Immune failure in the absence of profound CD4+ T-lymphocyte depletion in simian immunodeficiency virus-infected rapid progressor macaques

Abstract

A fraction of simian immunodeficiency virus (SIV)-infected macaques develop rapidly progressive disease in the apparent absence of detectable SIV-specific antibody responses. To characterize the immunopathogenesis of this syndrome, we studied viral load, CD4+ T-lymphocyte numbers as well as cellular and humoral immune responses to SIV and other exogenous antigens in four SIVsm-infected rhesus macaques that progressed to AIDS 9 to 16 weeks postinoculation. Each of these animals exhibited high levels of viremia but showed relatively preserved CD4 T lymphocytes in blood and lymphoid tissues at the time of death. Transient SIV-specific antibody responses and cytotoxic T-lymphocyte responses were observed at 2 to 4 weeks postinoculation. Two of the macaques that were immunized sequentially with tetanus toxoid and hepatitis A virus failed to develop antibody to either antigen. These studies show that the SIV-infected rapid progressor macaques initially mounted an appropriate but transient cellular and humoral immune response. The subsequent immune defect in these animals appeared to be global, affecting both cellular and humoral immunity to SIV as well as immune responses against unrelated antigens. The lack of CD4 depletion and loss of humoral and cellular immune responses suggest that their immune defect may be due to an early loss in T helper function.

FIG. 1.

Sequential plasma viremia in rapid progressor macaques. (A) Plasma viremia is shown graphically for the four study animals from the time of inoculation to euthanasia. (B) For comparison, plasma viremia during the same time period is shown for six conventional progressor macaques; two were selected from each cohort of the rapid progressor macaques.

FIG. 2.

SIV-specific in situ hybridization (bottom) in mesenteric lymph nodes collected at death from H445, H538, H567, and H635. Severe disruption of the lymphoid architecture is evident, with absence of secondary germinal centers and variable degrees of paracortical depletion. Large numbers of virus-expressing cells were observed in the lymph nodes of all four animals. Magnification, ×10.

FIG. 3.

(A) Sequential changes in absolute peripheral CD4⁺ T cells during the course of SIV infection in four rapid progressor macaques is shown graphically. (B) For comparison, CD4⁺ T cells are shown during the first 20 weeks after inoculation in the same six conventional progressor macaques in Fig. 1B.

FIG. 4.

Immunohistochemical detection of CD4⁺ T cells in mesenteric lymph nodes of four rapid progressor macaques at the time of autopsy, showing variable degrees of CD4 depletion in lymphoid tissues. Lymph nodes of H445 and H538 (top) demonstrated moderate to severe CD4⁺ T-cell depletion, whereas depletion was much less pronounced in nodes from H567 and H635 (middle). This contrasts with the preservation of CD4 cells in the paracortical region of a lymph node from a normal uninfected rhesus macaque (bottom left) and the severe depletion in a lymph node of a conventional progressor macaque, H120, in end-stage disease (bottom right).

FIG. 5.

Analysis of SIV-specific antibody responses of rapid progressor macaques H538, H567, and H445. (A) Radioimmunoprecipitation analysis of SIV-specific antibody in plasma of macaques H538, H567, and H445 during the primary phase of infection. Lanes are numbered according to the week post-SIV inoculation of the plasma samples. The locations of SIV gp120, gp160, p55, and p27 are indicated. (B) Sequential reciprocal neutralizing antibody titers in SIV-inoculated macaques assayed with the laboratory-adapted, homologous SIVsmH4 strain. Macaques H538, H567, and H445 did not develop detectable neutralizing antibody.

FIG. 6.

Env- and Gag-specific CTL responses in peripheral blood of macaque H445. Specific lysis of vaccinia virus-expressed Env (top) and Gag (bottom) target cells at different effector-to-target cell ratios are shown graphically throughout the course of infection of H445.

FIG. 7.

Gag peptide, p11C-specific CTL activity in the blood of MVA-immunized rhesus monkeys H538 and H567 after infection with SIVsmE660. (A) Sequential p11C-specific lysis in peripheral blood mononuclear cells at effector-to-target cell ratios of 5:1 to 1.25:1 with CTL activity detectable between days 14 and 28 following infection is shown graphically. (B) Sequential percent tetramer-positive CD8⁺ T cells in whole blood of macaques H538 and H567 shown sequentially throughout SIV infection.

FIG. 8.

Response of SIV-infected rhesus macaques to immunization with tetanus toxoid and hepatitis A virus. The antibody responses to tetanus toxoid (A) and hepatitis A virus antigen (B) are shown graphically with the rapid progressor macaques H445 and H635 shown on the left, the responses of conventional progressors from the same cohorts in the middle, and SIV-naïve macaques on the right.