Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz

Abstract

African primates are naturally infected with over 40 different simian immunodeficiency viruses (SIVs), two of which have crossed the species barrier and generated human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). Unlike the human viruses, however, SIVs do not generally cause acquired immunodeficiency syndrome (AIDS) in their natural hosts. Here we show that SIVcpz, the immediate precursor of HIV-1, is pathogenic in free-ranging chimpanzees. By following 94 members of two habituated chimpanzee communities in Gombe National Park, Tanzania, for over 9 years, we found a 10- to 16-fold higher age-corrected death hazard for SIVcpz-infected (n = 17) compared to uninfected (n = 77) chimpanzees. We also found that SIVcpz-infected females were less likely to give birth and had a higher infant mortality rate than uninfected females. Immunohistochemistry and in situ hybridization of post-mortem spleen and lymph node samples from three infected and two uninfected chimpanzees revealed significant CD4(+) T-cell depletion in all infected individuals, with evidence of high viral replication and extensive follicular dendritic cell virus trapping in one of them. One female, who died within 3 years of acquiring SIVcpz, had histopathological findings consistent with end-stage AIDS. These results indicate that SIVcpz, like HIV-1, is associated with progressive CD4(+) T-cell loss, lymphatic tissue destruction and premature death. These findings challenge the prevailing view that all natural SIV infections are non-pathogenic and suggest that SIVcpz has a substantial negative impact on the health, reproduction and lifespan of chimpanzees in the wild.

Figure 1. SIVcpz prevalence in Gombe

a, Prospective epidemiological study of 69 Kasekela (KK) and 25 Mitumba (MT) chimpanzees (F, female; M, male). Green fields denote the presence (‘1’) or absence (‘0’) of SIVcpz infection as determined by faecal and urine testing (grey fields indicate absence of data). Infected chimpanzees are highlighted in red (inferred results are denoted by an asterisk; see Methods). For each deceased chimpanzee, the date of death (DOD) or the date last seen (DLS) is listed. Parentheses indicate the natal community of females who immigrated during the course of the study (KL, Kalande). b, SIVcpz infection rates between 2002 and 2008. Only years with greater than 70% coverage of the combined KK and MT population are shown.

Figure 2. SIVcpz-associated mortality in Gombe

a, b, Kaplan–Meier survival curves are shown for SIVcpz-infected (red) and uninfected (blue) chimpanzees using maximally conservative (a) and less conservative (b) event definitions (see text for details). Under both scenarios, SIVcpz-infected chimpanzees die at a significantly faster rate (9.8- and 15.6-fold increased death hazard, respectively; P < 0.0001).

Figure 3. Histopathology of end-stage SIVcpz infection

a–c, Severe lymphatic depletion in mesenteric lymph node (a) and splenic tissue (b, c) of a Kasekela female (Ch-036) who died of an AIDS-like illness within 3 years of acquiring SIVcpz. d–f, Normal mesenteric lymph node with multiple primary and secondary lymphoid follicles (d) and normal splenic tissue with PALS (e, f) from an uninfected chimpanzee. a, d, Lymph node sections stained with haematoxylin and eosin (nuclei are blue). b, c, e, f, Spleen sections stained with anti-CD79a (b, e) and anti-CD3 (c, f) antibodies (positive cells are dark brown). Note the severe loss of both B (CD79a) and T (CD3) cells in the PALS of Ch-036. Arrows indicate follicular hyalinization. Original magnification ×4 (a, d) and ×20 (b, c, e, f and insets).

Figure 4. CD4⁺ T-cell depletion in SIVcpz-infected chimpanzees

Quantitative image analysis of splenic CD4⁺ T cells in SIVcpz-infected (red bars) and uninfected (solid black bars) chimpanzees, as well as in uninfected human (HU, black hatched bar), SIVmac-infected rhesus macaque (RM, blue hatched bar), and SIVsmm-infected sooty mangabey (SM, solid blue bar) controls. Representative PALS (8–24 per individual) were extracted and the percentage of area that stained positive for CD4 was determined,. Average values are shown, with error bars indicating s.e.m. All three SIVcpz-infected chimpanzees had significantly lower CD4⁺ T-cell counts than the two uninfected controls (ANOVA F-test; P = 0.024). The SIVmac-infected rhesus macaque had end-stage AIDS.