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. 1999 Nov 23;96(24):14049-54.
doi: 10.1073/pnas.96.24.14049.

Emergence of a highly pathogenic simian/human immunodeficiency virus in a rhesus macaque treated with anti-CD8 mAb during a primary infection with a nonpathogenic virus

T Igarashi  1 , Y Endo, G Englund, R Sadjadpour, T Matano, C Buckler, A Buckler-White, R Plishka, T Theodore, R Shibata, M Martin
Affiliations

Emergence of a highly pathogenic simian/human immunodeficiency virus in a rhesus macaque treated with anti-CD8 mAb during a primary infection with a nonpathogenic virus

T Igarashi et al. Proc Natl Acad Sci U S A. .

Abstract

Although simian/human immunodeficiency virus (SHIV) strain DH12 replicates to high titers and causes immunodeficiency in pig-tailed macaques, virus loads measured in SHIV(DH12)-infected rhesus monkeys are consistently 100-fold lower and none of 22 inoculated animals have developed disease. We previously reported that the administration of anti-human CD8 mAb to rhesus macaques at the time of primary SHIV(DH12) infection resulted in marked elevations of virus loads. One of the treated animals experienced rapid and profound depletions of circulating CD4(+) T lymphocytes. Although the CD4(+) T cell number partially recovered, this monkey subsequently suffered significant weight loss and was euthanized. A tissue culture virus stock derived from this animal, designated SHIV(DH12R), induced marked and rapid CD4(+) cell loss after i.v. inoculation of rhesus monkeys. Retrospective analyses of clinical specimens, collected during the emergence of SHIV(DH12R) indicated: (i) the input cloned SHIV remained the predominant virus during the first 5-7 months of infection; (ii) variants bearing only a few of the SHIV(DH12R) consensus changes first appeared 7 months after the administration of anti-CD8 mAb; (iii) high titers of neutralizing antibody directed against the input SHIV were detected by week 10 and persisted throughout the infection; and (iv) no neutralizing antibody against SHIV(DH12R) ever developed.

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Figures

Figure 1
Figure 1
(A) The dynamics of viral RNA levels and CD4+ T lymphocyte counts during the SHIVDH12 infection of rhesus macaque 565Z. The arrows indicate the times when anti-human CD8 mAb was administered. (B and C) SHIVDH12R induces p27 antigenemia and causes rapid CD4+ T cell depletion in rhesus macaques. Blood collected at the indicated times from two infected rhesus macaques were fractionated into plasma and cells and levels of p27 and CD4+ T lymphocytes, respectively, were determined as described in Methods.
Figure 2
Figure 2
Highly pathogenic SHIVDH12R evolves in a stepwise manner during the course of infection in rhesus macaque 565Z. The deduced amino acid sequence for the cloned SHIVDH12 (DH12) and the consensus sequence from 22 independent SHIVDH12R (DH12R) PCR clones are indicated in the top and bottom lines of each grouping. Independent PCR clones also were derived from PBMC samples collected at weeks 10 (9 clones), 20 (5 clones), 31 (6 clones), 39 (14 clones), 52 (8 clones), and 61 (6 clones) postinfection as described in Methods and their nucleotide sequence was determined. The locations of amino acid changes in gp120 and gp41 at various times during the evolution of SHIVDH12 to SHIVDH12R are indicated in red. The positions of the fusion domain (FD) and transmembrane (TM) regions of gp41 are shown.
Figure 3
Figure 3
Antiviral antibody responses during the course of the SHIVDH12 infection of rhesus monkey 565Z. Samples of blood, collected at the indicated times, were analyzed by immunoblotting as described in Methods. Lanes H and S, purified IgG (0.45 μg) from a chimpanzee infected with HIV-1DH12 (26) or plasma (1:200) from an SIVsm-infected rhesus macaque, respectively, were used as positive controls.
Figure 4
Figure 4
Neutralizing antibody responses during the course of the SHIVDH12 infection of rhesus monkey 565Z. Plasma samples prepared at the indicated times were subjected to neutralization assay as described (10).
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