Use of a Small Molecule CCR5 Inhibitor in Macaques to Treat Simian Immunodeficiency Virus Infection or Prevent Simian-human Immunodeficiency Virus Infection

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2003 Nov 19

PMID 14623909

Citations 65

Authors

Ronald S Veazey

Per Johan Klasse

Thomas J Ketas

Jacqueline D Reeves

Michael Piatak Jr

Kevin Kunstman

Shawn E Kuhmann

Preston A Marx

Jeffrey D Lifson

Jason Dufour

Megan Mefford

Ivona Pandrea

Steven M Wolinsky

Robert W Doms

Julie A Demartino

Salvatore J Siciliano

Kathy Lyons

Martin S Springer

John P Moore

Affiliations

Soon will be listed here.

Abstract

Human immunodeficiency virus type 1 (HIV-1) fuses with cells after sequential interactions between its envelope glycoproteins, CD4 and a coreceptor, usually CC chemokine receptor 5 (CCR5) or CXC receptor 4 (CXCR4). CMPD 167 is a CCR5-specific small molecule with potent antiviral activity in vitro. We show that CMPD 167 caused a rapid and substantial (4-200-fold) decrease in plasma viremia in six rhesus macaques chronically infected with simian immunodeficiency virus (SIV) strains SIVmac251 or SIVB670, but not in an animal infected with the X4 simian-human immunodeficiency virus (SHIV), SHIV-89.6P. In three of the SIV-infected animals, viremia reduction was sustained. In one, there was a rapid, but partial, rebound and in another, there was a rapid and complete rebound. There was a substantial delay (>21 d) between the end of therapy and the onset of full viremia rebound in two animals. We also evaluated whether vaginal administration of gel-formulated CMPD 167 could prevent vaginal transmission of the R5 virus, SHIV-162P4. Complete protection occurred in only 2 of 11 animals, but early viral replication was significantly less in the 11 CMPD 167-recipients than in 9 controls receiving carrier gel. These findings support the development of small molecule CCR5 inhibitors as antiviral therapies, and possibly as components of a topical microbicide to prevent HIV-1 sexual transmission.

Citing Articles

Translational Models to Predict Target Concentrations for Pre-Exposure Prophylaxis in Women.

Lantz A, Nicol M AIDS Res Hum Retroviruses. 2022; 38(12):909-923.

PMID: 36097755 PMC: 9805887. DOI: 10.1089/AID.2022.0057.

CCR5 as a Coreceptor for Human Immunodeficiency Virus and Simian Immunodeficiency Viruses: A Prototypic Love-Hate Affair.

Jasinska A, Pandrea I, Apetrei C Front Immunol. 2022; 13:835994.

PMID: 35154162 PMC: 8829453. DOI: 10.3389/fimmu.2022.835994.

Galectins as potential therapeutic targets in STIs in the female genital tract.

Lujan A, Croci D, Rabinovich G, Damiani M Nat Rev Urol. 2022; 19(4):240-252.

PMID: 35105978 DOI: 10.1038/s41585-021-00562-1.

Loss of CXCR6 coreceptor usage characterizes pathogenic lentiviruses.

Wetzel K, Yi Y, Yadav A, Bauer A, Bello E, Romero D PLoS Pathog. 2018; 14(4):e1007003.

PMID: 29659623 PMC: 5919676. DOI: 10.1371/journal.ppat.1007003.

CXCR6-Mediated Simian Immunodeficiency Virus SIVagmSab Entry into Sabaeus African Green Monkey Lymphocytes Implicates Widespread Use of Non-CCR5 Pathways in Natural Host Infections.

Wetzel K, Yi Y, Elliott S, Romero D, Jacquelin B, Hahn B J Virol. 2016; 91(4).

PMID: 27903799 PMC: 5286873. DOI: 10.1128/JVI.01626-16.

References

Pope M, Haase A . Transmission, acute HIV-1 infection and the quest for strategies to prevent infection. Nat Med. 2003; 9(7):847-52. DOI: 10.1038/nm0703-847. View

BERGER E, Murphy P, Farber J . Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol. 1999; 17:657-700. DOI: 10.1146/annurev.immunol.17.1.657. View

Chun T, Davey Jr R, Ostrowski M, Justement J, Engel D, Mullins J . Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy. Nat Med. 2000; 6(7):757-61. DOI: 10.1038/77481. View

Sharron M, Pohlmann S, Price K, Lolis E, Tsang M, Kirchhoff F . Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes. Blood. 2000; 96(1):41-9. View

Doms R, Moore J . HIV-1 membrane fusion: targets of opportunity. J Cell Biol. 2000; 151(2):F9-14. PMC: 2192632. DOI: 10.1083/jcb.151.2.f9. View

Kawamura T, COHEN S, Borris D, Aquilino E, Glushakova S, Margolis L . Candidate microbicides block HIV-1 infection of human immature Langerhans cells within epithelial tissue explants. J Exp Med. 2000; 192(10):1491-500. PMC: 2193188. DOI: 10.1084/jem.192.10.1491. View

Cocchi F, Devico A, Yarchoan R, Redfield R, Cleghorn F, Blattner W . Higher macrophage inflammatory protein (MIP)-1alpha and MIP-1beta levels from CD8+ T cells are associated with asymptomatic HIV-1 infection. Proc Natl Acad Sci U S A. 2000; 97(25):13812-7. PMC: 17658. DOI: 10.1073/pnas.240469997. View

Sabbe R, Picchio G, Pastore C, Chaloin O, Hartley O, Offord R . Donor- and ligand-dependent differences in C-C chemokine receptor 5 reexpression. J Virol. 2001; 75(2):661-71. PMC: 113963. DOI: 10.1128/JVI.75.2.661-671.2001. View

OBrien S, Moore J . The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS. Immunol Rev. 2001; 177:99-111. DOI: 10.1034/j.1600-065x.2000.17710.x. View

10.

Harouse J, Gettie A, Eshetu T, Tan R, Bohm R, Blanchard J . Mucosal transmission and induction of simian AIDS by CCR5-specific simian/human immunodeficiency virus SHIV(SF162P3). J Virol. 2001; 75(4):1990-5. PMC: 115146. DOI: 10.1128/JVI.75.4.1990-1995.2001. View

11.

Doms R . Chemokine receptors and HIV entry. AIDS. 2001; 15 Suppl 1:S34-5. DOI: 10.1097/00002030-200102001-00051. View

12.

Nagashima K, Thompson D, Rosenfield S, Maddon P, Dragic T, Olson W . Human immunodeficiency virus type 1 entry inhibitors PRO 542 and T-20 are potently synergistic in blocking virus-cell and cell-cell fusion. J Infect Dis. 2001; 183(7):1121-5. DOI: 10.1086/319284. View

13.

Richman D . HIV chemotherapy. Nature. 2001; 410(6831):995-1001. DOI: 10.1038/35073673. View

14.

Paxton W, Neumann A, Kang S, Deutch L, Brown R, Koup R . RANTES production from CD4+ lymphocytes correlates with host genotype and rates of human immunodeficiency virus type 1 disease progression. J Infect Dis. 2001; 183(11):1678-81. DOI: 10.1086/320701. View

15.

Moore J, Stevenson M . New targets for inhibitors of HIV-1 replication. Nat Rev Mol Cell Biol. 2001; 1(1):40-9. DOI: 10.1038/35036060. View

16.

Dragic T . An overview of the determinants of CCR5 and CXCR4 co-receptor function. J Gen Virol. 2001; 82(Pt 8):1807-1814. DOI: 10.1099/0022-1317-82-8-1807. View

17.

Lifson J, Rossio J, Piatak Jr M, Parks T, Li L, Kiser R . Role of CD8(+) lymphocytes in control of simian immunodeficiency virus infection and resistance to rechallenge after transient early antiretroviral treatment. J Virol. 2001; 75(21):10187-99. PMC: 114593. DOI: 10.1128/JVI.75.21.10187-10199.2001. View

18.

Pohlmann S, Baribaud F, Doms R . DC-SIGN and DC-SIGNR: helping hands for HIV. Trends Immunol. 2001; 22(12):643-6. DOI: 10.1016/s1471-4906(01)02081-6. View

19.

Pal R, Taylor B, Foulke J, Woodward R, Merges M, Praschunus R . Characterization of a simian human immunodeficiency virus encoding the envelope gene from the CCR5-tropic HIV-1 Ba-L. J Acquir Immune Defic Syndr. 2003; 33(3):300-7. DOI: 10.1097/00126334-200307010-00003. View

20.

Kawamura T, Gulden F, Sugaya M, McNamara D, Borris D, Lederman M . R5 HIV productively infects Langerhans cells, and infection levels are regulated by compound CCR5 polymorphisms. Proc Natl Acad Sci U S A. 2003; 100(14):8401-6. PMC: 166241. DOI: 10.1073/pnas.1432450100. View