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Journal of Virology, December 2005, p. 14887-14898, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14887-14898.2005

CD8⁺ and CD20⁺ Lymphocytes Cooperate To Control Acute Simian Immunodeficiency Virus/Human Immunodeficiency Virus Chimeric Virus Infections in Rhesus Monkeys: Modulation by Major Histocompatibility Complex Genotype

Hanwen Mao, Bernard A. P. Lafont, Tatsuhiko Igarashi, Yoshiaki Nishimura, Charlie Brown, Vanessa Hirsch, Alicia Buckler-White, Reza Sadjadpour, and Malcolm A. Martin^*

Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Received 21 July 2005/ Accepted 5 September 2005

We have previously described two isogenic molecularly cloned simian immunodeficiency virus/human immunodeficiency virus chimeric viruses (SHIVs) that differ from one another by 9 amino acids and direct distinct clinical outcomes in inoculated rhesus monkeys. SHIV_{DH12R-Clone 7}, like other highly pathogenic CXCR4-tropic SHIVs, induces rapid and complete depletions of CD4⁺ T lymphocytes and immunodeficiency in infected animals. In contrast, macaques inoculated with SHIV_{DH12R-Clone 8} experience only partial and transient losses of CD4⁺ T cells, show prompt control of their viremia, and remain healthy for periods of time extending for up to 4 years. The contributions of CD8⁺ and CD20⁺ lymphocytes in suppressing the replication of the attenuated SHIV_{DH12R-Clone 8} and maintaining a prolonged asymptomatic clinical course was assessed by treating animals with monoclonal antibodies that deplete each lymphocyte subset at the time of virus inoculation. The absence of either CD8⁺ or CD20⁺ cells during the SHIV_{DH12R-Clone 8} acute infection resulted in the rapid, complete, and irreversible loss of CD4⁺ T cells; sustained high levels of postpeak plasma viremia; and symptomatic disease in Mamu-A*01-negative Indian rhesus monkeys. In Mamu-A*01-positive animals, however, the aggressive, highly pathogenic phenotype was observed only in macaques depleted of CD8⁺ cells; SHIV_{DH12R-Clone 8} was effectively controlled in Mamu-A*01-positive monkeys in the absence of B lymphocytes. Taken together, these results indicate that both CD8⁺ and CD20⁺ B cells contribute to the control of primate lentiviral infection in Mamu-A*01-negative macaques. Furthermore, the major histocompatibility complex genotype of an infected animal, as exemplified by the Mamu-A*01 allele in this study, has the additional capacity to shift the balance of the composite immune response.

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* Corresponding author. Mailing address: NIAID, NIH, Bldg. 4, Room 315, 4 Center Drive, MSC 0460, Bethesda, MD 20892-0460. Phone: (301) 496-4012. Fax: (301) 402-0226. E-mail: malm{at}nih.gov.

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Journal of Virology, December 2005, p. 14887-14898, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14887-14898.2005

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