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| ISV Paper of the Month |
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June 2011 |
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Profound early control of highly pathogenic SIV
by an effector memory T-cell vaccine |
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Hansen SG, Ford JC, Lewis MS, Ventura AB, Hughes CM, Coyne-Johnson
L, Whizin N, Oswald K, Shoemaker R, Swanson T, Legasse AW, Chiuchiolo MJ, Parks
CL, Axthelm MK, Nelson JA, Jarvis MA, Piatak M Jr, Lifson JD, Picker LJ |
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Nature 2011 May 26; 473:523–527 |
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The acquired immunodeficiency syndrome (AIDS)-causing
lentiviruses human immunodeficiency virus (HIV) and simian immunodeficiency virus
(SIV) effectively evade host immunity and, once established, infections with these
viruses are only rarely controlled by immunological mechanisms. However, the initial
establishment of infection in the first few days after mucosal exposure, before
viral dissemination and massive replication, may be more vulnerable to immune control.
Here we report that SIV vaccines that include rhesus cytomegalovirus (RhCMV) vectors
establish indefinitely persistent, high-frequency, SIV-specific effector memory
T-cell (TEM) responses at potential sites of SIV replication in rhesus macaques
and stringently control highly pathogenic SIVMAC239 infection early after mucosal
challenge. Thirteen of twenty-four rhesus macaques receiving either RhCMV vectors
alone or RhCMV vectors followed by adenovirus 5 (Ad5) vectors (versus 0 of 9 DNA/Ad5-vaccinated
rhesus macaques) manifested early complete control of SIV (undetectable plasma virus),
and in twelve of these thirteen animals we observed long-term (?1 year) protection.
This was characterized by: occasional blips of plasma viraemia that ultimately waned;
predominantly undetectable cell- associated viral load in blood and lymph node mononuclear
cells; no depletion of effector-site CD4+ memory T cells; no induction or boosting
of SIV Env-specific antibodies; and induction and then loss of T-cell responses
to an SIV protein (Vif) not included in the RhCMV vectors. Protection correlated
with the magnitude of the peak SIV-specific CD8+ T-cell responses in the vaccine
phase, and occurred without anamnestic T-cell responses. Remarkably, long- term
RhCMV vector-associated SIV control was insensitive to either CD8+ or CD4+ lymphocyte
depletion and, at necropsy, cell-associated SIV was only occasionally measurable
at the limit of detection with ultrasensitive assays, observations that indicate
the possibility of eventual viral clearance. Thus, persistent vectors
such as CMV
and their associated TEM responses might significantly contribute to an efficacious
HIV/AIDS vaccine. |
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