Vaccines based on novel adeno-associated virus vectors elicit aberrant CD8+ T-cell responses in mice.
We recently discovered an expanded family of adeno-associated viruses (AAVs) that show promise as improved gene therapy vectors. In this study we evaluated the potential of vectors based on several of these novel AAVs as vaccine carriers for human immunodeficiency virus type 1 Gag. Studies with mice indicated that vectors based on AAV type 7 (AAV7), AAV8, and AAV9 demonstrate improved immunogenicity in terms of Gag CD8(+) T-cell and Gag antibody responses. The quality of these antigen-specific responses was evaluated in detail for AAV2/8 vectors and compared to results with an adenovirus vector expressing Gag (AdC7). AAV2/8 produced a vibrant CD8(+) T-cell effector response characterized by coexpression of gamma interferon and tumor necrosis factor alpha as well as in vivo cytolytic activity. No CD8(+) T-cell response generated by any of the AAVs was effectively boosted with AdC7, a result consistent with the finding of a relative lack of cells expressing interleukin-2 (IL-2) or a central memory phenotype at 3 months after the prime. The primary response to an AdC7 vaccine differed from that generated by AAVs in that the peak effector response evolved into populations of Gag-specific T cells expressing high levels of cytokines, including IL-2, and with effector memory and central memory phenotypes. A number of mechanisms could be considered to explain the aberrant activation of CD8(+) T cells by AAV, including insufficient inflammatory responses, CD4 help, and/or chronic antigen expression and T-cell exhaustion. Interestingly, the B-cell response to AAV-encoded Gag was quite vibrant and easily boosted with AdC7.
Lin
Jianping
J
Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 125 S. 31st Street, Philadelphia, PA 19104-3403, USA.
Zhi
Yan
Y
Mays
Lauren
L
Wilson
James M
JM
D016915:AIDS Vaccines / Q000737:chemistry; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics*; D015683:Gene Products, gag / Q000378:metabolism; D005822:Genetic Vectors; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008099:Liver / Q000821:virology; D008168:Lung / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016915:AIDS Vaccines; D015683:Gene Products, gag; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha
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