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.
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.
Shaheed A
SA
Abdulhaqq
Melween I
MI
Martinez
Guobin
G
Kang
Andrea S
AS
Foulkes
Idia V
IV
Rodriguez
Stephanie M
SM
Nichols
Meredith
M
Hunter
Carlos A
CA
Sariol
Lynnette A
LA
Ruiz
Brian N
BN
Ross
Xiangfan
X
Yin
David W
DW
Speicher
Ashley T
AT
Haase
Preston A
PA
Marx
Qinsheng
Q
Li
Edmundo N
EN
Kraiselburd
Luis J
LJ
Montaner
D000818:Animals; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002584:Cervix Uteri / Q000276:immunology* / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology*; D004717:Endometrium / Q000276:immunology* / Q000821:virology; D005260:Female; D008253:Macaca mulatta; D010949:Plasma / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D014621:Vagina / Q000276:immunology* / Q000821:virology; D019562:Viral Load