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Journal of Virology, February 2008, p. 1723-1738, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02084-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Patterns of CD8+ Immunodominance May Influence the Ability of Mamu-B*08-Positive Macaques To Naturally Control Simian Immunodeficiency Virus SIVmac239 Replication{triangledown} ,{dagger}

John T. Loffredo,1 Alex T. Bean,1 Dominic R. Beal,1 Enrique J. León,1 Gemma E. May,1 Shari M. Piaskowski,2 Jessica R. Furlott,1 Jason Reed,1 Solomon K. Musani,3 Eva G. Rakasz,1 Thomas C. Friedrich,1 Nancy A. Wilson,1 David B. Allison,3 and David I. Watkins1,2*

Wisconsin National Primate Research Center (WNPRC), University of Wisconsin—Madison, Madison, Wisconsin 53715,1 Department of Pathology and Laboratory Medicine, University of Wisconsin—Madison, Madison, Wisconsin 53706,2 Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama 352943

Received 19 September 2007/ Accepted 21 November 2007

Certain major histocompatibility complex (MHC) class I alleles are strongly associated with control of human immunodeficiency virus and simian immunodeficiency virus (SIV). CD8+ T cells specific for epitopes restricted by these molecules may be particularly effective. Understanding how CD8+ T cells contribute to control of viral replication should yield important insights for vaccine design. We have recently identified an Indian rhesus macaque MHC class I allele, Mamu-B*08, associated with elite control and low plasma viremia after infection with the pathogenic isolate SIVmac239. Here, we infected four Mamu-B*08-positive macaques with SIVmac239 to investigate why some of these macaques control viral replication. Three of the four macaques controlled SIVmac239 replication with plasma virus concentrations below 20,000 viral RNA copies/ml at 20 weeks postinfection; two of four macaques were elite controllers (ECs). Interestingly, two of the four macaques preserved their CD4+ memory T lymphocytes during peak viremia, and all four recovered their CD4+ memory T lymphocytes in the chronic phase of infection. Mamu-B*08-restricted CD8+ T-cell responses dominated the acute phase and accounted for 23.3% to 59.6% of the total SIV-specific immune responses. Additionally, the ECs mounted strong and broad CD8+ T-cell responses against several epitopes in Vif and Nef. Mamu-B*08-specific CD8+ T cells accounted for the majority of mutations in the virus at 18 weeks postinfection. Interestingly, patterns of viral variation in Nef differed between the ECs and the other two macaques. Natural containment of AIDS virus replication in Mamu-B*08-positive macaques may, therefore, be related to a combination of immunodominance and viral escape from CD8+ T-cell responses.

* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, University of Wisconsin—Madison, 555 Science Dr., Madison, WI 53711. Phone: (608) 265-3380. Fax: (608) 265-8084. E-mail: watkins{at}primate.wisc.edu

{triangledown} Published ahead of print on 5 December 2007.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, February 2008, p. 1723-1738, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02084-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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