Innate and adaptive immune responses in the vagina at the time of, and immediately after, vaginal SIV inoculation of rhesus macaques immunized with an attenuated lentivirus compared with the responses in nonimmunized rhesus macaques. The figure schematically depicts the vaginal mucosa and the draining lymph node of SHIV89.6-immunized RMs (a, b) and nonimmunized RMs (c, d) at day 0 (a, c) and day 3 (b, d) after SIVmac239 vaginal challenge. In all panels, nonspecific T cells are gray to black. a SIV-specific CD4⁺ T cells (blue circles) and CD8⁺ T cells (red circles) are present on the vaginal mucosa of immunized RMs on the day of SIV challenge. The number of IDO⁺ APCs (orange) are reduced, and the mRNA levels of proinflammatory cytokines (C-C motif chemokine 3 [CCL3], CCL20, and TNF) are reduced, while the mRNA levels of the immunoregulatory Siglec-5 molecule are increased. In the genital lymph node, expression of CCL3, CCL20, IL-8, and IL-17 are also downregulated. b Three days after challenge, SIV infection is limited to the mucosal site of challenge in immunized animals. This early containment is associated with the presence of SIV-specific effector CD8⁺ T cells in the vaginal mucosa and the proliferation of regulatory FOXP3⁺ CD4⁺ T cells (purple circles) in the mucosa. c In contrast, in nonimmunized RMs there are no SIV-specific memory effector T cells in the mucosa, and the levels of proinflammatory or regulatory T cells are normal on the day of challenge. d However, after the virus enters the mucosa, local viral replication leads to systemic dissemination, and the level of infection rapidly exceeds the ability of the immune system to contain viral replication. The pace of SIV replication accelerates over the first 2 to 5 days of infection, as the rapid increase in local and systemic proinflammatory cytokines recruits and activates viral target cells in the vaginal mucosa. APC antigen-presenting cell; FOXP3 forkhead box P3; IDO indoleamine 2,3-dioxygenase; IL interleukin; LN lymph node; RM rhesus macaque; SHIV simian-human immunodeficiency virus; Siglec sialic acid-binding immunoglobulin-like lectin; SIV simian immunodeficiency virus; TNF tumor necrosis factor