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. 2005 Dec;79(23):14887-98.
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  1 , Bernard A P Lafont, Tatsuhiko Igarashi, Yoshiaki Nishimura, Charlie Brown, Vanessa Hirsch, Alicia Buckler-White, Reza Sadjadpour, Malcolm A Martin
Affiliations

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 et al. J Virol. 2005 Dec.

Abstract

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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Figures

FIG. 1.
FIG. 1.
SHIVDH12R-Clone 7 and SHIVDH12R-Clone 8 induce distinct clinical outcomes in infected rhesus monkeys. Rhesus monkeys were inoculated intravenously with the indicated amounts (TCID50) of SHIVDH12R-Clone 7 or SHIVDH12R-Clone 8. The levels of CD4+ T cells (A and C) and plasma viral RNA (B) in the peripheral blood were monitored over the first 40 weeks (A and B) or over a 220-week period (C).
FIG. 2.
FIG. 2.
Treatment of individual rhesus macaques with an anti-CD8 MAb during acute SHIVDH12R-Clone 8 infection. Animals (CE96 and CK3A) were injected intravenously with the anti-CD8 MAb beginning 1day following virus inoculation. Peripheral blood CD8+ lymphocyte (A), CD4+ lymphocyte numbers (B), and plasma viral RNA levels (C) were measured at the indicated times. Animal CK1K received an isotype-matched control MAb. The arrows indicate the times of antibody treatment on days +1, +4, and +8 relative to SHIVDH12R-Clone 8 inoculation.
FIG. 3.
FIG. 3.
Treatment of individual rhesus macaques with an anti-CD20 MAb during the acute SHIVDH12R-Clone 8 infection. An uninfected monkey (CE43) was injected intravenously with three doses of the anti-CD20 MAb Rituxan, and the numbers of CD4+, CD8+, and CD20+ lymphocytes in its peripheral blood were determined (A). Intravenous administration of Rituxan to animals CJ55 and CJ61 was started 4 days prior to SHIVDH12R-Clone 8 inoculation. The number of peripheral blood CD20+ lymphocytes (B), number of CD4+ lymphocytes (C), plasma viral RNA levels (D), and CD8+ lymphocyte numbers (E) were measured at the indicated times. Animal CJ6F received an isotype-matched control MAb. The arrows indicate the times of the weekly antibody treatments.
FIG. 4.
FIG. 4.
Production of binding and neutralizing antibodies in untreated monkeys inoculated with SHIVDH12R-Clone 8. Virus-specific IgG (A) and IgM (B) binding antibodies were measured by ELISA using plasma samples, diluted 1:6, collected at the indicated times. OD, optical density. Neutralization of SHIVDH12R-Clone 8 was determined from the 32P-reverse transcriptase activity released into the medium on day 14 from quadruplicate cultures (C). Autoradiograms of 32P-reverse transcriptase assays, using plasma samples diluted 1:3 and collected at the indicated times, are shown.
FIG. 5.
FIG. 5.
Administration of anti-CD8 MAbs is associated with a rapid and complete depletion of CD4+ cells in Mamu-A*01-positive monkeys inoculated with the nonpathogenic SHIVDH12R-Clone 8. Animals (CF6T and H680) received the anti-CD8 antibody beginning 1 day following infection. The numbers of peripheral blood CD8+ lymphocytes (A), numbers of CD4+ lymphocytes (B), and plasma viral RNA levels (C) were measured at the indicated times. The arrows indicate the times of antibody treatment.
FIG. 6.
FIG. 6.
Administration of anti-CD20 MAb to Mamu-A*01-positive monkeys inoculated with SHIVDH12R-Clone 8 is not associated with a rapid and complete loss of CD4+ T cells. Rituxan was administered to animals H678 and CK48 4 days prior to intravenous inoculation with 5,000 TCID50 of SHIVDH12R-Clone 8. The numbers of peripheral blood CD20+ lymphocytes (A), numbers of CD4+ lymphocytes (B), and plasma viral RNA levels (C) were measured at the indicated times.
FIG. 7.
FIG. 7.
Gag peptide CM9-specific CD8+ T cells in infected Mamu-A*01-positive macaques. Sequential tetramer-positive CD8+ T-lymphocyte levels in anti-CD20 MAb-treated or untreated Mamu-A*01-positive animals during the SHIVDH12R-Clone 8 infection are shown.
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