Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge.
The rapid onset of massive, systemic viral replication during primary HIV or simian immunodeficiency virus (SIV) infection and the immune evasion capabilities of these viruses pose fundamental problems for vaccines that depend upon initial viral replication to stimulate effector T cell expansion and differentiation. We hypothesized that vaccines designed to maintain differentiated effector memory T cell (TEM cell) responses at viral entry sites might improve efficacy by impairing viral replication at its earliest stage, and we have therefore developed SIV protein-encoding vectors based on rhesus cytomegalovirus (RhCMV), the prototypical inducer of life-long TEM cell responses. RhCMV vectors expressing SIV Gag, Rev-Tat-Nef and Env persistently infected rhesus macaques, regardless of preexisting RhCMV immunity, and primed and maintained robust, SIV-specific CD4+ and CD8+ TEM cell responses (characterized by coordinate tumor necrosis factor, interferon-gamma and macrophage inflammatory protein-1beta expression, cytotoxic degranulation and accumulation at extralymphoid sites) in the absence of neutralizing antibodies. Compared to control rhesus macaques, these vaccinated rhesus macaques showed increased resistance to acquisition of progressive SIVmac239 infection upon repeated limiting-dose intrarectal challenge, including four macaques who controlled rectal mucosal infection without progressive systemic dissemination. These data suggest a new paradigm for AIDS vaccine development--vaccines capable of generating and maintaining HIV-specific TEM cells might decrease the incidence of HIV acquisition after sexual exposure.
Hansen
Scott G
SG
Vaccine and Gene Therapy Institute, Department of Molecular Microbiology, and the Oregon National Primate Research Center, Oregon Health & Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA.
Vieville
Cassandra
C
Whizin
Nathan
N
Coyne-Johnson
Lia
L
Siess
Don C
DC
Drummond
Derek D
DD
Legasse
Alfred W
AW
Axthelm
Michael K
MK
Oswald
Kelli
K
Trubey
Charles M
CM
Piatak
Michael
M
Lifson
Jeffrey D
JD
Nelson
Jay A
JA
Jarvis
Michael A
MA
Picker
Louis J
LJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D018928:Immunity, Mucosal; D007156:Immunologic Memory; D008253:Macaca mulatta; D008297:Male; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology
D014765:Viral Vaccines