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 mechanisms1,2,3. 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 control4. Here we report that SIV vaccines that include rhesus cytomegalovirus (RhCMV) vectors5 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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This work was supported by the National Institute of Allergy and Infectious Diseases (RO1 AI060392; contract #HHSN272200900037C); the International AIDS Vaccine Initiative (IAVI) and its donors, particularly the United States Agency for International Development (USAID); the Bill & Melinda Gates Foundation-supported Collaboration for AIDS Vaccine Discovery; the National Center for Research Resources (P51 RR00163; R24 RR016001); and the National Cancer Institute (contract HHSN261200800001E). We thank A. Sylwester, D. Seiss, R. Lum, H. Park and A. Okoye for specialized technical assistance; P. Barry, G. Pavlakis, G. Franchini, C. Miller, N. Wilson, and K. Reimann and Nonhuman Primate Reagent Resource for provision of crucial constructs or reagents; D. Watkins for MHC typing; D. Montefiori for neutralizing antibody assays; N. Letvin and L. Shen for TRIM5a typing; S. Mongoue-Tchokote and M. Mori for statistical assistance; A. Townsend and T. Schroyer for figure preparation; and K. Früh, D. Watkins, B. Beresford, A. McDermott, R. King and W. Koff for discussion and advice.

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  1. Vaccine and Gene Therapy Institute, Departments of Molecular Microbiology and Immunology and Pathology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA

    • Scott G. Hansen
    • , Julia C. Ford
    • , Matthew S. Lewis
    • , Abigail B. Ventura
    • , Colette M. Hughes
    • , Lia Coyne-Johnson
    • , Nathan Whizin
    • , Tonya Swanson
    • , Alfred W. Legasse
    • , Michael K. Axthelm
    • , Jay A. Nelson
    • , Michael A. Jarvis
    •  & Louis J. Picker
  2. AIDS and Cancer Virus Program, SAIC Frederick Inc., National Cancer Institute-Frederick, Frederick, Maryland 21702, USA

    • Kelli Oswald
    • , Rebecca Shoemaker
    • , Michael Piatak
    •  & Jeffrey D. Lifson
  3. International AIDS Vaccine Initiative, Vaccine Design and Development Laboratory, 140 58th Street, Building A, Unit 8J, Brooklyn, New York 11220, USA

    • Maria J. Chiuchiolo
    •  & Christopher L. Parks


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S.G.H. planned and performed experiments and analysed data, assisted by J.C.F., M.S.L., A.B.V., C.M.H., L.C.-J. and N.W. T.S., A.W.L. and M.K.A. managed the animal protocols. M.A.J. designed, constructed and characterized the RhCMV vectors. M.P. Jr and J.D.L. planned and performed SIV quantification studies, assisted by K.O. and R.S. C.L.P. and M.J.C. designed and constructed the DNA and Ad5 vectors used in this study. J.A.N. was involved in conception of the RhCMV vector strategy. L.J.P. conceived the RhCMV vector strategy, supervised experiments, analysed data and wrote the paper, assisted by S.G.H., M.A.J. and J.D.L.

Competing interests

[Competing financial interests: OHSU has licensed CMV vector technology, for which L.J.P., M.A.J. and J.A.N. are inventors, to the International AIDS Vaccine Initiative (IAVI).]

Corresponding author

Correspondence to Louis J. Picker.

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    This file contains Supplementary Figures 1-15 with legends, Supplementary Table 1, a Supplementary Discussion and additional references.

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