HIV-Associated Neurocognitive Disorder (HAND) and the Prospect of Brain-Penetrating Protease Inhibitors for Antiretroviral Treatment

Main Article Content

Arun K. Ghosh Anindya Sarkar Hiroaki Mitsuya


The advent of combined antiretroviral therapy (cART) has dramatically improved HIV management and patient care of HIV-infected individuals. The cART regimen resulted in a significant reduction of HIV/AIDS-related mortality and greatly improved life expectancies of those patients with access to cART. However, among many HIV-related complications, neurocognitive dysfunction, known as HIV-associated neurocognitive disorder (HAND), has now been a major issue.  While the cART regimen has been effective in reduction of HAND in many patients, the prevalence of HAND is increasing as HIV/AIDS patients live longer.  HIV infection and its subsequent manifestation of HAND is complex.   It is evident that the brain can serve as a sanctuary for HIV replication and HAND can remain in patients even with cART treatment due to poor blood-brain barrier permeability of the majority of current antiretroviral agents. Conceivably, cART needs to have improved central nervous system (CNS) penetration properties for effective treatment and possible prevention of HAND.  Therefore, design and development of new antiretroviral agents that can penetrate into the CNS effectively, could block HIV replication and significantly reduce the viral load in the CNS. This may prevent HAND and related symptoms. HIV protease inhibitors (PIs) are a critical component of cART.  Over the years, we have designed and synthesized a range of highly potent and novel PIs including the FDA approved drug, darunavir, which has been used as a first-line treatment.   In an effort to improve CNS penetration, we have been involved in the design and development of potent PIs with improved in vitro brain penetration properties. Herein we provide a brief review that covers insights and discussion of HAND and our work on PI development to ameliorate HIV-associated neurocognitive disorders.

Article Details

How to Cite
GHOSH, Arun K.; SARKAR, Anindya; MITSUYA, Hiroaki. HIV-Associated Neurocognitive Disorder (HAND) and the Prospect of Brain-Penetrating Protease Inhibitors for Antiretroviral Treatment. Medical Research Archives, [S.l.], v. 5, n. 4, apr. 2017. ISSN 2375-1924. Available at: <>. Date accessed: 16 apr. 2024.
Review Articles


[1] Joint United Nations Programme on HIV/AIDS. 2013. Global report: UNAIDS report on the global AIDS epidemic 2013. Joint United Nations Programme on HIV/AIDS, Geneva, Switzerland.

[2] Fauci AS, Marston HD. Ending the HIV-AIDS pandemic—follow the science. N Engl J Med. 2015;373(23):2197-2199.

[3] Tan IL, McArthur JC. HIV-Associated Neurological Disorders CNS Drugs. 2012;26(2):123-134.

[4] Ghafouri M, Amini S, Khalili K, Sawaya BE. HIV-1 associated dementia: Symptoms and causes. Retrovirology. 2006;3:28.

[5] McArthur JC, McClernon DR, Cronin MF, Nance-Sproson TF, Saah AJ, St Clair M, Lanier ER. Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol. 1997;42(5):689-698.

[6] Maschke M, Kastrup O, Esser S, Ross B, Hengge U, Hufnagel A. Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). J Neurol Neurosurg Psychiatry. 2000;69(3):376-380.

[7] Sacktor N, Nakasujja N, Skolasky R, Robertson K, Wong M, Musisi S, Ronald A, Katabira E. Antiretroviral therapy improves cognitive impairment in HIV+ individuals in sub-saharan Africa. Neurology. 2006;67(2):311-314.

[8] Spudich S. HIV and neurocognitive dysfunction. Curr HIV/AIDS Rep. 2013(3);10:235-243.

[9] Smurzynski M, Wu K, Letendre S, Robertson K, Bosch RJ, Clifford DB, Evans S, Collier AC, Taylor M, Ellis R. Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS. 2011;25(3):357-365.

[10] Navia BA, Cho ES, Petito CK, Price RW. The AIDS dementia complex: II. Neuropathology. Ann Neurol. 1986;19(6):525–535.

[11] Letendre SI, McCutchan JA, Childers ME, Woods SP, Lazzaretto D, Heaton RK, Grant I, Ellis RJ, HNRC Group. Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders. Ann Neurol. 2004;56(3):416-423.

[12] Lohse N, Hansen AB, Gerstoft J, Obel N. Improved survival in HIV-infected persons: consequences and perspectives. J Antimicrob Chemother. 2007;60(3):461–463.

[13] Zhou L, Saksena NK. HIV associated neurocognitive disorders. Infect Dis Rep. 2013;5(suppl 1): e8. PMC3892625/pdf/idr-2013-s1-e8.pdf.

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

[15] Müller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M. Immune reconstitution
inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta¬analysis. Lancet Infect Dis. 2010;10(4):251-2¬61.

[16] Rani P, Thomas FP. Central Nervous System Complications in HIV. Medscape. Dec 23, 2015. Retrieved from

[17] Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I; CHARTER Group. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75(23):2087-2096.

[18] 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. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789-1799.

[19] Simoes E, Justino JD. HIV-associated neurocognitive disorders: A review for NPs. The Nurse Practitioner. 2015;40(7):1–7.

[20] Clifford DB, Ances BM. HIV-associated neurocognitive disorder. Lancet Infect Dis. 2013;13(11):976–986.

[21] Price RW, Spudich S. Antiretroviral therapy and central nervous system HIV-1 infection. J Infect Dis. 2008;197(Suppl 3):S294-S306.

[22] Vazeux R, Brousse N, Jarry A, Henin D, Marche C, Vedrenne C, Mikol J, Wolff M, Michon C, Rozenbaum W, et al. AIDS subacute encephalitis. Identification of HIV-infected cells. Am J Pathol. 1987;126(3):403-410.

[23] Rawson T, Muir D, Mackie NE, Garvey LJ, Everitt A, Winston A. Factors associated with cerebrospinal fluid HIV RNA in HIV infected subjects undergoing lumbar puncture examination in a clinical setting. J Infect. 2012;65(3):239–245.

[24] Cysique LA, Vaida F, Letendre S, Gibson S, Cherner M, Woods SP, McCutchan JA, Heaton RK, Ellis RJ. Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology. 2009;73(5):342-348.

[25] Price RW, Brew B, Sidtis J, Rosenblum M, Scheck AC, Cleary P. The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science. 1988;239(4840):586–592.

[26] Brew B, Rosenblum M, Cronin K, Price R. AIDS dementia complex and HIV-1 brain infection: clinical-virological correlations. Annals of Neurology. 1995;38(4):563–570.

[27] Nabha L, Duong L, Timpone J. HIV-associated neurocognitive disorders: perspective on management strategies. Drugs. 2013;73(9):893-905.

[28] Manji H, Jäger H, Winston A. HIV Dementia and antiretroviral drugs: 30 years of an epidemic. J Neurol Neurosurg Psychiatry. 2013;84(10):1126-1137.

[29] Brew BJ, Pemberton L, Blennow K, Wallin A, Hagberg L. CSF amyloid beta42 and tau levels correlate with AIDS dementia complex. Neurology. 2005;65(9):1490-1492.

[30] Spudich S, Lollo N, Liegler T, Deeks SG, Price RW. Treatment benefit on cerebrospinal fluid HIV-1 levels in the setting of systemic virological suppression and failure. J Infect Dis.

[31] Mellgren A, Antinori A, Cinque P, Price RW, Eggers C, Hagberg L, Gisslén M. Cerebrospinal fluid HIV-1 infection usually responds well to antiretroviral treatment. Antivir Ther. 2005;10(6):701–707.

[32] Cysique LA, Waters EK, Brew BJ. Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research. BMC Neurol. 2011;11:148-158.

[33] Snider, WD, Simpson, DM, Nielson, S, Gold JW, Metroka CE, Posner JB. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol. 1983;14(4):403-418.

[34] Price, RW. Neurological complications of HIV infection. Lancet. 1996;348(9025):445-452.

[35] Robertson K, Kopinsky K, Mielke J, Appiah K, Hall C, Price R,
Kumwenda J, Kanyama C, Amod F, Marra C, Taylor T, Lalloo U, Jelsma J, Holding P, Boivin M, Birbeck G, Nakasujja N, Sanne I, Parsons TD, Parente A, Tucker K; Assessment of NeuroAIDS in Africa Conference Participants. Assessment of neuroAIDS in Africa. J
Neurovirol. 2005;11(Suppl 1):7-16.

[36] Maschke M, Kastrup O, Esser S, Ross B, Hengge U, Hufnagel A. Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). J Neurol Neurosurg Psychiatry. 2000;69(3):376–380.

[37] d’Arminio AM, Clinque P, Mocroft A, Goebel FD, Antunes F, Katlama C, Justesen US, Vella S, Kirk O, Lundgren J; EuroSIDA Study Group. Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol. 2004;55(3):320-328.

[38] 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.

[39] Cross H, Combrink M, Joska J. HIV-associated neurocognitive disorders: Antiretroviral regimen, CNS penetration effectiveness and cognitive outcomes. S African Medical Journal. 2013;103(10):758-762.

[40] Gisolf EH, Van Praaq R, Jurriaans S, Portegies P, Goudsmit J, Danner SA, Lange JM, Prins JM. Increasing cerebrospinal fluid chemokine concentrations despite undetectable cerebrospinal fluid HIV RNA in HIV-1-infected patients receiving antiretroviral therapy. J
Acquir Immune Defic Syndr. 2000;25(5):426–433.

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

[42] Cunningham PH, Smith DG, Satchell C, Cooper DA, Brew B. Evidence for independent development of resistance to HIV-1 reverse transcriptase inhibitors in the cerebrospinal fluid. AIDS. 2000;14(13):1949-1954.

[43] Pierson T, McArthur J, Siliciano RF. Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu Rev Immunol. 2000;18:665–708.

[44] de Oliveira FTM, do Olival GS, de Oliveira ACP. Central Nervous System Antiretroviral High Penetration Therapy. J AIDS Clin Res. 2015;6(12):529-531. doi:10.4172/2155-6113.1000529.

[45] Akay C, Cooper M, Odeleye A, Jensen BK, White MG, Vassoler F, Gannon PJ, Mankowski J, Dorsey JL, Buch AM, Cross SA, Cook DR, Peña MM, Andersen ES, Christofidou-Solomidou M, Lindl KA, Zink MC, Clements J, Pierce RC, Kolson DL, Jordan-Sciutto KL. Antiretroviral drugs induce oxidative stress and neuronal damage in the CNS. J Neurovirology. 2014;20(1):39–53.

[46] Nolan D, Mallal S. Complications associated with NRTI therapy: update on clinical features and possible pathogenic mechanisms. Antivir Ther. 2004;9(6):849–863.

[47] Cinque P, Koralnik IJ, Clifford DB. The evolving face of human immunodeficiency virus-related progressive multifocal leukoencephalopathy: defining a consensus terminology. J Neurovirol. 2003;9(Suppl 1):88–92.

[48] Kean, JM, Rao S, Wang M, Garcea RL. Atwood, Walter J, ed. Seroepidemiology of Human Polyomaviruses. PLoS Pathogens. 2009;5(3):e1000363. doi:10.1371/journal.ppat.1000363

[49] Ghosh AK, Sridhar PR, Kumaragurubaran N, Koh Y, Weber IT, Mitsuya H. Bis Tetrahydrofuran: a Privileged Ligand for Darunavir and a New Generation of HIV Protease Inhibitors That Combat Drug Resistance. ChemMedChem. 2006;1(9):939-950.

[50] Ghosh AK, Kincaid JF, Cho W, Walters DE, Krishnan K, Hussain KA, Koo Y, Cho H, Rudall C, Holland L, Buthod J. Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett. 1998;8(6):687-690.

[51] Ghosh AK, Dawson ZL, Mitsuya H. Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV. Bioorg Med Chem. 2007;15(24):7576-7580.

[52] Ghosh AK, Chapsal BD. “Design of the anti-HIV-1 protease inhibitor darunavir,” Chapter 13 in: Introduction to Drug Research and development, 2013, Elsevier, Ltd.

[53] Ghosh AK, Anderson DD, Weber IT, Mitsuya H. Enhancing backbond binding – a fruitful concept for combating drug-resistant HIV. Angew Chem Int Ed Engl. 2012;51(8):1778-1802.

[54] Ghosh AK, Chapsal BD, Weber IT, Mitsuya H. Design of HIV protease inhibitors targeting protein backbone: an effective strategy for combating drug resistance. Acc Chem Res. 2008;41(1):78-86.

[55] Ghosh AK, Krishnan K, Walters DE, Cho W, Cho H, Koo Y, Trevino J, Holland L, Buthod J. Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R) (hydroxyethylamino)sulphonamide isostere. Bioorg Med Chem Lett.

[56] Ghosh AK, Cho W, Walters DE, Krishnan K, Hussain KA, Koo Y, Cho H, Rudall C, Holland L, Buthod J. Structure based design: novel spirocyclic ethers as nonpeptidal P2-ligands for HIV protease inhibitors. Bioorg Med Chem Lett. 1998;8(8):979–982.

[57] Koh Y, Nakata H, Maeda K, Ogata H, Bilcer G, Devasamudram T, Kincaid JF, Boross P, Wang YF, Tie Y, Volarath P, Gaddis L, Harrison RW, Weber IT, Ghosh AK, Mitsuya H. Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC- 94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro. Antimicrob Agents Chemother. 2003;47(10):3123–3129.

[58] Ghosh AK, Xu CX, Rao KV, Baldridge A, Agniswamy J, Wang YF, Weber IT, Aoki M, Miguel SG, Amano M, Mitsuya H. Probing multidrug-resistance and protein-ligand interactions with oxatricyclic designed ligands in HIV-1 protease inhibitors. ChemMedChem. 2010;5(11):1850–1854.

[59] Koh Y, Matsumi S, Das D, Amano M, Davis DA, Leschenko S, Baldridge A, Shioda T, Yarchoan R, Ghosh AK, Mitsuya H. Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization. J Biol Chem. 2007;282(39):28709–28720.

[60] Calcagno A, Yilmaz A, Cusato J, Simiele M, Bertucci R, Siccardi M, Marinaro L, D’Avolio A, Di Perri G, Bonora S. Determinants of darunavir cerebrospinal fluid concentrations: impact of once-daily dosing and pharmacogenetics. AIDS. 2012;26(12):1529–1533.

[61] Langford D, Marquie-Beck J, de Almeida S, Lazzaretto D, Letendre S, Grant I, McCutchan JA, Masliah E, Ellis RJ. Relationship of antiretroviral treatment to postmortem brain tissue viral load in human immunodeficiency virus-infected patients. J Neurovirol. 2006;12(2):100–107.

[62] Salcedo-Gómez PM, Amano M, Yashchuk S, Mizuno A, Das D, Ghosh AK, Mitsuya H. GRL-04810 and GRL-05010; difluoride-containing nonpeptidic HIV-1 protease inhibitors(PIs) that inhibit the replication of multi-PI-resistant HIV-1 in vitro and possess favorable lipophilicity that may allow blood-brain barrier penetration. Antimicrob Agents Chemother. 2013;57(12):6110–6121.

[63] Ghosh AK, Yashchuk S, Mizuno A, Chakraborty N, Agniswamy J, Wang YF, Aoki M, Salcedo-Gómez PM, Amano M, Weber IT, Mitsuya H. Design of gem-difluoro-bis-tetrahydrofuran as P2 ligand for HIV-1 protease inhibitors to improve brain penetration: synthesis, X-ray studies, and biological evaluation. ChemMedChem. 2015;10(1):107–115.

[64] Amano M, Tojo Y, Salcedo-Gómez PM, Parham GL, Nyalapatla PR, Das D, Ghosh AK, Mitsuya H. A novel tricyclic ligand-containing nonpeptidic HIV-1 protease inhibitor, GRL-0739, effectively inhibits the replication of multidrug-resistant HIV-1 variants and has a desirable central nervous system penetration property in vitro. Antimicrob Agents Chemother. 2015;59(5):2625–2635.

[65] Amano M, Salcedo-Gómez PM, Zhao R, Yedidi RS, Das D, Bulut H, Delino NS, Sheri VR, Ghosh AK, Mitsuya H. A modified P1 moiety enhances in vitro antiviral activity against various multidrug-resistant HIV-1 variants and in vitro central nervous system penetration properties of a novel nonpeptidic protease inhibitor, GRL-10413. Antimicrob Agents Chemother. 2016;60(12):7046–7059.

[66] Purser S, Moore PR, Swallow S, Gouverneur V. Fluorine in medicinal chemistry Chem Soc Rev. 2008;37(2):320-330.
[67] Zhou P, Zou J, Tian F, Shang Z. Fluorine Bonding — How Does It Work In Protein−Ligand Interactions? J Chem Inf Model. 2009;49(10):2344–2355.

[67] Valcour V, Sithinamsuwan P, Letendre S, Ances B. Pathogenesis of HIV in the central nervous system. Curr HIV/AIDS Rep. 2011;8(1):51–60.

[68] Bright TV, Dalton F, Elder VL, Murphy CD, O’Connor NK, Sandford G. A convenient medical-microbial method for developing fluorinated pharmaceuticals. Org Biomol Chem. 2013;11(7):1135–1142.

[69] Liu P, Sharon A, Chu CK. Fluorinated nucleosides: synthesis and biological implication. J Fluor Chem. 2008;129(9):743–766.

[70] Cecchelli R, Berezowski V, Lundquist S, Culot M, Renftel M, Dehouck MP, Fenart L. Modelling of the blood brain barrier in drug discovery and development. Nat Rev Drug Discov. 2007;6(8):650–661.

[71] Nakagawa S, Deli MA, Nakao S, Honda M, Hayashi K, Nakaoke R, Kataoka Y, Niwa M. Pericytes from brain microvessels strengthenthe barrier integrity in primary cultures of rat brain endothelial cells. Cell Mol Neurobiol. 2007;27(6):687–694.

[72] Hughes JD, Blagg J, Price DA, Bailey S, Decrescenzo GA, Devraj RV, Ellsworth E, Fobian YM, Gibbs ME, Gilles RW, Greene N, Huang E, Krieger-Burke T, Loesel J, Wager T, Whiteley L, Zhang Y. Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorg Med Chem Lett. 2008;18(17):4872–4875.

[73] Ryckmans T, Edwards MP, Horne VA, Correia AM, Owen DR, Thompson LR, Tran I, Tutt MF, Young T. Rapid assessment of a novel series of selective CB2 agonists using parallel synthesis protocols: a lipophilic efficiency (LipE) analysis. Bioorg Med Chem Lett. 2009;19(15):4406–4409.

[74] Waring MJ. Defining optimum lipophilicity and molecular weight ranges for drug candidates—molecular weight dependent lower log D limits based on permeability. Bioorg Med Chem Lett. 2009;19(10):2844–2851.

[75] Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H. A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL- 98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro. Antimicrob Agents Chemother. 2007;51(6):2143–2155. doi .org/10.1128/AAC.01413-06.

[76] Xu Z, Yang Z, Liu Y, Lu Y, Chen K, Zhu W. Halogen bond: its role beyond drug-target binding affinity for drug discovery and development. J Chem Inf Model. 2014;54(1):69–78.

[77] Wilcken R, Zimmermann MO, Lange A, Joerger AC, Boeckler FM. Principles and applications of halogen bonding in medicinal chemistry and chemical biology. J Med Chem. 2013;56(4):1363–1388. /10.1021/jm3012068.

[78] Müller K, Faeh C, Diederich F. Fluorine in pharmaceuticals: looking beyond intuition. Science. 2007;317(5846):1881–1886. /science.1131943.

[79] Navia BA, Jordan BD, Price RW. The AIDS dementia complex: I.
Clinical features Ann Neurol. 1986;19(6):517–524.