Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques

Abstract

Parenteral administration of a mouse anti-human CD8 monoclonal antibody (MAb) to rhesus macaques resulted in a transient depletion of CD8+ cells in both the peripheral blood and lymphoid tissues. When administered during primary chimeric simian/human immunodeficiency virus infections, the CD8 MAb caused marked elevations of plasma and cell-associated virus levels in both the peripheral blood and lymphoid tissues and led to prolonged depletion of CD4 cells. Taken together, these results directly demonstrate that CD8+ T lymphocytes are actively involved in controlling the acute phase of primate lentivirus infections.

FIG. 1

Comparison of virus loads in pig-tailed and rhesus macaques infected with SHIV_MD14YE. Animals were inoculated intravenously with 1.2 × 10⁴ to 3.0 × 10⁵ TCID₅₀ of SHIV_MD14YE. Proviral DNA copy numbers in PBMC (A) and the concentration of p27 Gag antigen in plasma (B) are shown.

FIG. 2

Effect of CD8 MAb administration on macaque T-lymphocyte subsets. (A) The indicated amounts of the T87PT3F9 anti-CD8 MAb were injected intravenously into three cynomolgus macaques, and the number of CD8 cells in peripheral blood was determined. Three naive rhesus macaques were injected (2 mg/kg) with either the T87PT3F9 anti-CD8 MAb (animals T14 and AH37) or control IgG (animal W59). The number of cells present in different T-lymphocyte subsets in peripheral blood (B) and the percentage of CD4 or CD8 cells in unfractionated lymphocytes from inguinal lymph node samples (C) were measured by flow cytometry as described in Materials and Methods. Ab, antibody; Tx, transfusion.

FIG. 3

The effect of CD8 MAb administration on the number of circulating CD8⁺ T lymphocytes during primary SHIV infections. Six rhesus macaques were inoculated intravenously with SHIV_MD14YE (3 × 10⁴ TCID₅₀) on day 0. (A) On days 7 and 14 following infection, monkey AN47 received anti-CD8 MAb (2 mg/kg), monkey 865C was administered IgG (2 mg/kg), and monkey AM45 served as an untreated control. (B) Three days prior to and 4 days following SHIV infection, monkeys 565Z and 84324 received anti-CD8 MAb (2 mg/kg) and monkey B9727 was given IgG (2 mg/kg). Tx, transfusion.

FIG. 4

The effect of CD8 MAb administration on virus loads and CD4 cell levels in acutely infected animals. Arrows indicate the times of CD8 MAb administration. The three control macaques were inoculated with purified IgG or received no treatment. The concentration of p27 Gag antigen in plasma (A), the proviral DNA copy number in CD4⁺ PBMC (B), and the number of CD4 cells (C) are shown for the 15-week period following virus inoculation. The proviral DNA copy number and the percentage of CD4 in lymph node samples from three of the animals are also shown (D). Tx, transfusion.

FIG. 5

The in vivo effect of T87PT3F9 anti-CD8 MAb administration on the CD28 subpopulation of CD8⁺ T lymphocytes in the peripheral blood. CD8⁺ PBMC from three naive (top) and three acutely infected (bottom) macaques were examined for surface expression of CD28. The total number of CD8⁺ cells is shown as 100%. The arrows indicate the times of antibody administration (IgG or anti-CD8 [2 mg/kg]) and SHIV challenge.