Macaques vaccinated with live-attenuated SIV control replication of heterologous virus

To improve the efficacy of T cell-based vaccination, we pursued the principle that CD4 + T cells provide help for functional CD8 + T cell immunity. To do so, we administered HIV gag to mice successively as protein and DNA vaccines. To achieve strong CD4 + T cell immunity, the protein vaccine was targeted selectively to DEC-205, a receptor for antigen presentation on dendritic cells. This targeting helped CD8 + T cell immunity develop to a subsequent DNA vaccine and improved protection to intranasal challenge with recombinant vaccinia gag virus, including more rapid accumulation of CD8 + T cells in the lung. The helper effect of dendritic cell-targeted protein vaccine was mimicked by immunization with specific MHC II binding HIV gag peptides but not peptides from a disparate Yersinia pestis microbe. CD4 + helper cells upon adoptive transfer allowed wild-type, but not CD40 −/− , recipient mice to respond better to the DNA vaccine. The transfer also enabled recipients to more rapidly accumulate gagspecific CD8 + T cells in the lung following challenge with vaccinia gag virus. Thus, complementary prime boost vaccination, in which prime and boost favor distinct types of T cell immunity, improves plasmid DNA immunization, including mobilization of CD8 + T cells to sites of infection.

Section: Discussionmentioning

confidence: 99%

Dendritic cell targeted HIV gag protein vaccine provides help to a DNA vaccine including mobilization of protective CD8 ⁺ T cells

Nchinda

Amadu²,

Trumpfheller³

et al. 2010

“…Cytotoxic T cells can control viral load in various models of simian immunodeficiency virus (SIV) infection in rhesus macaques (3)(4)(5)(6)(7). However, the quantitative and qualitative features of vaccine-elicited T-cell responses that mediate protection are yet to be defined (8,9).…”

mentioning

confidence: 99%

Single-cell gene-expression profiling reveals qualitatively distinct CD8 T cells elicited by different gene-based vaccines

Flatz

Roychoudhuri

Honda

et al. 2011

CD8 T cells play a key role in mediating protective immunity against selected pathogens after vaccination. Understanding the mechanism of this protection is dependent upon definition of the heterogeneity and complexity of cellular immune responses generated by different vaccines. Here, we identify previously unrecognized subsets of CD8 T cells based upon analysis of gene-expression patterns within single cells and show that they are differentially induced by different vaccines. Three prime-boost vector combinations encoding HIV Env stimulated antigen-specific CD8 T-cell populations of similar magnitude, phenotype, and functionality. Remarkably, however, analysis of single-cell gene-expression profiles enabled discrimination of a majority of central memory (CM) and effector memory (EM) CD8 T cells elicited by the three vaccines. Subsets of T cells could be defined based on their expression of Eomes, Cxcr3, and Ccr7, or Klrk1, Klrg1, and Ccr5 in CM and EM cells, respectively. Of CM cells elicited by DNA prime-recombinant adenoviral (rAd) boost vectors, 67% were Eomes − Ccr7 + Cxcr3 − , in contrast to only 7% and 2% stimulated by rAd5-rAd5 or rAd-LCMV, respectively. Of EM cells elicited by DNArAd, 74% were Klrk1 − Klrg1 − Ccr5 − compared with only 26% and 20% for rAd5-rAd5 or rAd5-LCMV. Definition by single-cell gene profiling of specific CM and EM CD8 T-cell subsets that are differentially induced by different gene-based vaccines will facilitate the design and evaluation of vaccines, as well as enable our understanding of mechanisms of protective immunity.lymphocyte subsets | microarray | immune differentiation

“…Finally, vaccine studies in rhesus macaques implicate a protective role for vaccine-induced, virus-specific CD4 ϩ T cells. Vaccination with SIVmac239⌬Nef induces a high frequency, effector-phenotype CD4 ϩ T cell response and protects against subsequent homologous and heterologous virus challenge (15)(16)(17). Moreover, protection against SIV replication mediated by vaccine-induced CD8 ϩ T cells is diminished when the vaccine is administered in the setting of CD4 ϩ T cell lymphopenia (18).…”

mentioning

confidence: 99%

Gag- and Nef-specific CD4⁺T cells recognize and inhibit SIV replication in infected macrophages early after infection

Sacha¹,

Giraldo-Vela²,

Buechler³

et al. 2009

Self Cite

The precise immunological role played by CD4 ؉ T cells in retroviral infections is poorly defined. Here, we describe a new function of these cells, the elimination of retrovirus-infected macrophages. After experimental CD8 ؉ cell depletion, elite controlling macaques with set-point viral loads <500 viral RNA copies/mL mounted robust Gagand Nef-specific CD4 ؉ T cell responses during reestablishment of control with >54% of all virus-specific CD4 ؉ T cells targeting these 2 proteins. Ex vivo, these simian immunodeficiency virus (SIV)-specific CD4 ؉ T cells neither recognized nor suppressed viral replication in SIV-infected CD4 ؉ T cells. In contrast, they recognized SIV-infected macrophages as early as 2 h postinfection because of presentation of epitopes derived from virion-associated Gag and Nef proteins. Furthermore, virus-specific CD4 ؉ T cells displayed direct effector function and eliminated SIV-infected macrophages. These results suggest that retrovirus-specific CD4 ؉ T cells may contribute directly to elite control by inhibiting viral replication in macrophages.antigen processing and presentation ͉ HIV