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Use of nonhuman primate models to develop mucosal AIDS vaccines.

Genescà M, Miller CJ - Curr HIV/AIDS Rep (2010)

Bottom Line: Controlling the level of mucosal T-cell activation may be a critical factor in developing an effective mucosal AIDS vaccine.Immunization routes and adjuvants that can boost antiviral immunity in mucosal surfaces offer a reasonable opportunity to improve AIDS vaccine efficacy.Nonhuman primate models offer the best system for preclinical evaluation of these approaches.

View Article: PubMed Central - PubMed

Affiliation: Center for Comparative Medicine, California National Primate Research Center, University of California, Davis, One Shields Avenue, Davis, CA, 95616, USA. mgenesca@primate.ucdavis.edu

ABSTRACT
The HIV vaccines tested in the halted Step efficacy trial and the modestly successful phase 3 RV144 trial were designed to elicit strong systemic immune responses; therefore, strategies to direct immune responses into mucosal sites should be tested in an effort to improve AIDS vaccine efficacy. However, as increased CD4(+) T-cell activation and recruitment to mucosal sites have the potential to enhance HIV transmission, mucosal immune responses to HIV vaccines should primarily consist of effector CD8(+) T cells and plasma cells. Controlling the level of mucosal T-cell activation may be a critical factor in developing an effective mucosal AIDS vaccine. Immunization routes and adjuvants that can boost antiviral immunity in mucosal surfaces offer a reasonable opportunity to improve AIDS vaccine efficacy. Nonhuman primate models offer the best system for preclinical evaluation of these approaches.

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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
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Fig1: 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

Mentions: We recently completed a series of studies that defined antiviral T-cell responses in the mucosal and systemic tissues of SHIV-immunized rhesus macaques before and after vaginal SIV challenge. The results of these studies demonstrated that SIV Gag-specific CD8+ T cells in the vaginal mucosa at the time of SIV challenge are the key immune effector function mediating protection in this model [10, 28–30], and that CD8+ lymphocyte depletion leaves SHIV-immunized animals completely unprotected from the vaginal SIV challenge [10, 29]. Despite the evidence for the critical role of SIV-specific CD8+ T-cell responses in SHIV-immunized monkeys, expansion of SIV-specific CD8+ T cells is limited to the vaginal mucosa, and there is minimal immune activation after the SIV challenge [29]. The extent of host inflammation and immune activation affects viral transcription directly and determines the number of target cells available for virus replication. HIV and SIV replication are regulated by a complex network of cytokines and chemokines, as these soluble factors directly influence reverse transcription, HIV RNA expression, and expression of viral receptors and coreceptors [31–33]. Cytokine and chemokines also regulate migration and activation of viral target cells, amplifying HIV infection and replication [31–33]. Thus, both the strength of the CD8+ T-cell response and the degree of immune activation and inflammation can influence the level of viral replication. After vaginal SIV challenge, immune activation in the SHIV-immunized animals was controlled and limited, in contrast to the aberrant T-cell activation in the unimmunized animals [29]. On the day of SIV challenge, the antiviral CD8+ T-cell responses of SHIV-immunized animals existed in a relatively quiescent tissue environment [28] (Fig. 1). After SIV challenge, this quiescent tissue environment was actively maintained by a T-regulatory cell response that rapidly expanded to suppress any immune activation and prevent the generation of more activated target cells to support SIV replication (Genescà and Miller, unpublished data) (Fig. 1). The decreased levels of proinflammatory cytokines and indoleamine 2,3-dioxygenase (IDO+) cells in SHIV-immunized animals after vaginal SIV challenge are consistent with immunoregulatory mechanisms playing an active role in achieving this condition (Genescà and Miller, unpublished data) (Fig. 1).Fig. 1


Use of nonhuman primate models to develop mucosal AIDS vaccines.

Genescà M, Miller CJ - Curr HIV/AIDS Rep (2010)

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
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Related In: Results  -  Collection

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Fig1: 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
Mentions: We recently completed a series of studies that defined antiviral T-cell responses in the mucosal and systemic tissues of SHIV-immunized rhesus macaques before and after vaginal SIV challenge. The results of these studies demonstrated that SIV Gag-specific CD8+ T cells in the vaginal mucosa at the time of SIV challenge are the key immune effector function mediating protection in this model [10, 28–30], and that CD8+ lymphocyte depletion leaves SHIV-immunized animals completely unprotected from the vaginal SIV challenge [10, 29]. Despite the evidence for the critical role of SIV-specific CD8+ T-cell responses in SHIV-immunized monkeys, expansion of SIV-specific CD8+ T cells is limited to the vaginal mucosa, and there is minimal immune activation after the SIV challenge [29]. The extent of host inflammation and immune activation affects viral transcription directly and determines the number of target cells available for virus replication. HIV and SIV replication are regulated by a complex network of cytokines and chemokines, as these soluble factors directly influence reverse transcription, HIV RNA expression, and expression of viral receptors and coreceptors [31–33]. Cytokine and chemokines also regulate migration and activation of viral target cells, amplifying HIV infection and replication [31–33]. Thus, both the strength of the CD8+ T-cell response and the degree of immune activation and inflammation can influence the level of viral replication. After vaginal SIV challenge, immune activation in the SHIV-immunized animals was controlled and limited, in contrast to the aberrant T-cell activation in the unimmunized animals [29]. On the day of SIV challenge, the antiviral CD8+ T-cell responses of SHIV-immunized animals existed in a relatively quiescent tissue environment [28] (Fig. 1). After SIV challenge, this quiescent tissue environment was actively maintained by a T-regulatory cell response that rapidly expanded to suppress any immune activation and prevent the generation of more activated target cells to support SIV replication (Genescà and Miller, unpublished data) (Fig. 1). The decreased levels of proinflammatory cytokines and indoleamine 2,3-dioxygenase (IDO+) cells in SHIV-immunized animals after vaginal SIV challenge are consistent with immunoregulatory mechanisms playing an active role in achieving this condition (Genescà and Miller, unpublished data) (Fig. 1).Fig. 1

Bottom Line: Controlling the level of mucosal T-cell activation may be a critical factor in developing an effective mucosal AIDS vaccine.Immunization routes and adjuvants that can boost antiviral immunity in mucosal surfaces offer a reasonable opportunity to improve AIDS vaccine efficacy.Nonhuman primate models offer the best system for preclinical evaluation of these approaches.

View Article: PubMed Central - PubMed

Affiliation: Center for Comparative Medicine, California National Primate Research Center, University of California, Davis, One Shields Avenue, Davis, CA, 95616, USA. mgenesca@primate.ucdavis.edu

ABSTRACT
The HIV vaccines tested in the halted Step efficacy trial and the modestly successful phase 3 RV144 trial were designed to elicit strong systemic immune responses; therefore, strategies to direct immune responses into mucosal sites should be tested in an effort to improve AIDS vaccine efficacy. However, as increased CD4(+) T-cell activation and recruitment to mucosal sites have the potential to enhance HIV transmission, mucosal immune responses to HIV vaccines should primarily consist of effector CD8(+) T cells and plasma cells. Controlling the level of mucosal T-cell activation may be a critical factor in developing an effective mucosal AIDS vaccine. Immunization routes and adjuvants that can boost antiviral immunity in mucosal surfaces offer a reasonable opportunity to improve AIDS vaccine efficacy. Nonhuman primate models offer the best system for preclinical evaluation of these approaches.

Show MeSH
Related in: MedlinePlus