Live-Attenuated Lentivirus Immunization Modulates Innate Immunity and Inflammation while Protecting Rhesus Macaques from Vaginal Simian Immunodeficiency Virus Challenge

Abstract

Immunization with attenuated lentiviruses is the only reliable method of protecting rhesus macaques (RM) from vaginal challenge with pathogenic simian immunodeficiency virus (SIV). CD8 + lymphocyte depletion prior to SIVmac239 vaginal challenge demonstrated that a modest, Gag-specific CD8 + T cell response induced by immunization with simian-human immunodeficiency virus 89.6 (SHIV89.6) protects RM. Although CD8 + T cells are required for protection, there is no anamnestic expansion of SIV-specific CD8 + T cells in any tissues except the vagina after challenge. Further, SHIV immunization increased the number of viral target cells in the vagina and cervix, suggesting that the ratio of target cells to antiviral CD8 + T cells was not a determinant of protection. We hypothesized that persistent replication of the attenuated vaccine virus modulates inflammatory responses and limits T cell activation and expansion by inducing immunoregulatory T cell populations. We found that attenuated SHIV infection decreased the number of circulating plasmacytoid dendritic cells, suppressed T cell activation, decreased mRNA levels of proinflammatory mediators, and increased mRNA levels of immunoregulatory molecules. Three days after SIV vaginal challenge, SHIV-immunized RM had significantly more T regulatory cells in the vagina than the unimmunized RM. By day 14 postchallenge, immune activation and inflammation were characteristic of unimmunized RM but were minimal in SHIV-immunized RM. Thus, a modest vaccine-induced CD8 + T cell response in the context of immunoregulatory suppression of T cell activation may protect against vaginal HIV transmission.

High immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected Chinese rhesus macaques

“…CD8 ? T cells [12]; (3) transiently increased frequency of circulating Tregs in blood at the time of primary infection and significantly decreased frequency of Tregs in blood 6 months after challenge [12]; (4) decreased number of cells expressing IDO in the vaginal mucosa [12]; (5) reduced frequency of circulating plasmacytoid dendritic cells (pDCs), concentration of pDCs, and ability to produce IFN-a in response to HSV-1 stimulation [12]; and (6) altered expression of genes encoding proinflammatory cytokines and regulatory molecules, such as IL-1, IL-4, IL-8 and MIP1-a [2,12]. After inoculation with SHIV89.6, 60 % of female rhesus macaques are protected from uncontrolled virus replication after vaginal SIV challenge.…”

“…T cells immediately after vaginal SIV challenge, and this contributes to maintaining the ability of the antiviral CD8 ? T cell response to control SIV replication in SHIV-immunized rhesus macaques [1,2,12].…”

“…Although SHIV89.6 is usually attenuated, after two serial passages in vivo by intravenous blood inoculation of naïve rhesus monkeys, the resulting virus (SHIV-89.6P) induces CD4 lymphopenia and an AIDS-like disease with wasting and opportunistic infections [12,35]. Although the viral load is not as high as in SIVmac239 infection, the circulating CD4 ?…”

Mucosal Immune Regulation: Does it Help Thwart HIV?

“…The modest antiviral effector CD8 + T cell response elicited by SHIV immunization could then participate in the elimination of the few HIV-infected cells at mucosal sites. Thus, a modest CTL response, insufficient to control HIV replication in other immunization models, in the context of mucosal immunoregulatory T cell populations and an anti-inflammatory environment was able to maintain control of SIV replication [138].…”

HIV-1 vaccines

“…104 Prior infection of rhesus macaques with an attenuated SHIV conferred protection against vaginal challenge associated with SIV-specific CTL in cervical vaginal tissues, 105 suggesting that a modest vaccine-induced CD8+ T-cell response in the context of immunoregulatory suppression of T-cell activation may protect against vaginal HIV-1 transmission. 106 Supporting this hypothesis, macaques immunized with an oral vaccine comprised of Lactobacillus plantarum, a commensal bacterium that favors immune tolerance, and inactivated SIVmac239 induced CD8+ regulatory T cells (Tregs) completely protected 15 of 16 animals without inducing SIV-specific antibodies or CTL. Infection was seen after re-challenge but viral load was undetectable.…”