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Journal of Virology, April 2008, p. 4135-4148, Vol. 82, No. 8
0022-538X/08/$08.00+0     doi:10.1128/JVI.00015-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Vaccine Protection by Live, Attenuated Simian Immunodeficiency Virus in the Absence of High-Titer Antibody Responses and High-Frequency Cellular Immune Responses Measurable in the Periphery{triangledown}

Keith Mansfield,1,{dagger} Sabine M. Lang,1,{dagger} Marie-Claire Gauduin,1 Hannah B. Sanford,1 Jeffrey D. Lifson,2 R. Paul Johnson,1 and Ronald C. Desrosiers1*

New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, Box 9102, Southborough, Massachusetts 01772-9102,1 Laboratory of Retroviral Pathogenesis, AIDS Vaccine Program, SAIC Frederick Cancer Research and Development Center, Building 535, Room 524, P.O. Box B, Frederick, Maryland 217022

Received 3 January 2008/ Accepted 1 February 2008

An attenuated derivative of simian immunodeficiency virus strain 239 deleted of V1-V2 sequences in the envelope gene (SIV239{Delta}V1-V2) was used for vaccine/challenge experiments in rhesus monkeys. Peak levels of viral RNA in plasma of 104 to 106.5 copies/ml in the weeks immediately following inoculation of SIV239{Delta}V1-V2 were 10- to 1,000-fold lower than those observed with parental SIV239 (~107.3 copies/ml). Viral loads consistently remained below 200 copies/ml after 8 weeks of infection by the attenuated SIV239{Delta}V1-V2 strain. Viral localization experiments revealed large numbers of infected cells within organized lymphoid nodules of the colonic gut-associated lymphoid tissue at 14 days; double-labeling experiments indicated that 93.5% of the virally infected cells at this site were positive for the macrophage marker CD68. Cellular and humoral immune responses measured principally by gamma interferon enzyme-linked immunospot and neutralization assays were variable in the five vaccinated monkeys. One monkey had responses in these assays comparable to or only slightly less than those observed in monkeys infected with parental, wild-type SIV239. Four of the vaccinated monkeys, however, had low, marginal, or undetectable responses in these same assays. These five vaccinated monkeys and three naïve control monkeys were subsequently challenged intravenously with wild-type SIV239. Three of the five vaccinated monkeys, including the one with strong anti-SIV immune responses, were strongly protected against the challenge on the basis of viral load measurements. Surprisingly, two of the vaccinated monkeys were strongly protected against SIV239 challenge despite the presence of cellular anti-SIV responses of low-frequency and low-titer anti-SIV antibody responses. These results indicate that high-titer anti-SIV antibody responses and high-frequency anti-SIV cellular immune responses measurable by standard assays from the peripheral blood are not needed to achieve strong vaccine protection, even against a difficult, neutralization-resistant strain such as SIV239.

* Corresponding author. Mailing address: New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, Box 9102, Southborough, MA 01772-9102. Phone: (508) 624-8042. Fax: (508) 624-8190. E-mail: ronald_desrosiers{at}hms.harvard.edu

{triangledown} Published ahead of print on 13 February 2008.

{dagger} Both authors contributed to similar extents, and both should be considered first authors.

Journal of Virology, April 2008, p. 4135-4148, Vol. 82, No. 8
0022-538X/08/$08.00+0     doi:10.1128/JVI.00015-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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