**Acknowledgement**

I thank Dr. Rogier Sanders for assistance with the preparation of Figure 3.

#### **7. References**


[11] Bleul CC, Farzan M, Choe H, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 1996; 382(6594): 829-833.

Chemokine Receptors as Therapeutic Targets in HIV Infection 139

[28] Viola A, Luster AD. Chemokines and their receptors: drug targets in immunity and inflammation. Annual Review of Pharmacology and Toxicology 2008; 48: 171-197. [29] Lederman MM, Penn-Nicholson A, Cho M, Mosier D. Biology of CCR5 and its role in HIV infection and treatment. Journal of the American Medical Association 2006; 296(7):

[30] Oppermann M. Chemokine receptor CCR5: insights into structure, function, and

[31] Anastassopoulou CG, Kostrikis LG. The impact of human allelic variation on HIV-1

[32] Steen A, Schwartz TW, Rosenkilde MM. Targeting CXCR4 in HIV cell-entry inhibition.

[33] McCandless EE, Zhang B, Diamond MS, Klein RS. CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis. Proceedings of the National Academy of Sciences of the United States of

[34] Wilen CB, Tilton JC, Doms RW. Molecular mechanisms of HIV entry. Advances in

[35] Wyatt R, Sodroski J. The HIV-1 envelope glycoproteins: fusogens, antigens, and

[36] Stein BS, Gowda SD, Lifson JD, Penhallow RC, Bensch KG, Engleman EG. pHindependent HIV entry into CD4-positive T cells via virus envelope fusion to the

[37] Miyauchi K, Kim Y, Latinovic O, Morozov V, Melikyan GB. HIV enters cells via endocytosis and dynamin-dependent fusion with endosomes. Cell 2009; 137(3): 433-444. [38] Daecke J, Fackler OT, Dittmar MT, Krausslich HG. Involvement of clathrin-mediated endocytosis in human immunodeficiency virus type 1 entry. Journal of Virology 2005;

[39] Gorry PR, Ancuta P. Coreceptors and HIV-1 pathogenesis. Current HIV/AIDS reports

[40] Cormier EG, Dragic T. The crown and stem of the V3 loop play distinct roles in human immunodeficiency virus type 1 envelope glycoprotein interactions with the CCR5

[41] Dragic T. An overview of the determinants of CCR5 and CXCR4 co-receptor function.

[42] Huang CC, Lam SN, Acharya P, et al. Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science 2007; 317(5846): 1930-

[43] Anastassopoulou CG, Kostrikis LG. Viral correlates of HIV-1 disease. Current HIV

[44] Berger EA, Doms RW, Fenyo EM, et al. A new classification for HIV-1. Nature 1998;

regulation. Cellular Signalling 2004; 16(11): 1201-1210.

Mini Reviews in Medicinal Chemistry 2009; 9(14): 1605-1621.

Experimental Medicine and Biology 2012; 726: 223-242.

coreceptor. Journal of Virology 2002; 76(17): 8953-8957.

The Journal of General Virology 2001; 82(Pt 8): 1807-1814.

immunogens. Science 1998; 280(5371): 1884-1888.

plasma membrane. Cell 1987; 49(5): 659-668.

79(3): 1581-1594.

2011; 8(1): 45-53.

Research 2005; 3(2): 113-132.

1934.

391(6664): 240.

disease. Current HIV Research 2003; 1(2): 185-203.

America 2008; 105(32): 11270-11275.

815-826.


[28] Viola A, Luster AD. Chemokines and their receptors: drug targets in immunity and inflammation. Annual Review of Pharmacology and Toxicology 2008; 48: 171-197.

138 Immunodeficiency

382(6594): 833-835.

272(5270): 1955-1958.

85(7): 1149-1158.

637-647.

601-629.

4(2): 96-103.

[11] Bleul CC, Farzan M, Choe H, et al. The lymphocyte chemoattractant SDF-1 is a ligand

[12] Oberlin E, Amara A, Bachelerie F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 1996;

[13] Alkhatib G. The biology of CCR5 and CXCR4. Current Opinion in HIV and AIDS 2009;

[14] Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced

[15] Alkhatib G, Combadiere C, Broder CC, et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 1996;

[16] Choe H, Farzan M, Sun Y, et al. The beta-chemokine receptors CCR3 and CCR5

[17] Deng H, Liu R, Ellmeier W, et al. Identification of a major co-receptor for primary

[18] Doranz BJ, Rucker J, Yi Y, et al. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 1996;

[19] Dragic T, Litwin V, Allaway GP, et al. HIV-1 entry into CD4+ cells is mediated by the

[20] Moore JP, Kitchen SG, Pugach P, Zack JA. The CCR5 and CXCR4 coreceptors--central to understanding the transmission and pathogenesis of human immunodeficiency virus

[23] Allen SJ, Crown SE, Handel TM. Chemokine: receptor structure, interactions, and

[24] Choi WT, An J. Biology and clinical relevance of chemokines and chemokine receptors CXCR4 and CCR5 in human diseases. Experimental Biology and Medicine 2011; 236(6):

[25] Pollakis G, Paxton WA. HIV-1 (co)receptors: implications for vaccine and therapy

[26] Schlyer S, Horuk R. I want a new drug: G-protein-coupled receptors in drug

[27] Marchese A, Paing MM, Temple BR, Trejo J. G protein-coupled receptor sorting to endosomes and lysosomes. Annual Review of Pharmacology and Toxicology 2008; 48:

type 1 infection. AIDS Research and Human Retroviruses 2004; 20(1): 111-126. [21] Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annual Review of Immunology 1999; 17: 657-700. [22] Kuhmann SE, Hartley O. Targeting chemokine receptors in HIV: a status report. Annual

facilitate infection by primary HIV-1 isolates. Cell 1996; 85(7): 1135-1148.

chemokine receptor CC-CKR-5. Nature 1996; 381(6584): 667-673.

Review of Pharmacology and Toxicology 2008; 48: 425-461.

antagonism. Annual Review of Immunology 2007; 25: 787-820.

design. Current Pharmaceutical Design 2010; 16(33): 3701-3715.

development. Drug Discovery Today 2006; 11(11-12): 481-493.

for LESTR/fusin and blocks HIV-1 entry. Nature 1996; 382(6594): 829-833.

by CD8+ T cells. Science 1995; 270(5243): 1811-1815.

isolates of HIV-1. Nature 1996; 381(6584): 661-666.


[45] Hartley O, Klasse PJ, Sattentau QJ, Moore JP. V3: HIV's switch-hitter. AIDS Research and Human Retroviruses 2005; 21(2): 171-189.

Chemokine Receptors as Therapeutic Targets in HIV Infection 141

[62] Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR. Change in coreceptor use correlates with disease progression in HIV-1--infected individuals. The Journal of

[63] Hutter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. The New England Journal of Medicine 2009;

[64] Allers K, Hutter G, Hofmann J, et al. Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood 2011; 117(10): 2791-2799. [65] Telenti A. Safety concerns about CCR5 as an antiviral target. Current Opinion in HIV

[66] de Silva E, Stumpf MP. HIV and the CCR5-Delta32 resistance allele. FEMS

[67] Tsibris AM, Kuritzkes DR. Chemokine antagonists as therapeutics: focus on HIV-1.

[68] Glass WG, McDermott DH, Lim JK, et al. CCR5 deficiency increases risk of symptomatic West Nile virus infection. The Journal of Experimental Medicine 2006;

[69] Lim JK, Louie CY, Glaser C, et al. Genetic deficiency of chemokine receptor CCR5 is a strong risk factor for symptomatic West Nile virus infection: a meta-analysis of 4 cohorts in the US epidemic. The Journal of Infectious Diseases 2008; 197(2): 262-265. [70] Kindberg E, Mickiene A, Ax C, et al. A deletion in the chemokine receptor 5 (CCR5) gene is associated with tickborne encephalitis. The Journal of Infectious Diseases 2008;

[71] Hartley O, Offord RE. Engineering chemokines to develop optimized HIV inhibitors.

[72] Lobritz MA, Ratcliff AN, Arts EJ. HIV-1 Entry, Inhibitors, and Resistance. Viruses 2010;

[73] Simmons G, Clapham PR, Picard L, et al. Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 1997; 276(5310):

[74] Hartley O, Gaertner H, Wilken J, et al. Medicinal chemistry applied to a synthetic protein: development of highly potent HIV entry inhibitors. Proceedings of the National

[76] Pugach P, Ketas TJ, Michael E, Moore JP. Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors.

[77] Westby M, van der Ryst E. CCR5 antagonists: host-targeted antiviral agents for the treatment of HIV infection, 4 years on. Antiviral Chemistry & Chemotherapy 2010;

Academy of Sciences of the United States of America 2004; 101(47): 16460-16465. [75] Khatib N, Das S. PRO 140--a novel CCR5 co-receptor inhibitor. Recent Patents on Anti-

Experimental Medicine 1997; 185(4): 621-628.

360(7): 692-698.

203(1): 35-40.

197(2): 266-269.

2(5): 1069-1105.

20(5): 179-192.

276-279.

and AIDS 2009; 4(2): 131-135.

Microbiology Letters 2004; 241(1): 1-12.

Annual Review of Medicine 2007; 58: 445-459.

Current Protein & Peptide Science 2005; 6(3): 207-219.

Infective Drug Discovery 2010; 5(1): 18-22.

Virology 2008; 377(2): 401-407.


[62] Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR. Change in coreceptor use correlates with disease progression in HIV-1--infected individuals. The Journal of Experimental Medicine 1997; 185(4): 621-628.

140 Immunodeficiency

[45] Hartley O, Klasse PJ, Sattentau QJ, Moore JP. V3: HIV's switch-hitter. AIDS Research

[46] De Jong JJ, De Ronde A, Keulen W, Tersmette M, Goudsmit J. Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytiuminducing phenotype: analysis by single amino acid substitution. Journal of Virology

[47] Fouchier RA, Groenink M, Kootstra NA, et al. Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120

[48] Schuitemaker H, van 't Wout AB, Lusso P. Clinical significance of HIV-1 coreceptor

[49] Rose JD, Rhea AM, Weber J, Quinones-Mateu ME. Current tests to evaluate HIV-1

[50] Lin NH, Kuritzkes DR. Tropism testing in the clinical management of HIV-1 infection.

[51] Low AJ, Swenson LC, Harrigan PR. HIV coreceptor phenotyping in the clinical setting.

[52] Braun P, Wiesmann F. Phenotypic assays for the determination of coreceptor tropism in HIV-1 infected individuals. European Journal of Medical Research 2007; 12(9): 463-472. [53] Kuhmann S, Moore JP. The HIV-1 Phenotypic Variants: Deadly and Deadlier. Journal of

[54] Keele BF, Derdeyn CA. Genetic and antigenic features of the transmitted virus. Current

[55] Salazar-Gonzalez JF, Salazar MG, Keele BF, et al. Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1

[56] Grivel JC, Shattock RJ, Margolis LB. Selective transmission of R5 HIV-1 variants: where

[57] Gorry PR, Churchill M, Crowe SM, Cunningham AL, Gabuzda D. Pathogenesis of

[58] Repits J, Sterjovski J, Badia-Martinez D, et al. Primary HIV-1 R5 isolates from end-stage disease display enhanced viral fitness in parallel with increased gp120 net charge.

[59] Moir S, Chun TW, Fauci AS. Pathogenic mechanisms of HIV disease. Annual Review of

[60] Cicala C, Arthos J, Fauci AS. HIV-1 envelope, integrins and co-receptor use in mucosal

[61] Shankarappa R, Margolick JB, Gange SJ, et al. Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection.

transmission of HIV. Journal of Translational Medicine 2011; 9 Suppl 1: S2.

infection. The Journal of Experimental Medicine 2009; 206(6): 1273-1289.

is the gatekeeper? Journal of Translational Medicine 2011; 9 Suppl 1: S6.

macrophage tropic HIV-1. Current HIV Research 2005; 3(1): 53-60.

coreceptor tropism. Current Opinion in HIV and AIDS 2009; 4(2): 136-142.

and Human Retroviruses 2005; 21(2): 171-189.

molecule. Journal of Virology 1992; 66(5): 3183-3187.

Current Opinion in HIV and AIDS 2009; 4(6): 481-487.

AIDS Reviews 2008; 10(3): 143-151.

Opinion in HIV and AIDS 2009; 4(5): 352-357.

Journal of Virology 1999; 73(12): 10489-10502.

Viral Entry 2005; 1(1): 4-16.

Virology 2008; 379(1): 125-134.

Pathology 2011; 6: 223-248.

usage. Journal of Translational Medicine 2011; 9 Suppl 1: S5.

1992; 66(11): 6777-6780.


Chemokine Receptors as Therapeutic Targets in HIV Infection 143

[92] Palani A, Shapiro S, Josien H, et al. Synthesis, SAR, and biological evaluation of oximino-piperidino-piperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity. Journal of Medicinal Chemistry 2002; 45(14):

[93] Strizki JM, Tremblay C, Xu S, et al. Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus

[94] Tagat JR, McCombie SW, Nazareno D, et al. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-[4-[2-

[95] Maeda K, Nakata H, Koh Y, et al. Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. Journal of Virology 2004; 78(16): 8654-

[96] Dorr P, Westby M, Dobbs S, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broadspectrum anti-human immunodeficiency virus type 1 activity. Antimicrobial Agents

[97] Fatkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nature

[98] Veazey RS, Springer MS, Marx PA, Dufour J, Klasse PJ, Moore JP. Protection of macaques from vaginal SHIV challenge by an orally delivered CCR5 inhibitor. Nature

[99] MacArthur RD, Novak RM. Reviews of anti-infective agents: maraviroc: the first of a new class of antiretroviral agents. Clinical Infectious Diseases 2008; 47(2): 236-241. [100] Castonguay LA, Weng Y, Adolfsen W, et al. Binding of 2-aryl-4-(piperidin-1 yl)butanamines and 1,3,4-trisubstituted pyrrolidines to human CCR5: a molecular modeling-guided mutagenesis study of the binding pocket. Biochemistry 2003; 42(6):

[101] Maeda K, Das D, Ogata-Aoki H, et al. Structural and molecular interactions of CCR5 inhibitors with CCR5. The Journal of Biological Chemistry 2006; 281(18): 12688-12698. [102] Dragic T, Trkola A, Thompson DA, et al. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proceedings of the National Academy of Sciences of the United States of America 2000; 97(10): 5639-5644. [103] Tsamis F, Gavrilov S, Kajumo F, et al. Analysis of the mechanism by which the smallmolecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human

immunodeficiency virus type 1 entry. Journal of Virology 2003; 77(9): 5201-5208.

methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable

type 1. Antimicrobial Agents and Chemotherapy 2005; 49(12): 4911-4919.

methoxy-1(R)-4-(trifluoromethyl)phenyl]ethyl-3(S)-methyl-1-piperazinyl]-4-

CCR5 antagonist. Journal of Medicinal Chemistry 2004; 47(10): 2405-2408.

and Chemotherapy 2005; 49(11): 4721-4732.

Medicine 2005; 11(11): 1170-1172.

Medicine 2005; 11(12): 1293-1294.

3143-3160.

8662.

1544-1550.


[92] Palani A, Shapiro S, Josien H, et al. Synthesis, SAR, and biological evaluation of oximino-piperidino-piperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity. Journal of Medicinal Chemistry 2002; 45(14): 3143-3160.

142 Immunodeficiency

[78] Hannon GJ. RNA interference. Nature 2002; 418(6894): 244-251.

Molecular Therapeutics 2004; 6(4): 373-380.

HIV-1. Gene Therapy 2011; 18(12): 1134-1138.

and AIDS 2011; 6(1): 74-79.

11(8): 940-950.

[79] Dykxhoorn DM, Lieberman J. The silent revolution: RNA interference as basic biology,

[80] Boden D, Pusch O, Ramratnam B. HIV-1-specific RNA interference. Current Opinion in

[81] Zhou J, Rossi JJ. Current progress in the development of RNAi-based therapeutics for

[82] Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD. Genome editing with

[83] Cannon P, June C. Chemokine receptor 5 knockout strategies. Current Opinion in HIV

[84] Baba M, Nishimura O, Kanzaki N, et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proceedings of the National

[85] Baba M, Takashima K, Miyake H, et al. TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in

[86] Klibanov OM, Williams SH, Iler CA. Cenicriviroc, an orally active CCR5 antagonist for the potential treatment of HIV infection. Current Opinion in Investigational Drugs 2010;

[87] Tagat JR, McCombie SW, Steensma RW, et al. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element. Bioorganic

[88] Tagat JR, Steensma RW, McCombie SW, et al. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4- methyl-4- [3(S)-methyl-4-[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]-piperidine N1 oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist. Journal of Medicinal

[89] Billick E, Seibert C, Pugach P, et al. The differential sensitivity of human and rhesus macaque CCR5 to small-molecule inhibitors of human immunodeficiency virus type 1 entry is explained by a single amino acid difference and suggests a mechanism of action

[90] Palani A, Shapiro S, Clader JW, et al. Discovery of 4-[(Z)-(4-bromophenyl)- (ethoxyimino)methyl]-1'-[(2,4-dimethyl-3- pyridinyl)carbonyl]-4'-methyl-1,4' bipiperidine N-oxide (SCH 351125): an orally bioavailable human CCR5 antagonist for the treatment of HIV infection. Journal of Medicinal Chemistry 2001; 44(21): 3339-3342. [91] Strizki JM, Xu S, Wagner NE, et al. SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo. Proceedings of the National Academy of Sciences of the

Academy of Sciences of the United States of America 1999; 96(10): 5698-5703.

humans. Antimicrobial Agents and Chemotherapy 2005; 49(11): 4584-4591.

& Medicinal Chemistry Letters 2001; 11(16): 2143-2146.

for these inhibitors. Journal of Virology 2004; 78(8): 4134-4144.

United States of America 2001; 98(22): 12718-12723.

Chemistry 2001; 44(21): 3343-3346.

research tool, and therapeutic. Annual Review of Medicine 2005; 56: 401-423.

engineered zinc finger nucleases. Nature Reviews 2010; 11(9): 636-646.


[104] Watson C, Jenkinson S, Kazmierski W, Kenakin T. The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor. Molecular Pharmacology 2005; 67(4): 1268-1282.

Chemokine Receptors as Therapeutic Targets in HIV Infection 145

[118] Maeda Y, Yoshimura K, Miyamoto F, et al. In vitro and In vivo Resistance to Human Immunodeficiency Virus Type 1 Entry Inhibitors. Journal of AIDS & Clinical Research

[119] Baba M, Miyake H, Wang X, Okamoto M, Takashima K. Isolation and characterization of human immunodeficiency virus type 1 resistant to the smallmolecule CCR5 antagonist TAK-652. Antimicrobial Agents and Chemotherapy

[120] Moncunill G, Armand-Ugon M, Pauls E, Clotet B, Este JA. HIV-1 escape to CCR5 coreceptor antagonism through selection of CXCR4-using variants in vitro. AIDS 2008;

[121] Yusa K, Maeda Y, Fujioka A, Monde K, Harada S. Isolation of TAK-779-resistant HIV-1 from an R5 HIV-1 GP120 V3 loop library. The Journal of Biological Chemistry 2005;

[122] Tsibris AM, Sagar M, Gulick RM, et al. In vivo emergence of vicriviroc resistance in a human immunodeficiency virus type 1 subtype C-infected subject. Journal of Virology

[123] Ogert RA, Hou Y, Ba L, et al. Clinical resistance to vicriviroc through adaptive V3 loop mutations in HIV-1 subtype D gp120 that alter interactions with the N-terminus and

[124] Ogert RA, Wojcik L, Buontempo C, et al. Mapping resistance to the CCR5 co-receptor antagonist vicriviroc using heterologous chimeric HIV-1 envelope genes reveals key

[125] Ogert RA, Ba L, Hou Y, et al. Structure-function analysis of human immunodeficiency virus type 1 gp120 amino acid mutations associated with resistance to the CCR5

[127] Anastassopoulou CG, Ketas TJ, Depetris RS, Thomas AM, Klasse PJ, Moore JP. Resistance of a human immunodeficiency virus type 1 isolate to a small molecule CCR5 inhibitor can involve sequence changes in both gp120 and gp41. Virology 2011; 413(1):

[128] Kitrinos KM, Amrine-Madsen H, Irlbeck DM, Word JM, Demarest JF. Virologic failure in therapy-naive subjects on aplaviroc plus lopinavir-ritonavir: detection of aplaviroc resistance requires clonal analysis of envelope. Antimicrobial Agents and

[129] Tilton JC, Wilen CB, Didigu CA, et al. A maraviroc-resistant HIV-1 with narrow crossresistance to other CCR5 antagonists depends on both N-terminal and extracellular loop

domains of drug-bound CCR5. Journal of Virology 2010; 84(20): 10863-10876.

determinants in the C2-V5 domain of gp120. Virology 2008; 373(2): 387-399.

coreceptor antagonist vicriviroc. Journal of Virology 2009; 83(23): 12151-12163. [126] Anastassopoulou CG, Ketas TJ, Klasse PJ, Moore JP. Resistance to CCR5 inhibitors caused by sequence changes in the fusion peptide of HIV-1 gp41. Proceedings of the National Academy of Sciences of the United States of America 2009; 106(13):

2011; S2: 004.

22(1): 23-31.

5318-5323.

47-59.

2007; 51(2): 707-715.

280(34): 30083-30090.

2008; 82(16): 8210-8214.

ECL2 of CCR5. Virology 2010; 400(1): 145-155.

Chemotherapy 2009; 53(3): 1124-1131.


[118] Maeda Y, Yoshimura K, Miyamoto F, et al. In vitro and In vivo Resistance to Human Immunodeficiency Virus Type 1 Entry Inhibitors. Journal of AIDS & Clinical Research 2011; S2: 004.

144 Immunodeficiency

800.

2359-2371.

33421.

974.

81(15): 8165-8179.

[104] Watson C, Jenkinson S, Kazmierski W, Kenakin T. The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor.

[105] Seibert C, Ying W, Gavrilov S, et al. Interaction of small molecule inhibitors of HIV-1

[106] Kondru R, Zhang J, Ji C, et al. Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists. Molecular Pharmacology 2008; 73(3): 789-

[107] Kuhmann SE, Pugach P, Kunstman KJ, et al. Genetic and phenotypic analyses of human immunodeficiency virus type 1 escape from a small-molecule CCR5 inhibitor.

[108] Trkola A, Kuhmann SE, Strizki JM, et al. HIV-1 escape from a small molecule, CCR5 specific entry inhibitor does not involve CXCR4 use. Proceedings of the National

[109] Marozsan AJ, Kuhmann SE, Morgan T, et al. Generation and properties of a human immunodeficiency virus type 1 isolate resistant to the small molecule CCR5 inhibitor,

[110] Westby M, Smith-Burchnell C, Mori J, et al. Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. Journal of Virology 2007; 81(5):

[111] Ray N, Harrison JE, Blackburn LA, Martin JN, Deeks SG, Doms RW. Clinical resistance to enfuvirtide does not affect susceptibility of human immunodeficiency virus type 1 to

[112] Garcia-Perez J, Rueda P, Staropoli I, et al. New insights into the mechanisms whereby low molecular weight CCR5 ligands inhibit HIV-1 infection. The Journal of Biological

[113] Garcia-Perez J, Rueda P, Alcami J, et al. Allosteric model of maraviroc binding to CC chemokine receptor 5 (CCR5). The Journal of Biological Chemistry 2011; 286(38): 33409-

[114] Maeda K, Das D, Yin PD, et al. Involvement of the second extracellular loop and transmembrane residues of CCR5 in inhibitor binding and HIV-1 fusion: insights into the mechanism of allosteric inhibition. Journal of Molecular Biology 2008; 381(4): 956-

[115] Pastore C, Ramos A, Mosier DE. Intrinsic obstacles to human immunodeficiency virus

[116] Pastore C, Nedellec R, Ramos A, et al. Conserved changes in envelope function during human immunodeficiency virus type 1 coreceptor switching. Journal of Virology 2007;

[117] Moore JP, Kuritzkes DR. A piece de resistance: how HIV-1 escapes small molecule

type 1 coreceptor switching. Journal of Virology 2004; 78(14): 7565-7574.

CCR5 inhibitors. Current Opinion in HIV and AIDS 2009; 4(2): 118-124.

other classes of entry inhibitors. Journal of Virology 2007; 81(7): 3240-3250.

Academy of Sciences of the United States of America 2002; 99(1): 395-400.

Molecular Pharmacology 2005; 67(4): 1268-1282.

entry with CCR5. Virology 2006; 349(1): 41-54.

Journal of Virology 2004; 78(6): 2790-2807.

Chemistry 2011; 286(7): 4978-4990.

SCH-417690 (SCH-D). Virology 2005; 338(1): 182-199.


[130] Yuan Y, Maeda Y, Terasawa H, Monde K, Harada S, Yusa K. A combination of polymorphic mutations in V3 loop of HIV-1 gp120 can confer noncompetitive resistance to maraviroc. Virology 2011; 413(2): 293-299.

Chemokine Receptors as Therapeutic Targets in HIV Infection 147

[145] Berro R, Klasse PJ, Lascano D, et al. Multiple CCR5 conformations on the cell surface are used differentially by human immunodeficiency viruses resistant or sensitive to

[146] Laakso MM, Lee FH, Haggarty B, et al. V3 loop truncations in HIV-1 envelope impart resistance to coreceptor inhibitors and enhanced sensitivity to neutralizing antibodies.

[147] Agrawal-Gamse C, Lee FH, Haggarty B, et al. Adaptive mutations in a human immunodeficiency virus type 1 envelope protein with a truncated V3 loop restore function by improving interactions with CD4. Journal of Virology 2009; 83(21): 11005-

[148] Lin G, Bertolotti-Ciarlet A, Haggarty B, et al. Replication-competent variants of human immunodeficiency virus type 2 lacking the V3 loop exhibit resistance to chemokine

[149] Nolan KM, Jordan AP, Hoxie JA. Effects of partial deletions within the human immunodeficiency virus type 1 V3 loop on coreceptor tropism and sensitivity to entry

[150] Nolan KM, Del Prete GQ, Jordan AP, et al. Characterization of a human immunodeficiency virus type 1 V3 deletion mutation that confers resistance to CCR5 inhibitors and the ability to use aplaviroc-bound receptor. Journal of Virology 2009;

[151] Platt EJ, Kozak SL, Durnin JP, Hope TJ, Kabat D. Rapid dissociation of HIV-1 from cultured cells severely limits infectivity assays, causes the inactivation ascribed to entry inhibitors, and masks the inherently high level of infectivity of virions. Journal of

[152] Fatkenheuer G, Nelson M, Lazzarin A, et al. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. The New England Journal of Medicine 2008;

[153] Gulick RM, Su Z, Flexner C, et al. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-Infected, treatment-experienced patients: AIDS clinical trials

[154] Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. The New England Journal of Medicine 2008; 359(14): 1429-

[155] Whitcomb JM, Huang W, Fransen S, et al. Development and characterization of a novel single-cycle recombinant-virus assay to determine human immunodeficiency virus type 1 coreceptor tropism. Antimicrobial Agents and Chemotherapy 2007; 51(2):

[156] Su Z, Gulick RM, Krambrink A, et al. Response to vicriviroc in treatment-experienced subjects, as determined by an enhanced-sensitivity coreceptor tropism assay: reanalysis of AIDS clinical trials group A5211. The Journal of Infectious Diseases 2009; 200(11):

group 5211. The Journal of Infectious Diseases 2007; 196(2): 304-312.

CCR5 inhibitors. Journal of Virology 2011; 85(16): 8227-8240.

receptor antagonists. Journal of Virology 2007; 81(18): 9956-9966.

inhibitors. Journal of Virology 2008; 82(2): 664-673.

PLoS Pathogens 2007; 3(8): e117.

11015.

83(8): 3798-3809.

359(14): 1442-1455.

1441.

566-575.

1724-1728.

Virology 2010; 84(6): 3106-3110.


[145] Berro R, Klasse PJ, Lascano D, et al. Multiple CCR5 conformations on the cell surface are used differentially by human immunodeficiency viruses resistant or sensitive to CCR5 inhibitors. Journal of Virology 2011; 85(16): 8227-8240.

146 Immunodeficiency

428(2): 86-97.

107(3): 1166-1171.

2(2): 137-144.

5(8): e1000548.

e79.

[130] Yuan Y, Maeda Y, Terasawa H, Monde K, Harada S, Yusa K. A combination of polymorphic mutations in V3 loop of HIV-1 gp120 can confer noncompetitive resistance

[131] Anastassopoulou CG, Ketas TJ, Sanders RW, Klasse PJ, Moore JP. Effects of sequence changes in the HIV-1 gp41 fusion peptide on CCR5 inhibitor resistance. Virology 2012;

[132] Pfaff JM, Wilen CB, Harrison JE, et al. HIV-1 resistance to CCR5 antagonists associated with highly efficient use of CCR5 and altered tropism on primary CD4+ T cells. Journal

[133] Anastassopoulou CG, Marozsan AJ, Matet A, et al. Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss. PLoS Pathogens 2007; 3(6):

[134] Finzi A, Xiang SH, Pacheco B, et al. Topological layers in the HIV-1 gp120 inner domain regulate gp41 interaction and CD4-triggered conformational transitions.

[135] Helseth E, Olshevsky U, Furman C, Sodroski J. Human immunodeficiency virus type 1 gp120 envelope glycoprotein regions important for association with the gp41

[136] Pancera M, Majeed S, Ban YE, et al. Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility. Proceedings of the National Academy of Sciences of the United States of America 2010;

[137] Yang X, Mahony E, Holm GH, Kassa A, Sodroski J. Role of the gp120 inner domain beta-sandwich in the interaction between the human immunodeficiency virus envelope

[138] Huang CC, Tang M, Zhang MY, et al. Structure of a V3-containing HIV-1 gp120 core.

[141] Westby M. Resistance to CCR5 antagonists. Current Opinion in HIV and AIDS 2007;

[142] Pugach P, Marozsan AJ, Ketas TJ, Landes EL, Moore JP, Kuhmann SE. HIV-1 clones resistant to a small molecule CCR5 inhibitor use the inhibitor-bound form of CCR5 for

[143] Hirsch MS, Gunthard HF, Schapiro JM, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA

[144] Berro R, Sanders RW, Lu M, Klasse PJ, Moore JP. Two HIV-1 variants resistant to small molecule CCR5 inhibitors differ in how they use CCR5 for entry. PLoS Pathogens 2009;

transmembrane glycoprotein. Journal of Virology 1991; 65(4): 2119-2123.

glycoprotein subunits. Virology 2003; 313(1): 117-125.

[140] PyMOL. http://www.pymol.org/ (accessed 1 July 2009).

panel. Clinical Infectious Diseases 2008; 47(2): 266-285.

[139] Swiss-Model. http://swissmodel.expasy.org/ (accessed 1 July 2009).

to maraviroc. Virology 2011; 413(2): 293-299.

of Virology 2010; 84(13): 6505-6514.

Molecular Cell 2010; 37(5): 656-667.

Science 2005; 310(5750): 1025-1028.

entry. Virology 2007; 361(1): 212-228.


[157] Swenson LC, Mo T, Dong WW, et al. Deep V3 sequencing for HIV type 1 tropism in treatment-naive patients: a reanalysis of the MERIT trial of maraviroc. Clinical Infectious Diseases 2011; 53(7): 732-742.

**Chapter 6** 

© 2012 Jerez Puebla, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

The principal mediators of innate immunity against fungi are neutrophils and macrophages. Patients with neutropenia are extremely susceptible to opportunistic fungal infections. Phagocytes and dendritic cells sense fungal organisms by TLRs and lectin-like receptors called dectins . Neutrophils presumably liberate fungicidal substances, such as reactive oxygen species and lysosomal enzymes, and phagocytose fungi for intracellular

and reproduction in any medium, provided the original work is properly cited.

**Fungal Infections in Immunosuppressed Patients** 

Fungal infections, also called mycoses, are important causes of morbidity and mortality in humans. Some fungal infections are endemic, and these infections are usually caused by fungi that are present in the environment and whose spores enter humans. Other fungal infections are said to be opportunistic because the causative agents cause mild or no disease in healthy individuals but may infect and cause severe disease in immunodeficient persons. The human airway is continuously open to the nonsterile environment where fungal spores have the potential to reach lung tissue and produce disease. In the immunocompromised host, many fungi, including species of fungi typically considered nonpathogenic, have the potential to cause serious morbidity and mortality. Over the last several decades the advent of the human immunodeficiency virus (HIV) epidemic and the increasing use of immunosuppressive drugs for serious medical conditions have dramatically increased the number of persons who are severely immunocompromised. In addition, the range and diversity of fungi that cause disease have broadened. Although *Candida* and *Aspergillus* species continue to be the fungal pathogens that most frequently cause invasive fungal disease in immunocompromised persons overall, infections due to previously uncommon hyaline and dematiaceous filamentous fungi are being reported with increasing frequency. This is significant because, despite marked advances in antifungal therapy, infections caused by opportunistic fungal infections (rare and emerging) continue to be associated with high morbidity, high mortality, and poor patient outcomes. This results from a combination of drug-resistant strains, lack of robust clinical studies evaluating treatments,

Luis Enrique Jerez Puebla

http://dx.doi.org/10.5772/51512

**1. Introduction** 

Additional information is available at the end of the chapter

and severe underlying diseases in the patient [2].

