Immunodeficiency in the absence of high viral load in pig-tailed macaques infected with Simian immunodeficiency virus SIVsun or SIVlhoest

Abstract

Simian immunodeficiency virus (SIV) is known to result in an asymptomatic infection of its natural African monkey host. However, some SIV strains are capable of inducing AIDS-like symptoms and death upon experimental infection of Asian macaques. To further investigate the virulence of natural SIV isolates from African monkeys, pig-tailed (PT) macaques were inoculated intravenously with either of two recently discovered novel lentiviruses, SIVlhoest and SIVsun. Both viruses were apparently apathogenic in their natural hosts but caused immunodeficiency in PT macaques. Infection was characterized by a progressive loss of CD4(+) lymphocytes in the peripheral blood and lymph nodes, generalized lymphoid depletion, a wasting syndrome, and opportunistic infections, such as Mycobacterium avium or Pneumocystis carinii infections. However, unlike SIVsm/mac infection of macaques, SIVlhoest and SIVsun infections in PT macaques were not accompanied by high viral loads during the chronic disease stage. In addition, no significant correlation between the viral load at set point (12 weeks postinfection) and survival could be found. Five out of eight SIVlhoest-infected and three out of four SIVsun-infected macaques succumbed to AIDS during the first 5 years of infection. Thus, the survival of SIVsun- and SIVlhoest-infected animals was significantly longer than that of SIVagm- or SIVsm-infected macaques. All PT macaques maintained strong SIV antibody responses despite progression to SIV-induced AIDS. The development of immunodeficiency in the face of low viremia suggests that SIVlhoest and SIVsun infections of macaques may model unique aspects of the pathogenesis of human immunodeficiency virus infection in humans.

FIG. 1.

Kaplan-Meier survival plot of macaques infected with SIVlhoest (n = 8), SIVsun (n = 4), SIVsmE543-3 (n = 16), or SIVagm90 (n = 8). The plot was generated with GraphPad Prism 3.0. Survival of SIVlhoest- and SIVsun-infected animals is prolonged compared to that of SIVagm- and SIVsm-infected macaques.

FIG. 2.

Viral RNA loads of PT macaques infected with SIVsun (A), PBMC-derived SIVlhoest (B), or spleen-derived SIVlhoest (C). Viral RNA loads were determined by quantitative TAQMAN RT-PCR. Viral loads peaked at 1 to 2 weeks after infection and then remained below or around 10⁴ RNA copies per ml for the remainder of the observation period. Gray bars indicate viral loads at set point.

FIG. 3.

SIV-specific hybridization showed a low number of SIV-expressing cells in tissues of a SIVlhoest-infected macaque (PT622) collected terminally. (A) Four SIV-positive cells in the mesenteric lymph node. Magnification, ×10. (B) A SIV-expressing intraepithelial lymphocyte in the ileum. Magnification, ×40. (C) A SIV-expressing cell in the lung. Magnification, ×10.

FIG. 4.

Absolute numbers of CD4⁺ lymphocytes in PT macaques infected with SIVsun (A), PBMC-derived SIVlhoest (B), or spleen-derived SIVlhoest (C). CD4⁺ lymphocyte numbers decreased continuously during the course of infection, in particular during the first 2 years.

FIG.5.

SIVlhoest infection leads to severe lymphoid depletion. (A) H&E-stained section of the mesenteric lymph node at the time of death of PT 626, demonstrating severe paracortical and follicular depletion. (B) Marked depletion of CD4⁺ T lymphocytes in the lymph node of PT 626 demonstrated by immunohistochemical staining. (C) Normal distribution of CD4⁺ T lymphocytes in the lymph node of an uninfected macaque.

FIG. 6.

Absolute numbers of CD8⁺ lymphocytes in PT macaques infected with SIVsun (A), PBMC-derived SIVlhoest (B), or spleen-derived SIVlhoest (C). CD8⁺ lymphocyte numbers decreased continuously during the course of infection.

FIG. 7.

Absolute numbers of B lymphocytes in PT macaques infected with SIVsun (A), PBMC-derived SIVlhoest (B), or spleen-derived SIVlhoest (C). B-lymphocyte numbers decreased continuously during the course of infection.

FIG. 8.

Antibodies against SIVlhoest and SIVsun were detected by Western blotting. (A) SIVsun-infected PT macaques; (B) PT macaques infected with spleen-derived SIVlhoest. SIVlhoest virus lysates were separated by sodium dodecyl sulfate-acrylamide gel electrophoresis and blotted onto a nitrocellulose membrane. Sera from weeks 0 to 292 (SIVlhoest-infected macaques) and weeks 0 to 220 (SIVsun-infected macaques) were tested for SIVlhoest-specific antibodies. SIVsun serologically cross-reacts with SIVlhoest.