, Krebs SJ, Dewar R, Jagodzinski L, Ubolyam S, Trichavaroj R, Tovanabutra S, Spudich S, Valcour V, Sereti I, Michael N, Robb M, Phanuphak P, Kim JH, Phanuphak N (2016) Virological and immunological characteristics of HIV-infected individuals at the earliest stage of infection. J Virus Erad 2:43–48
Shive CL, Jiang W, Anthony DD, Lederman MM (2015) Soluble CD14 is a nonspecific marker of monocyte activation. AIDS 29:1263–1265
Burdo TH, Lentz MR, Autissier P, Krishnan A, Halpern E, Letendre S, Rosenberg ES, Ellis RJ, Williams KC (2011) Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after anti-retroviral therapy. J Infect Dis 204:154–163
Takata H, Buranapraditkun S, Kessing C, Fletcher JL, Muir R, Tardif V, Cartwright P, Vandergeeten C, Bakeman W, Nichols CN, Pinyakorn S, Hansasuta P, Kroon E, Chalermchai T, O'Connell R, Kim J, Phanuphak N, Robb ML, Michael NL, Chomont N, Haddad EK, Ananworanich J, Trautmann L, Rv254/Search, the RVSSG (2017) Delayed differentiation of potent effector CD8(+) T cells reducing viremia and reservoir seeding in acute HIV infection. Sci Transl Med 9(377):eaag1809
Sailasuta N, Ross W, Ananworanich J, Chalermchai T, DeGruttola V, Lerdlum S, Pothisri M, Busovaca E, Ratto-Kim S, Jagodzinski L, Spudich S, Michael N, Kim JH, Valcour V, teams RSp. (2012) Change in brain magnetic resonance spectroscopy after treatment during acute HIV infection. PLoS ONE 7:e49272
Tovanabutra S, Sirijatuphat R, Pham PT, Bonar L, Harbolick EA, Bose M, Song H, Chang D, Oropeza C, O'Sullivan AM, Balinang J, Kroon E, Colby DJ, Sacdalan C, Hellmuth J, Chan P, Prueksakaew P, Pinyakorn S, Jagodzinski LL, Sutthichom D, Pattamaswin S, de Souza M, Gramzinski RA, Kim JH, Michael NL, Robb ML, Phanuphak N, Ananworanich J, Valcour V, Kijak GH, Sanders-Buell E, Spudich S, Core MVS, Team RSS (2019) Deep sequencing reveals central nervous system compartmentalization in multiple transmitted/founder virus acute HIV-1 infection. Cells 8
Joseph SB, Kincer LP, Bowman NM, Evans C, Vinikoor MJ, Lippincott CK, Gisslen M, Spudich S, Menezes P, Robertson K, Archin N, Kashuba A, Eron JJ, Price RW, Swanstrom R (2019) Human immunodeficiency virus type 1 RNA detected in the central nervous system (CNS) after years of suppressive antiretroviral therapy can originate from a replicating CNS reservoir or clonally expanded cells. Clin Infect Dis 69:1345–1352
Schnell G, Joseph S, Spudich S, Price RW, Swanstrom R (2011) HIV-1 replication in the central nervous system occurs in two distinct cell types. PLoS Pathog 7:e1002286
Lustig G, Cele S, Karim F, Derache A, Ngoepe A, Khan K, Gosnell BI, Moosa MS, Ntshuba N, Marais S, Jeena PM, Govender K, Adamson J, Kloverpris H, Gupta RK, Harrichandparsad R, Patel VB, Sigal A (2021) T cell derived HIV-1 is present in the CSF in the face of suppressive antiretroviral therapy. PLoS Pathog 17:e1009871
Balinang JCD, Jobe O, Sanders-Buell E, Chenine A, Mann B, Merbah M, Alvarez-Carbonell D, Bose M, Barrows B et al October 21–25 (2018) Differential infection of cultured peripheral and CNS cells by distinct transmitted/founder HIV-1 infectious molecular clones. Presented at Proceedings of the HIV Research for Prevention (HIVR4P 2018), Madrid, Spain
Spudich S, Clements JE (2019) HIV persistence in the central nervous system during antiretroviral therapy: evidence and implications. AIDS 33(Suppl 2):S103–S106
Honeycutt JB, Liao B, Nixon CC, Cleary RA, Thayer WO, Birath SL, Swanson MD, Sheridan P, Zakharova O, Prince F, Kuruc J, Gay CL, Evans C, Eron JJ, Wahl A, Garcia JV (2018) T cells establish and maintain CNS viral infection in HIV-infected humanized mice. J Clin Invest 128:2862–2876
Smolders J, Remmerswaal EB, Schuurman KG, Melief J, van Eden CG, van Lier RA, Huitinga I, Hamann J (2013) Characteristics of differentiated CD8(+) and CD4 (+) T cells present in the human brain. Acta Neuropathol 126:525–535
Strazielle N, Creidy R, Malcus C, Boucraut J, Ghersi-Egea JF (2016) T-lymphocytes traffic into the brain across the blood-CSF barrier: evidence using a reconstituted choroid plexus epithelium. PLoS ONE 11:e0150945
Farhadian SF, Mehta SS, Zografou C, Robertson K, Price RW, Pappalardo J, Chiarella J, Hafler DA, Spudich SS (2018) Single-cell RNA sequencing reveals microglia-like cells in cerebrospinal fluid during virologically suppressed HIV. JCI Insight 3(18):e121718
Gray LR, Cowley D, Welsh C, Lu HK, Brew BJ, Lewin SR, Wesselingh SL, Gorry PR, Churchill MJ (2016) CNS-specific regulatory elements in brain-derived HIV-1 strains affect responses to latency-reversing agents with implications for cure strategies. Mol Psychiatry 21:574–584
Li J, Chen C, Ma X, Geng G, Liu B, Zhang Y, Zhang S, Zhong F, Liu C, Yin Y, Cai W, Zhang H (2016) Long noncoding RNA NRON contributes to HIV-1 latency by specifically inducing tat protein degradation. Nat Commun 7:11730
Turrini F, Marelli S, Kajaste-Rudnitski A, Lusic M, Van Lint C, Das AT, Harwig A, Berkhout B, Vicenzi E (2015) HIV-1 transcriptional silencing caused by TRIM22 inhibition of Sp1 binding to the viral promoter. Retrovirology 12:104
Marcello A, Ferrari A, Pellegrini V, Pegoraro G, Lusic M, Beltram F, Giacca M (2003) Recruitment of human cyclin T1 to nuclear bodies through direct interaction with the PML protein. EMBO J 22:2156–2166
Maine GN, Mao X, Komarck CM, Burstein E (2007) COMMD1 promotes the ubiquitination of NF-kappaB subunits through a cullin-containing ubiquitin ligase. EMBO J 26:436–447
Alvarez-Carbonell D, Ye F, Ramanath N, Garcia-Mesa Y, Knapp PE, Hauser KF, Karn J (2019) Cross-talk between microglia and neurons regulates HIV latency. PLoS Pathog 15:e1008249
Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212:991–999
Chaillon A, Gianella S, Dellicour S, Rawlings SA, Schlub TE, De Oliveira MF, Ignacio C, Porrachia M, Vrancken B, Smith DM (2020) HIV persists throughout deep tissues with repopulation from multiple anatomical sources. J Clin Invest 130:1699–1712
Wei J, Hou J, Su B, Jiang T, Guo C, Wang W, Zhang Y, Chang B, Wu H, Zhang T (2020) The prevalence of Frascati-criteria-based HIV-associated neurocognitive disorder (HAND) in HIV-infected adults: a systematic review and meta-analysis. Front Neurol 11:581346
Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799
Nightingale S, Dreyer AJ, Saylor D, Gisslen M, Winston A, Joska JA (2021) Moving on from HAND: why we need new criteria for cognitive impairment in persons living with human immunodeficiency virus and a proposed way forward. Clin Infect Dis 73:1113–1118
Wang Y, Liu M, Lu Q, Farrell M, Lappin JM, Shi J, Lu L, Bao Y (2020) Global prevalence and burden of HIV-associated neurocognitive disorder: a meta-analysis. Neurology 95:e2610–e2621
Langford D, Marquie-Beck J, de Almeida S, Lazzaretto D, Letendre S, Grant I, McCutchan JA, Masliah E, Ellis RJ (2006) Relationship of antiretroviral treatment to postmortem brain tissue viral load in human immunodeficiency virus-infected patients. J Neurovirol 12:100–107
Jessen Krut J, Mellberg T, Price RW, Hagberg L, Fuchs D, Rosengren L, Nilsson S, Zetterberg H, Gisslen M (2014) Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients. PLoS ONE 9:e88591
D’Antoni ML, Byron MM, Chan P, Sailasuta N, Sacdalan C, Sithinamsuwan P, Tipsuk S, Pinyakorn S, Kroon E, Slike BM, Krebs SJ, Khadka VS, Chalermchai T, Kallianpur KJ, Robb M, Spudich S, Valcour V, Ananworanich J, Ndhlovu LC, Rv254/Search S Groups RSS (2018) Normalization of soluble CD163 levels after institution of antiretroviral therapy during acute HIV infection tracks with fewer neurological abnormalities. J Infect Dis 218:1453–1463
Gisslen M, Heslegrave A, Veleva E, Yilmaz A, Andersson LM, Hagberg L, Spudich S, Fuchs D, Price RW, Zetterberg H (2019) CSF concentrations of soluble TREM2 as a marker of microglial activation in HIV-1 infection. Neurol Neuroimmunol Neuroinflamm 6:e512
Hellmuth J, Slike BM, Sacdalan C, Best J, Kroon E, Phanuphak N, Fletcher JLK, Prueksakaew P, Jagodzinski LL, Valcour V, Robb M, Ananworanich J, Allen IE, Krebs SJ, Spudich S (2019) Very early initiation of antiretroviral therapy during acute HIV infection is associated with normalized levels of immune activation markers in cerebrospinal fluid but not in plasma. J Infect Dis 220:1885–1891
Burbelo PD, Price RW, Hagberg L, Hatano H, Spudich S, Deeks SG, Gisslen M (2018) Anti-human immunodeficiency virus antibodies in the cerebrospinal fluid: evidence of early treatment impact on central nervous system reservoir? J Infect Dis 217:1024–1032
Bundell C, Brunt SJ, Cysique LA, Brusch A, Brew BJ, Price P (2018) The high frequency of autoantibodies in HIV patients declines on antiretroviral therapy. Pathology 50:313–316
Oliveira MF, Chaillon A, Nakazawa M, Vargas M, Letendre SL, Strain MC, Ellis RJ, Morris S, Little SJ, Smith DM, Gianella S (2017) Early antiretroviral therapy is associated with lower HIV DNA molecular diversity and lower inflammation in cerebrospinal fluid but does not prevent the establishment of compartmentalized HIV DNA Populations. PLoS Pathog 13:e1006112
Winston A, Antinori A, Cinque P, Fox HS, Gisslen M, Henrich TJ, Letendre S, Persaud D, Price RW, Spudich S (2019) Defining cerebrospinal fluid HIV RNA escape: editorial review AIDS. AIDS 33(Suppl 2):S107–S111
Eden A, Fuchs D, Hagberg L, Nilsson S, Spudich S, Svennerholm B, Price RW, Gisslen M (2010) HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J Infect Dis 202:1819–1825
Handoko R, Chan P, Jagodzinski L, Pinyakorn S, Ubolyam S, Phanuphak N, Sacdalan C, Kroon E, Dumrongpisutikul N, Paul R, Valcour V, Ananworanich J, Vasan S, Spudich S, Team SRS (2021) Minimal detection of cerebrospinal fluid escape after initiation of antiretroviral therapy in acute HIV-1 infection. AIDS 35:777–782
de Almeida SM, Rotta I, de Pereira AP, Tang B, Umlauf A, Ribeiro CEL, Letendre S, Ellis RJ, Group HIVNRC (2020) Cerebrospinal fluid pleocytosis as a predictive factor for CSF and plasma HIV RNA discordance and escape. J Neurovirol 26:241–251
Manesh A, Barnabas R, Mani S, Karthik R, Abraham OC, Chacko G, Kannangai R, Varghese GM (2019) Symptomatic HIV CNS viral escape among patients on effective cART. Int J Infect Dis 84:39–43
Moloney PB, Hutchinson S, Heskin J, Mulcahy F, Langan Y, Conlon NP, Linas BP, Takahashi C, Cervantes-Arslanian AM (2020) Possible N-methyl-D-aspartate receptor antibody-mediated encephalitis in the setting of HIV cerebrospinal fluid escape. J Neurol 267:1348–1352
Peluso MJ, Ferretti F, Peterson J, Lee E, Fuchs D, Boschini A, Gisslen M, Angoff N, Price RW, Cinque P, Spudich S (2012) Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load. AIDS 26:1765–1774
Narvid J, Callen A, Talbott J, Uzelac A, Dupont SM, Chow F, Price RW, Rehani B (2018) Brain MRI features of CSF human immunodeficiency virus escape. J Neuroimaging 28:601–607
Mukerji SS, Misra V, Lorenz D, Cervantes-Arslanian AM, Lyons J, Chalkias S, Wurcel A, Burke D, Venna N, Morgello S, Koralnik IJ, Gabuzda D (2017) Temporal patterns and drug resistance in CSF viral escape among ART-experienced HIV-1 infected adults. J Acquir Immune Defic Syndr 75:246–255
Nightingale S, Geretti AM, Beloukas A, Fisher M, Winston A, Else L, Nelson M, Taylor S, Ustianowski A, Ainsworth J, Gilson R, Haddow L, Ong E, Watson V, Leen C, Minton J, Post F, Pirmohamed M, Solomon T, Khoo S (2016) Discordant CSF/plasma HIV-1 RNA in patients with unexplained low-level viraemia. J Neurovirol 22:852–860
Swanta N, Aryal S, Nejtek V, Shenoy S, Ghorpade A, Borgmann K (2020) Blood-based inflammation biomarkers of neurocognitive impairment in people living with HIV. J Neurovirol 26:358–370
Hong S, Banks WA (2015) Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications. Brain Behav Immun 45:1–12
Vera JH, Guo Q, Cole JH, Boasso A, Greathead L, Kelleher P, Rabiner EA, Kalk N, Bishop C, Gunn RN, Matthews PM, Winston A (2016) Neuroinflammation in treated HIV-positive individuals: A TSPO PET study. Neurology 86:1425–1432
Kamat A, Lyons JL, Misra V, Uno H, Morgello S, Singer EJ, Gabuzda D (2012) Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection. J Acquir Immune Defic Syndr 60:234–243
Nolan RA, Muir R, Runner K, Haddad EK, Gaskill PJ (2019) Role of macrophage dopamine receptors in mediating cytokine production: implications for neuroinflammation in the context of HIV-associated neurocognitive disorders. J Neuroimmune Pharmacol 14:134–156
Yilmaz A, Yiannoutsos CT, Fuchs D, Price RW, Crozier K, Hagberg L, Spudich S, Gisslen M (2013) Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy. J Neuroinflammation 10:62
Brew BJ, Dunbar N, Pemberton L, Kaldor J (1996) Predictive markers of AIDS dementia complex: CD4 cell count and cerebrospinal fluid concentrations of beta 2-microglobulin and neopterin. J Infect Dis 174:294–298
Farhadian SF, Mistry H, Kirchwey T, Chiarella J, Calvi R, Chintanaphol M, Patel P, Landry ML, Robertson K, Spudich SS (2019) Markers of CNS injury in adults living with HIV with CSF HIV not detected vs detected <20 copies/mL. Open Forum Infect Dis 6: ofz528
Pfefferbaum A, Rogosa DA, Rosenbloom MJ, Chu W, Sassoon SA, Kemper CA, Deresinski S, Rohlfing T, Zahr NM, Sullivan EV (2014) Accelerated aging of selective brain structures in human immunodeficiency virus infection: a controlled, longitudinal magnetic resonance imaging study. Neurobiol Aging 35:1755–1768
Jernigan TL, Archibald SL, Fennema-Notestine C, Taylor MJ, Theilmann RJ, Julaton MD, Notestine RJ, Wolfson T, Letendre SL, Ellis RJ, Heaton RK, Gamst AC, Jr Franklin DR, Clifford DB, Collier AC, Gelman BB, Marra C, McArthur JC, McCutchan JA, Morgello S, Simpson DM, Grant I, Group C (2011) Clinical factors related to brain structure in HIV: the CHARTER study. J Neurovirol 17:248–257
Kovacsics CE, Gill AJ, Ambegaokar SS, Gelman BB, Kolson DL (2017) Degradation of heme oxygenase-1 by the immunoproteasome in astrocytes: a potential interferon-gamma-dependent mechanism contributing to HIV neuropathogenesis. Glia 65:1264–1277
Dos Reis RS, Sant S, Keeney H, Wagner MCE, Ayyavoo V (2020) Modeling HIV-1 neuropathogenesis using three-dimensional human brain organoids (hBORGs) with HIV-1 infected microglia. Sci Rep 10:15209
Lucas SB, Wong KT, Nightingale S, Miller RF (2021) HIV-associated CD8 encephalitis: a UK case series and review of histopathologically confirmed cases. Front Neurol 12:628296
Sharma SK, Soneja M (2011) HIV & immune reconstitution inflammatory syndrome (IRIS). Indian J Med Res 134:866–877
Huis in ’tVeld D, Sun HY, Hung CC, Colebunders R (2012) The immune reconstitution inflammatory syndrome related to HIV co-infections: a review. Eur J Clin Microbiol Infect Dis 31:919–927
Gendelman HE (2020) Predictive biomarkers for cognitive decline during progressive HIV infection. EBioMedicine 51:102538
Guha D, Mukerji SS, Chettimada S, Misra V, Lorenz DR, Morgello S, Gabuzda D (2019) Cerebrospinal fluid extracellular vesicles and neurofilament light protein as biomarkers of central nervous system injury in HIV-infected patients on antiretroviral therapy. AIDS 33:615–625
Pulliam L, Sun B, Mustapic M, Chawla S, Kapogiannis D (2019) Plasma neuronal exosomes serve as biomarkers of cognitive impairment in HIV infection and Alzheimer’s disease. J Neurovirol 25:702–709
Sun B, Dalvi P, Abadjian L, Tang N, Pulliam L (2017) Blood neuron-derived exosomes as biomarkers of cognitive impairment in HIV. AIDS 31:F9–F17
Paudel YN, Shaikh MF, Chakraborti A, Kumari Y, Aledo-Serrano A, Aleksovska K, Alvim MKM, Othman I (2018) HMGB1: a common biomarker and potential target for TBI, neuroinflammation, epilepsy, and cognitive dysfunction. Front Neurosci 12:628
Megra BW, Eugenin EA, Berman JW (2017) The role of shed PrP(c) in the neuropathogenesis of HIV Infection. J Immunol 199:224–232
Roberts TK, Eugenin EA, Morgello S, Clements JE, Zink MC, Berman JW (2010) PrPC, the cellular isoform of the human prion protein, is a novel biomarker of HIV-associated neurocognitive impairment and mediates neuroinflammation. Am J Pathol 177:1848–1860
Seegar TCM, Killingsworth LB, Saha N, Meyer PA, Patra D, Zimmerman B, Janes PW, Rubinstein E, Nikolov DB, Skiniotis G, Kruse AC, Blacklow SC (2017) Structural basis for regulated proteolysis by the alpha-secretase ADAM10. Cell 171(1638–48):e7
de Almeida SM, Ribeiro CE, Rotta I, Piovesan M, Tang B, Vaida F, Raboni SM, Letendre S, Potter M, BatistelaFernandes MS, Ellis RJ, Group HIVNRC (2018) Biomarkers of neuronal injury and amyloid metabolism in the cerebrospinal fluid of patients infected with HIV-1 subtypes B and C. J Neurovirol 24:28–40
Ellis RJ, Moore DJ, Sundermann EE, Heaton RK, Mehta S, Hulgan T, Samuels D, Fields JA, Letendre SL (2020) Nucleic acid oxidation is associated with biomarkers of neurodegeneration in CSF in people with HIV. Neurol Neuroimmunol Neuroinflamm 7(6):e902
Velasquez S, Prevedel L, Valdebenito S, Gorska AM, Golovko M, Khan N, Geiger J, Eugenin EA (2020) Circulating levels of ATP is a biomarker of HIV cognitive impairment. EBioMedicine 51:102503
Bandera A, Taramasso L, Bozzi G, Muscatello A, Robinson JA, Burdo TH, Gori A (2019) HIV-associated neurocognitive impairment in the modern ART era: are we close to discovering reliable biomarkers in the setting of virological suppression? Front Aging Neurosci 11:187
Weiss JJ, Calvi R, Naganawa M, Toyonaga T, Farhadian SF, Chintanaphol M, Chiarella J, Zheng MQ, Ropchan J, Huang Y, Pietrzak RH, Carson RE, Spudich S (2021) Preliminary in vivo evidence of reduced synaptic density in human immunodeficiency virus (HIV) despite antiretroviral therapy. Clin Infect Dis 73:1404–1411
Gong Y, Chowdhury P, Nagesh PKB, Rahman MA, Zhi K, Yallapu MM, Kumar S (2020) Novel elvitegravir nanoformulation for drug delivery across the blood-brain barrier to achieve HIV-1 suppression in the CNS macrophages. Sci Rep 10:3835
Roy U, Drozd V, Durygin A, Rodriguez J, Barber P, Atluri V, Liu X, Voss TG, Saxena S, Nair M (2018) Characterization of Nanodiamond-based anti-HIV drug Delivery to the Brain. Sci Rep 8:1603
Pausch P, Al-Shayeb B, Bisom-Rapp E, Tsuchida CA, Li Z, Cress BF, Knott GJ, Jacobsen SE, Banfield JF, Doudna JA (2020) CRISPR-CasPhi from huge phages is a hypercompact genome editor. Science 369:333–337
Yan WX, Hunnewell P, Alfonse LE, Carte JM, Keston-Smith E, Sothiselvam S, Garrity AJ, Chong S, Makarova KS, Koonin EV, Cheng DR, Scott DA (2019) Functionally diverse type V CRISPR-Cas systems. Science 363:88–91
Kunze C, Borner K, Kienle E, Orschmann T, Rusha E, Schneider M, Radivojkov-Blagojevic M, Drukker M, Desbordes S, Grimm D, Brack-Werner R (2018) Synthetic AAV/CRISPR vectors for blocking HIV-1 expression in persistently infected astrocytes. Glia 66:413–427
Dash PK, Kaminski R, Bella R, Su H, Mathews S, Ahooyi TM, Chen C, Mancuso P, Sariyer R, Ferrante P, Donadoni M, Robinson JA, Sillman B, Lin Z, Hilaire JR, Banoub M, Elango M, Gautam N, Mosley RL, Poluektova LY, McMillan J, Bade AN, Gorantla S, Sariyer IK, Burdo TH, Young WB, Amini S, Gordon J, Jacobson JM, Edagwa B, Khalili K, Gendelman HE (2019) Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice. Nat Commun 10:2753
Gavegnano C, Haile WB, Hurwitz S, Tao S, Jiang Y, Schinazi RF, Tyor WR (2019) Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro. J Neuroinflammation 16:182
Ambrosius B, Gold R, Chan A, Faissner S (2019) Antineuroinflammatory drugs in HIV-associated neurocognitive disorders as potential therapy. Neurol Neuroimmunol Neuroinflamm 6:e551
Cross SA, Cook DR, Chi AW, Vance PJ, Kolson LL, Wong BJ, Jordan-Sciutto KL, Kolson DL (2011) Dimethyl fumarate, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and macrophage-mediated neurotoxicity: a novel candidate for HIV neuroprotection. J Immunol 187:5015–5025
Read SW, DeGrezia M, Ciccone EJ, DerSimonian R, Higgins J, Adelsberger JW, Starling JM, Rehm C, Sereti I (2010) The effect of leflunomide on cycling and activation of T-cells in HIV-1-infected participants. PLoS ONE 5:e11937
Sacktor N, Miyahara S, Evans S, Schifitto G, Cohen B, Haughey N, Drewes JL, Graham D, Zink MC, Anderson C, Nath A, Pardo CA, McCarthy S, Hosey L, Clifford D, team AA (2014) Impact of minocycline on cerebrospinal fluid markers of oxidative stress, neuronal injury, and inflammation in HIV-seropositive individuals with cognitive impairment. J Neurovirol 20:620–626
Barber-Axthelm IM, Barber-Axthelm V, Sze KY, Zhen A, Suryawanshi GW, Chen IS, Zack JA, Kitchen SG, Kiem HP, Peterson CW (2021) Stem cell-derived CAR T cells traffic to HIV reservoirs in macaques. JCI Insight 6(1):e141502
Ait-Ammar A, Kula A, Darcis G, Verdikt R, De Wit S, Gautier V, Mallon PWG, Marcello A, Rohr O, Van Lint C (2019) Current status of latency reversing agents facing the heterogeneity of HIV-1 cellular and tissue reservoirs. Front Microbiol 10:3060
Eden A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslen M (2007) Immune activation of the central nervous system is still present after >4 years of effective highly active antiretroviral therapy. J Infect Dis 196:1779–1783
Acknowledgements
We express our gratitude to the many individuals who have volunteered to partake in the studies reviewed here. Without their generosity, this work would not be possible.
Funding
LK is supported by NIH training grant 5T32GM136651-02. SS is supported by grants from the NIH including R01MH125737, R01MH125396, R01MH106466, and UM1DA051410.
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This article is a contribution to the special issue on: Neuroimmune Interactions in Health and Disease - Guest Editors: David Hafler & Lauren Sansing
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Killingsworth, L., Spudich, S. Neuropathogenesis of HIV-1: insights from across the spectrum of acute through long-term treated infection. Semin Immunopathol 44, 709–724 (2022). https://doi.org/10.1007/s00281-022-00953-5
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DOI: https://doi.org/10.1007/s00281-022-00953-5