The potential of maraviroc (MVC), a small-molecule CCR5 antagonist, as a candidate to prevent HIV-1 sexual transmission by oral or topical dosing has not yet been completely established. Using relevant cellular and mucosal tissue explant models, we show partial antiviral activity of MVC when tested in multiple preclinical dosing strategies.
Get full access to this article
View all access options for this article.
References
1.
GrivelJC, ShattockRJ, MargolisLB: Selective transmission of R5 HIV-1 variants: Where is the gatekeeper?. J Transl Med, 2011; 9(Suppl 1):S6.
2.
Salazar-GonzalezJF, SalazarMG, KeeleBF, et al.: Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection. J Exp Med, 2009; 206:1273–1289.
3.
DorrP, WestbyM, DobbsS, et al.: Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother, 2005; 49:4721–4732.
4.
DumondJB, PattersonKB, PechaAL, et al.: Maraviroc concentrates in the cervicovaginal fluid and vaginal tissue of HIV-negative women. J Acquir Immune Defic Syndr, 2009; 51:546–553.
5.
ForbesCJ, LowryD, GeerL, et al.: Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc. J Control Release, 2011; 156:161–169.
6.
MalcolmRK, ForbesCJ, GeerL, et al.: Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques. J Antimicrob Chemother, 2013; 68:678–683.
7.
VeazeyRS, KetasTJ, DufourJ, et al.: Protection of rhesus macaques from vaginal infection by vaginally delivered maraviroc, an inhibitor of HIV-1 entry via the CCR5 co-receptor. J Infect Dis, 2010; 202:739–744.
8.
HerreraC, ShattockRJ: Candidate microbicides and their mechanisms of action. Curr Top Microbiol Immunol, 2014; 383:1–25.
9.
LeeB, SharronM, MontanerLJ, WeissmanD, DomsRW: Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc Natl Acad Sci U S A, 1999; 96:5215–5220.
10.
JacqminP, McFadyenL, WadeJR: A receptor theory-based semimechanistic PD model for the CCR5 noncompetitive antagonist maraviroc. Br J Clin Pharmacol, 2008; 65(Suppl 1):95–106.
11.
HuQ, FrankI, WilliamsV, et al.: Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue. J Exp Med, 2004; 199:1065–1075.
12.
HaaseAT: Early events in sexual transmission of HIV and SIV and opportunities for interventions. Annu Rev Med, 2011; 62:127–139.
13.
ShattockRJ, RosenbergZ: Microbicides: Topical Prevention against HIV. Cold Spring Harb Perspect Med, 2012; 2:a007385.
14.
AntonPA, ElliottJ, PolesMA, et al.: Enhanced levels of functional HIV-1 co-receptors on human mucosal T cells demonstrated using intestinal biopsy tissue. AIDS, 2000; 14:1761–1765.
15.
LapentaC, BoirivantM, MariniM, et al.: Human intestinal lamina propria lymphocytes are naturally permissive to HIV-1 infection. Eur J Immunol, 1999; 29:1202–1208.
16.
PolesMA, ElliottJ, TaingP, AntonPA, ChenIS: A preponderance of CCR5(+) CXCR4(+) mononuclear cells enhances gastrointestinal mucosal susceptibility to human immunodeficiency virus type 1 infection. J Virol, 2001; 75:8390–8399.
17.
Garcia-PerezJ, RuedaP, AlcamiJ, et al.: Allosteric model of maraviroc binding to CC chemokine receptor 5 (CCR5). J Biol Chem, 2011; 286:33409–33421.
18.
Garcia-PerezJ, RuedaP, StaropoliI, et al.: New insights into the mechanisms whereby low molecular weight CCR5 ligands inhibit HIV-1 infection. J Biol Chem, 2011; 286:4978–4990.
19.
MelladoM, Rodriguez-FradeJM, Vila-CoroAJ, et al.: Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. EMBO J, 2001; 20:2497–2507.
20.
FletcherPS, ElliottJ, GrivelJC, et al.: Ex vivo culture of human colorectal tissue for the evaluation of candidate microbicides. AIDS, 2006; 20:1237–1245.
21.
GrivelJC, MargolisL: Use of human tissue explants to study human infectious agents. Nat Protoc, 2009; 4:256–269.
22.
ColinP, BenureauY, StaropoliI, et al.: HIV-1 exploits CCR5 conformational heterogeneity to escape inhibition by chemokines. Proc Natl Acad Sci U S A, 2013; 110:9475–9480.
23.
FleglerAJ, CianciGC, HopeTJ: CCR5 conformations are dynamic and modulated by localization, trafficking and G protein association. PLoS One, 2014; 9:e89056.
24.
GornalusseGG, MummidiS, GaitanAA, et al.: Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor. Proc Natl Acad Sci U S A, 2015; 112:E4762–E4771.
25.
MoH, MonardS, PollackH, et al.: Expression patterns of the HIV type 1 coreceptors CCR5 and CXCR4 on CD4+ T cells and monocytes from cord and adult blood. AIDS Res Hum Retroviruses, 1998; 14:607–617.
26.
de VouxA, ChanMC, FolefocAT, MadzivaMT, FlanaganCA: Constitutively active CCR5 chemokine receptors differ in mediating HIV envelope-dependent fusion. PLoS One, 2013; 8:e54532.
27.
NakanoY, MondeK, TerasawaH, et al.: Preferential recognition of monomeric CCR5 expressed in cultured cells by the HIV-1 envelope glycoprotein gp120 for the entry of R5 HIV-1. Virology, 2014; 452–453:117–124.
28.
TanQ, ZhuY, LiJ, et al.: Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science, 2013; 341:1387–1390.
29.
AbrolR, TrzaskowskiB, GoddardWA3rd, NesterovA, OlaveI, IronsC: Ligand- and mutation-induced conformational selection in the CCR5 chemokine G protein-coupled receptor. Proc Natl Acad Sci U S A, 2014; 111:13040–13045.
30.
BerroR, YasmeenA, AbrolR, et al.: Use of G-protein-coupled and -uncoupled CCR5 receptors by CCR5 inhibitor-resistant and -sensitive human immunodeficiency virus type 1 variants. J Virol, 2013; 87:6569–6581.
31.
HijaziK, CupponeAM, SmithK, et al.: Expression of genes for drug transporters in the human female genital tract and modulatory effect of antiretroviral drugs. PLoS One, 2015; 10:e0131405.
32.
MukhopadhyaI, MurrayGI, BerryS, et al.: Drug transporter gene expression in human colorectal tissue and cell lines: Modulation with antiretrovirals for microbicide optimization. J Antimicrob Chemother 2016 [Epub ahead of print]. 2016; 71:372–386.
33.
Garcia-LermaJG, AungW, CongME, et al.: Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors. J Virol, 2011; 85:6610–6617.
34.
MassudI, AungW, MartinA, et al.: Lack of prophylactic efficacy of oral maraviroc in macaques despite high drug concentrations in rectal tissues. J Virol, 2013; 87:8952–8961.
35.
FoxJ, TiraboschiJM, HerreraC, et al.: A Phase IV PrEP Study Reveals Limited Ex Vivo Potency of Oral Maraviroc Against HIV-1 [Abstract]. CROI, Seattle, WA, 2015.
36.
GarciaE, CabreraC, CollJ, et al.: Oral Single-Dose Maraviroc Does Not Prevent Ex Vivo HIV Infection of Rectal Mucosa in Healthy HIV-1–Negative Human Volunteers in Tissue Explants [Abstract]. CROI, Seattle, WA, 2015.
37.
TrezzaCR, KashubaAD: Pharmacokinetics of antiretrovirals in genital secretions and anatomic sites of HIV transmission: Implications for HIV prevention. Clin Pharmacokinet, 2014; 53:611–624.
38.
DobardCW, TaylorA, SharmaS, et al.: Protection against rectal SHIV transmission in macaques by rectal specific-gel formulations of maraviroc and tenofovir. J Infect Dis, 2015.
