Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus–cell fusion

Abstract

Human immunodeficiency virus type 1 (HIV-1) continues to spread, principally by heterosexual sex, but no vaccine is available1. Hence, alternative prevention methods are needed to supplement educational and behavioural-modification programmes. One such approach is a vaginal microbicide: the application of inhibitory compounds before intercourse2. Here, we have evaluated the microbicide concept using the rhesus macaque ‘high dose’ vaginal transmission model with a CCR5-receptor-using simian–human immunodeficiency virus (SHIV-162P3) and three compounds that inhibit different stages of the virus–cell attachment and entry process. These compounds are BMS-378806, a small molecule that binds the viral gp120 glycoprotein and prevents its attachment to the CD4 and CCR5 receptors3,4, CMPD167, a small molecule that binds to CCR5 to inhibit gp120 association5, and C52L, a bacterially expressed peptide inhibitor of gp41-mediated fusion6. In vitro, all three compounds inhibit infection of T cells and cervical tissue explants, and C52L acts synergistically with CMPD167 or BMS-378806 to inhibit infection of cell lines. In vivo, significant protection was achieved using each compound alone and in combinations. CMPD167 and BMS-378806 were protective even when applied 6 h before challenge.

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Figure 1: Vaginally delivered inhibitors can protect macaques against vaginal challenge with SHIV-162P3.

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Acknowledgements

We thank J. LeBlanc, M. Dodd and T. Williams for technical support, and we appreciate receiving advice from M. Pope. This work was supported by an NIH grant, and by an Unrestricted Infectious Diseases Award from the Bristol-Myers Squibb Foundation to J.P.M. Author Contributions R.S.V. was responsible for designing, organizing and executing the macaque studies, which were carried out by J.D. P.A.M. provided advice on the macaque model and supervised the performance of serology studies on samples from the test monkeys. P.J.K. contributed to the design of the monkey and cell culture experiments and performed all the mathematical and statistical analyses. S.M.S. was responsible for in vitro studies of inhibitor combinations, and T.J.K. for infection-inhibition experiments with human and macaque PBMCs. Q.H. carried out the experiments involving cervical tissue explants and macrophages (including combination studies), under the supervision of R.J.S., who was also involved in the design and interpretation of the macaque studies. M.L. synthesized the C52L peptide and advised on its use. R.J.C. provided BMS-378806 and advised on its use. M.S.S. provided CMPD167 and advised on its use. J.P.M. made a lot of phone calls and sent out many emails.

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Correspondence to John P. Moore.

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Competing interests

R.A.C. and M.S.S. are employees of Bristol-Myers Squibb Inc and Merck Inc, respectively, but neither company funded this study. M.L. has filed patents related to the C52L peptide.

Supplementary information

Supplementary Notes*

This section contains details on synergy between entry inhibitors in vitro, vaginal challenges with SHIV-162P4 and plasma viral load in SHIV-162P3-infected animals. * This Supplementary Information was substituted for an earlier version on 14/11/05. The replacement is identical, except that it contains a detailed directive for reagent requests on page 4. (PDF 253 kb)

Supplementary Figure 1

Challenge studies with SHIV-162P4, partial protection by CMPD167 and C52L. (PDF 385 kb)

Supplementary Figure 2

Plasma VL in SHIV-162P3-infected animals. (PDF 506 kb)

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Veazey, R., Klasse, P., Schader, S. et al. Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus–cell fusion. Nature 438, 99–102 (2005). https://doi.org/10.1038/nature04055

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