Induction of Cytotoxic and Helper T Cell Responses by Modified Simian Immunodeficiency Virus Hypervariable Epitope Constructs

Yao

Guo

et al. 2003

To enhance the efficiency of antigen uptake at mucosal surfaces, CTB was conjugated to simian immunodeficiency virus (SIV) virus-like particles (VLPs). We characterized the immune responses to the Env and Gag proteins after intranasal administration. Intranasal immunization with a mixture of VLPs and CTB as an adjuvant elicited higher levels of SIV gp160-specific immunoglobulin G (IgG) in sera and IgA in mucosae, including saliva, vaginal-wash samples, lung, and intestine, as well as a higher level of neutralization activities than immunization with VLPs alone. Conjugation of CTB to VLPs also enhanced the SIV VLP-specific antibodies in sera and in mucosae to similar levels. Interestingly, CTB-conjugated VLPs showed higher levels of cytokine (gamma interferon)-producing splenocytes and cytotoxic-T-lymphocyte activities of immune cells than VLPs plus CTB, as well as an increased level of both IgG1 and IgG2a serum antibodies, which indicates enhancement of both Th1-and Th2-type cellular immune responses. These results demonstrate that CTB can be an effective mucosal adjuvant in the context of VLPs to induce enhanced humoral, as well as cellular, immune responses.

Section: Resultsmentioning

confidence: 99%

Section: Siv Env and Gag Proteinsmentioning

confidence: 99%

Mucosal Immunization with Virus-Like Particles of Simian Immunodeficiency Virus Conjugated with Cholera Toxin Subunit B

Yao

Guo

et al. 2003

“…This assay measures lactate dehydrogenase, a stable cytosolic enzyme that is released upon cell lysis in the same way as 51 Cr is released in the radioactive assay. The results from these two assays were shown to be almost identical (10,28), and several studies used this nonradioactive cytotoxic assay for CTL analysis (2,5,42). The percentage of specific target cell lysis was represented based on total cell lysis with 0.1% Triton X-100.…”

Section: Ctl Analysis P815 Target Cells (Major Histocompatibility Comentioning

confidence: 99%

Enhancement of Mucosal Immunization with Virus-Like Particles of Simian Immunodeficiency Virus

Compans

2003

Cholera toxin (CT) is the most potent known mucosal adjuvant, but its toxicity precludes its use in humans. Here, in an attempt to develop safe and effective mucosal adjuvants, we compared immune responses to simian immunodeficiency virus (SIV) virus-like particles (VLPs) after intranasal coimmunization with RANTES, CpG oligodeoxynucleotides (ODN), or CT. Antibody analysis demonstrated that RANTES and CpG ODN had capacities for mucosal adjuvanticity, i.e., for enhancing serum and vaginal antibodies specific to SIV Env, similar to those for CT. RANTES and CpG ODN skewed serum antibodies predominantly to the immunoglobulin G2a isotype. Most importantly, RANTES and CpG ODN were more effective than CT in increasing neutralizing titers of both serum and vaginal antibodies. After intranasal coadministration with VLPs, RANTES or CpG ODN also induced increased levels of gamma interferon (IFN-␥)-producing lymphocyte and cytotoxic T-lymphocyte activities in both spleen and lymph nodes but did not increase the levels of interleukin-4-producing lymphocytes. The results suggest that RANTES and CpG ODN enhance immune responses in a T-helper-cell-type-1 (Th1)-oriented manner and that they can be used as effective mucosal adjuvants for enhancing both humoral and cellular immune responses in the context of VLPs, which are particulate antigens.

“…This assay measures lactate dehydrogenase, a stable cytosolic enzyme that is released upon cell lysis, in the same way 51 Cr is released in a radioactive assay. The results from these two assays were shown to be almost identical (10,25), and several studies have used this nonradioactive cytotoxic assay for CTL analysis (3,6,33). The percentage of specific target cell lysis was represented based on total cell lysis with 0.1% Triton X-100.…”

Section: Methodsmentioning

confidence: 99%

Intranasal Immunization with Inactivated Influenza Virus Enhances Immune Responses to Coadministered Simian-Human Immunodeficiency Virus-Like Particle Antigens

Guo

Yao

et al. 2004

Intranasal immunization with inactivated influenza virus vaccine can provide protective immunity, whereas many other antigens are less effective when used for mucosal immunization. To determine whether influenza virus could enhance immune responses to an antigen coadministered to a mucosal surface, we studied the intranasal immunization of mice with a mixture of simian-human immunodeficiency virus (SHIV) virus-like particles (VLPs) and inactivated influenza virus. Compared to mice immunized with SHIV VLPs alone, mice coimmunized with SHIV VLPs and inactivated influenza virus showed significant increases in serum immunoglobulin G (IgG) and mucosal IgA antibodies specific to the human immunodeficiency virus envelope protein, neutralizing activities, numbers of gamma interferon-and interleukin 4-secreting lymphocytes, and cytotoxic-T-lymphocyte activities. The levels of enhancement of immune response by coimmunization with inactivated influenza virus were equivalent to those induced by inclusion of immunostimulatory CpG oligodeoxynucleotides (CpG DNA). We also observed that SHIV VLPs bind to influenza virus virions, forming mixed aggregates. These results indicate that inactivated influenza virus can play a role as a mucosal adjuvant to coadministered antigens.