Non-human primate model of Kaposi's sarcoma-associated herpesvirus infection.

Since Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8) was first identified in Kaposi's sarcoma (KS) lesions of HIV-infected individuals with AIDS, the basic biological understanding of KSHV has progressed remarkably. However, the absence of a proper animal model for KSHV continues to impede direct in vivo studies of viral replication, persistence, and pathogenesis. In response to this need for an animal model of KSHV infection, we have explored whether common marmosets can be experimentally infected with human KSHV. Here, we report the successful zoonotic transmission of KSHV into common marmosets (Callithrix jacchus, Cj), a New World primate. Marmosets infected with recombinant KSHV rapidly seroconverted and maintained a vigorous anti-KSHV antibody response. KSHV DNA and latent nuclear antigen (LANA) were readily detected in the peripheral blood mononuclear cells (PBMCs) and various tissues of infected marmosets. Remarkably, one orally infected marmoset developed a KS-like skin lesion with the characteristic infiltration of leukocytes by spindle cells positive for KSHV DNA and proteins. These results demonstrate that human KSHV infects common marmosets, establishes an efficient persistent infection, and occasionally leads to a KS-like skin lesion. This is the first animal model to significantly elaborate the important aspects of KSHV infection in humans and will aid in the future design of vaccines against KSHV and anti-viral therapies targeting KSHV coinfected tumor cells.

Interleukin-18 predicts atherosclerosis progression in SIV-infected and uninfected rhesus monkeys (Macaca mulatta) on a high-fat/high-cholesterol diet.

Interleukin (IL)-18 levels have been identified as important predictors of cardiovascular mortality and are often elevated in human immunodeficiency virus (HIV)-infected individuals. To investigate a possible function for IL-18 in atherogenesis in the context of early HIV infection, we used the simian immunodeficiency model of HIV infection. Acutely simian immunodeficiency virus-infected and uninfected rhesus monkeys (Macaca mulatta) on an atherogenic diet were evaluated prospectively for atherosclerotic lesion development relative to a panel of plasma markers including IL-18, IL-8, IL-1beta, IL-6, C-reactive protein, soluble vascular cell adhesion molecule-1, soluble E-selectin, and soluble intercellular adhesion molecule-1. Although no significant differences in lesion development were identified between groups after 35 days of infection, levels of plasma IL-18 measured 1 month before virus inoculation correlated significantly with atherosclerotic plaque cross-sectional area at the carotid bifurcation (P<0.001, R=0.946), common iliac bifurcation (P<0.01, R=0.789), and cranial abdominal aorta (P<0.01, R=0.747), as well as with extent of CD3+ and CD68+ cellular infiltration in vascular lesions (both P<0.001, R>or=0.835) in both groups. Atherosclerotic plaque area at the carotid and common iliac bifurcations also showed a weaker inverse correlation with baseline IL-8 levels, as did CD68+ signal area. Results implicate a strong role for IL-18 in early atherosclerosis progression and raise the possibility that the chronically elevated IL-18 levels seen in later stages of HIV infection may contribute significantly to accelerated atherogenesis in this population.

Structural and biochemical alterations in Giardia lamblia cysts exposed to ozone.

Because of its efficacy in inactivating waterborne protozoan cysts and oocysts, ozone is frequently used for disinfection of drinking water. The effect of ozone on cysts of Giardia lamblia was investigated in gerbils (Meriones unguiculatus), using an infectivity assay by scanning electron microscopy, immunoblotting, and flow cytometry. Cysts recovered from experimentally infected gerbils were exposed to an initial ozone concentration of 1.5 mg/L for 0, 30, 60, and 120 sec. This treatment resulted in a dose-dependent reduction in cysts concentration, loss of infectivity in gerbils, and profound structural modifications to the cyst wall. Exposure for 60 sec or longer resulted in extensive protein degradation and in the disappearance of a cyst wall and a trophozoite antigen.

Alternative activation of macrophages in rhesus macaques (Macaca mulatta) with endometriosis.

Endometriosis is one of the most frequently encountered gynecologic diseases and a common cause of chronic pelvic pain and infertility. The pathophysiology of this syndrome can best be described as the presence of ectopic endometrium and a pelvic inflammatory process with associated immune dysfunction and alteration in the peritoneal environment. Macrophages play an important role in the progression and propagation of endometriosis. Alternative macrophage activation occurs in rodents and women with endometriosis but had not been examined previously in nonhuman primates. This case-control study aimed to characterize macrophage polarization in the ectopic and eutopic endometrial tissue of nonhuman primates with and without endometriosis. In addition, circulating cytokines in endometriosis cases and normal controls were investigated in an effort to identify serum factors that contribute to or result from macrophage polarization. Endometriosis lesions demonstrated increased infiltration by macrophages polarized toward the M2 phenotype when compared with healthy control endometrium. No serum cytokine trends consistent with alternative macrophage activation were identified. However, serum transforming growth factor α was elevated in macaques with endometriosis compared with healthy controls. Findings indicated that the activation state of macrophages in endometriosis tissue in nonhuman primates is weighted toward the M2 phenotype. This important finding enables rhesus macaques to serve as an animal model to investigate the contribution of macrophage polarization to the pathophysiology of endometriosis.

Antigenic stimulation in the simian model of HIV infection yields dilated cardiomyopathy through effects of TNFalpha.

OBJECTIVE: To investigate a role for endogenous myocardial cytokine production in the development of HIV-associated cardiomyopathy. DESIGN: Cardiomyopathy is a late-stage sequela of HIV infection. Although pathogenesis of this condition in HIV infection is poorly defined, inflammatory cytokines are recognized for their detrimental effects on myocardial structure and function. HIV infection is characterized by chronic immune activation and inflammatory cytokine dysregulation. As the myocardium itself is a rich potential source of inflammatory cytokines, HIV-mediated cytokine dysregulation may be an important contributor to development of HIV cardiomyopathy. An antigenic stimulation protocol conducted in the simian immunodeficiency virus (SIV) model of HIV infection was used to study the effects of endogenous cytokine production on myocardial structure and function. METHODS: Twenty-six rhesus monkeys were assigned to treatment groups for a 35-day study. Animals were SIV-infected; SIV-infected and treated with killed Mycobacterium avium complex bacteria (MAC); SIV-infected, MAC-treated, and given the TNFalpha antagonist etanercept; or uninfected and MAC-treated. All animals were subjected to weekly echocardiographic studies. Hearts were collected for further evaluation at euthanasia. RESULTS: SIV-infected, MAC-treated animals developed significant systolic dysfunction [left ventricular ejection fraction (LVEF) decline of 19 +/- 2%] and ventricular chamber dilatation [left ventricular end-diastolic diameter (LVEDD) increase of 26 +/- 6%] not seen in other groups. Concurrent treatment with etanercept prevented development of these changes, implicating a causative role of myocardial TNFalpha. CONCLUSIONS: SIV-infected animals develop exaggerated myocardial pathology on stimulation with the ubiquitous environmental agent MAC. These responses are TNFalpha-dependent and may play a significant role in the development of cardiomyopathy in HIV infection.