Classic AIDS in a sooty mangabey after an 18-year natural infection

Abstract

Prevailing theory holds that simian immunodeficiency virus (SIV) infections are nonpathogenic in their natural simian hosts and that lifelong infections persist without disease. Numerous studies have reported that SIV-infected sooty mangabeys (SMs; Cercocebus atys) remain disease free for up to 24 years despite relatively high levels of viral replication. Here, we report that classic AIDS developed after an 18-year incubation in an SM (E041) with a natural SIVsm infection. Unlike that described in previous reports of SIV-related disease in SMs, the SIVsm infecting E041 was not first passaged through macaques; moreover, SM E041 was simian T-cell leukemia virus antibody negative. SM E041 was euthanized in 2002 after being diagnosed with severe disseminated B-cell lymphoma. The plasma virus load had been approximately the same for 16 years when a 100-fold increase in virus load occurred in years 17 and 18. Additional findings associated with AIDS were CD4(+)-cell decline, loss of p27 core antibody, and loss of control of SIVsm replication with disseminated giant cell disease. These findings suggest that the time to development of AIDS exceeds the average lifetime of SMs in the wild and that the principal adaptation of SIV to its natural African hosts does not include complete resistance to disease. Instead, AIDS may develop slowly, even in the presence of high virus loads. However, a long-term relatively high virus load, such as that in SM E041, is consistent with AIDS development in less than 18 years in humans and macaques. Therefore, the results also suggest that SMs have a special mechanism for resisting AIDS development.

FIG. 1.

(A) HE-stained sections of lymphoma tissue. The tumor consisted of sheets of densely packed round cells that completely effaced the architecture of the mesenteric lymph nodes. Neoplastic cells were moderate- to large-sized lymphoid cells with moderate pleomorphism. (B) Immunophenotyping of neoplastic cells. The majority of large, atypical cells were CD20⁺ (B cells) as demonstrated by immunohistochemistry (stained brown). (C) HE stain of giant cells (arrows) in the connective tissue surrounding lung hilus. Inset, a giant cell that tested positive for SIV by immunohistochemistry (stained brown). (D) Lung showing multiple SIVp27⁺ giant cells (stained brown). Giant cell disease is also characteristic of AIDS seen in macaques infected with SIVsm. Immunohistochemistry was performed as described previously (44, 45).

FIG. 2.

Western blot analysis of plasma from E041 over an 18-year period of SIV infection. p27 antibody was detected from 1984 (lanes 84a and 84b) through 1995 (lanes 85, 87, 90, and 95). p27 antibody was undetectable in 2000 (lane 00) and on the day of euthanasia in 2002 (lane 02). gp140 antibody was the only SIV antibody detected in 2002 (lane 02). Specimens 84a and 84b were taken prior to M. leprae inoculation. SIV antibody-positive (lane Pos) and -negative (lane Neg) controls are shown.

FIG.3.

Phylogenetic analysis of 460-bp env sequences of SIVsmE041 in 1986, 2000, and 2002 (boxed). These sequences were compared with known SIVsm reference sequences from the GenBank database. Phylogenetic trees were estimated by the neighbor-joining method (36). The reliability was estimated from 1,000 bootstrap replicates; bootstrap values of less than 70% are not shown on the branches. SIVsm A022 (underlined) showed a different branching order from that of SIVsm E041 (boxed).

FIG. 4.

Plasma RNA viral load in SM E041 over an 18-year period. The plasma viral load was about 80,000 to 110,000 copies/ml over an 11-year period, from 1984 to 1995. The virus load with AIDS increased 100-fold between 1996 and 2002, the time of euthanasia. CD4 cell numbers were between 1,500 and 2,700 cells/μl from 1984 through 1986. No CD4 cell data were available between 1985 and 2000. By 2000, the CD4 cell count had declined to 765, and it dropped to 50 cells/μl on the day of euthanasia. The mean plasma viral loads of SIVsm-infected SMs, HIV-1- or HIV-2-infected persons, and experimentally SIVmac-infected Chinese (Ch RM) and Indian (In RM) rhesus monkeys (24) are also shown for comparison.