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Serial Cervicovaginal Exposures With Replication-Deficient SIVsm Induce Higher Dendritic Cell (pDC) and CD4+ T-Cell Infiltrates Not Associated With Prevention but a More Severe SIVmac251 Infection of Rhesus Macaques

Abdulhaqq, Shaheed A. BS*; Martinez, Melween I. DVM; Kang, Guobin BS; Foulkes, Andrea S. ScD§; Rodriguez, Idia V. DVM; Nichols, Stephanie M. PhD; Hunter, Meredith MS; Sariol, Carlos A. MD†,¶,#; Ruiz, Lynnette A. PhD; Ross, Brian N. MS*; Yin, Xiangfan MS*; Speicher, David W. PhD*; Haase, Ashley T. MD; Marx, Preston A. PhD; Li, Qinsheng PhD**,††; Kraiselburd, Edmundo N. PhD†,¶; Montaner, Luis J. DVM, PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 1st, 2014 - Volume 65 - Issue 4 - p 405–413
doi: 10.1097/QAI.0000000000000047
Basic and Translational Science

Objective: Intravaginal exposure to simian immunodeficiency virus (SIV) acutely recruits interferon-alpha (IFN-α) producing plasmacytoid dendritic cells (pDC) and CD4+ T-lymphocyte targets to the endocervix of nonhuman primates. We tested the impact of repeated cervicovaginal exposures to noninfectious, defective SIV particles over 72 hours on a subsequent cervicovaginal challenge with replication competent SIV.

Methods: Thirty-four female Indian Rhesus macaques were given a 3-day twice-daily vaginal exposures to either SIVsmB7, a replication-deficient derivative of SIVsmH3 produced by a T lymphoblast CEMx174 cell clone (n = 16), or to CEM supernatant controls (n = 18). On the fourth day, animals were either euthanized to assess cervicovaginal immune cell infiltration or intravaginally challenged with SIVmac251. Challenged animals were tracked for plasma viral load and CD4 counts and euthanized at 42 days after infection.

Results: At the time of challenge, macaques exposed to SIVsmB7, had higher levels of cervical CD123 pDCs (P = 0.032) and CD4+ T cells (P = 0.036) than those exposed to CEM control. Vaginal tissues showed a significant increase in CD4+ T-cell infiltrates (P = 0.048) and a trend toward increased CD68+ cellular infiltrates. After challenge, 12 SIVsmB7-treated macaques showed 2.5-fold greater daily rate of CD4 decline (P = 0.0408), and viral load rise (P = 0.0036) as compared with 12 control animals.

Conclusions: Repeated nonproductive exposure to viral particles within a short daily time frame did not protect against infection despite pDC recruitment, resulting instead in an accelerated CD4+ T-cell loss with an increased rate of viral replication.

*Department of Immunology, The Wistar Institute, Philadelphia, PA;

Caribbean Primate Research Center and Animal Resources Center, University of Puerto Rico (UPR), San Juan, PR;

University of Minnesota Medical School, Minneapolis, MN;

§Division of Biostatistics and Epidemiology, University of Massachusetts, Amherst, MA;

Tulane National Primate Research Center, Covington, LA;

Departments of Microbiology and

#Internal Medicine, UPR Medical School, San Juan, PR; and

**School of Biological Sciences and

††Nebraska Center for Virology, University of Nebraska, Lincoln, NE.

Correspondence to: Luis J. Montaner, DVM, Department of Immunology, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104 (e-mail:

Supported by NIH Grants R01 AI084142 and R01 AI094603 to E.N.K. and L.J.M., NIH Grant P40 OD012217 to M.I.M., R01 HL107196 to A.S.F., and T32 AI070099 to S.A.A. Additional support was provided by The Philadelphia Foundation (Robert I. Jacobs Fund), Henry S. Miller, Jr. and J. Kenneth Nimblett, AIDS funds from the Commonwealth of Pennsylvania and from the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health, the Penn Center for AIDS Research (P30 AI 045008) and Cancer Center Grant (P30 CA10815), the American Foundation for AIDS Research, the National Cancer Institute, National Institutes of Health (Contract No. HHSN261200800001E), and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Presented at the Nonhuman Primate Models for AIDS 29th Annual Symposium, October 25–28, 2011, Seattle, WA.

The authors have no conflicts of interest to disclose.

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Received October 25, 2013

Accepted October 25, 2013

© 2014 by Lippincott Williams & Wilkins