The SIV-infected rhesus monkey model for HIV-associated dementia and implications for neurological diseases

The neuropathogenesis of human immunodeficiency virus (HIV)-associated dementia has remained elusive, despite identification of HIV as the causal agent. Although a number of contributing factors have been identified, the series of events that culminate in motor and cognitive impairments after HIV infection of the central nervous system (CNS) are still not known. Rhesus monkeys infected with simian immunodeficiency virus (SIV) manifest immunosuppression and CNS disease that is pathologically [L. R. Sharer et al. (1991) J. Med. Primatol. 20, 211-217] and behaviorally [E. A. Murray et al. (1992) Science 255, 1246-1249] similar to humans. The SIV model of HIV-associated dementia (HAD) is widely recognized as a highly relevant model in which to investigate neuropathogenesis. With better understanding of neuropathogenesis comes the opportunity to interrupt progression and to design better treatments for HAD. This becomes increasingly important as patients live longer yet still harbor HIV-infected cells in the CNS. The use of the SIV model has allowed the identification of neurochemical markers of neuropathogenesis important not only for HAD, but also for other inflammatory neurological diseases.     

Early viral replication in the brain of SIV-infected rhesus monkeys.

To investigate the mechanism of simian immunodeficiency virus (SIV) entry into the central nervous system (CNS) and the initial events leading to neuropathogenesis, SIV replication was studied by in situ hybridization in the CNS of 5 Rhesus macaques at 7 days, 1, 2, and 3 months after SIV intravenous inoculation. CNS infection was found to be a frequent and early event, as SIV was detected in the CNS of all the animals studied and as early as 7 days postinoculation. At the earliest stage, the infection localized mainly to perivascular cells. Using combined immunohistochemistry and in situ hybridization, infected cells were shown to express the CD68 marker, suggesting that infected mononuclear phagocytes crossing the blood-brain barrier represent the main source of virus in the CNS. Early viral replication coincided with neuropathologic changes, consisting in gliosis, perivascular infiltrates and rare glial nodules. Immunophenotyping of brain tissue showed that increased macrophage infiltration, microglial reactivity and MHC class II induction occurred within the first week of infection, indicating a possible immunopathologic mechanism in early CNS pathogenesis.     

Salt hunger in the rhesus monkey

Five rhesus monkeys (Macaca mulatta) were placed on a low-sodium diet and given injections of furosemide in order to promote sodium loss. The results indicated that these methods elicit a substantial and specific salt hunger. Issues surrounding salt hunger are discussed.     

Sham feeding in the rhesus monkey.

Adult male rhesus monkeys with chronic gastric fistulas were adapted to eating a liquid food during a 90 min test period after an overnight food deprivation. When the fistulas were opened for the first time, monkeys sham fed more than three times as much as they had eaten the previous day when the gastric fistulas were closed. The observed incidences of resting and non-ingestive activity were reduced during the sham feeding test. When monkeys sham fed for 5 successive test days, intake increased progressively with a concomitant decrease in the incidence of non-ingestive activity. The results demonstrate that under, these experimental conditions pregastric food stimuli (and their conditioned and/or unconditioned responses) are not sufficient to limit meal size at control levels, and they are not sufficient to elicit the behavioral sequence of normal satiety.     

Reversal learning in the neonatal rhesus monkey

Twenty-one day old and 31 day old monkeys were presented with a black-versus-white discrimination reversal problem after having completed 20 days of learning on the original problem. Age at the time of reversal was not a significant factor, but reversing to the white stimulus was significantly faster than reversing to the black stimulus. This preference persisted over repeated reversals. The infant monkey shows improvement in repeated reversal learning that is very similar to the behavior of the adult rat.     

Experimental autoimmune gastritis in the rhesus monkey

Three rhesus monkeys were injected with pooled monkey gastric mucosa suspension plus complete Freund adjuvant. All three animals developed organ-specific autoantibodies and delayed skin tests to gastric antigen. The circulating antibodies were demonstrated by tanned cell haemagglutination using a well-centrifuged, heated gastric extract, and by complement fixation tests employing a lightly centrifuged gastric suspension. In immunofluorescent tests, antibodies localized primarily in the parietal cell cytoplasm of the gastric mucosa. All three monkeys showed histological evidence of chronic multifocal gastritis consisting of monocytic infiltration of the mucosal layer with atrophy of the neighbouring glands. The thyroids and other organs of these monkeys were normal. Normal monkeys, or control monkeys injected with monkey thyroid, adrenal or testis extract did not show these gastric changes.     

Muscle spindles in the rhesus monkey platysma

The platysma of the rhesus monkey consists of two parts: a platysma myoides located similar to the human platysma, and a platysma cervicale passing the dorsal cervical region and being in contact with the cheek pouch. Our investigation showed that the muscle fiber morphology was comparable in both parts. Muscle spindles were only present in regions connected to the cheek pouch and contained only nuclear chain fibers. It is tempting to speculate that they sense the filling of the cheek pouch rather than mimic activities.     

Gastric emptying and secretion in the rhesus monkey.

The volume and composition of the gastric contents as well as the rates of gastric emptying and secretion were determined simultaneously in conscious chair-adapted monkeys. These determinations were made during fasting and after a liquid meal, thereby allowing studies of the physiologic variables which regulate gastric emptying and gastric secretion. Administration of a water meal is followed by a complex pattern of changes in rates of secretion as well as the fractional rate of emptying. During administration of a 100-ml water meal (pH 7.4), intragastric volume increased while acid concentration decreased; both then returned to fasting values 50 min later. The fractional rate of emptying increased fivefold during administration of the water meal, returned to basal values after 30 min, and then increased again, indicating that gastric emptying cannot be characterized as a simple first-order process with a constant coefficient. The pattern of the change in the rate of water secretion was similar to that for fractional gastric emptying. In contrast, after the meal, gastric acid secretion increased steadily and did not become maximal until 20 min.     

Spontaneous rhabdomyosarcoma in a rhesus monkey

In an adult male rhesus monkey, a large pelvic mass causing lysis of the ilium and destruction of pelvic musculature was diagnosed as a spontaneous rhabdomyosarcoma by the use of histological, ultrastructural and immunohistochemical techniques.     

Implantation in the rhesus monkey: Endometrial responses

In this continuing series of studies of implantation in the rhesus monkey, eight specimens, ranging in gestation age from 9.5 days to 16.5 days after ovulation, were examined with a focus on localized modifications in the endometrium as a response to implantation. Additionally, evidence of continuing changes in early pregnancy was provided by three specimens at the end of the first month of gestation (days 24, 28, and 35). The responses of the endometrium to pregnancy start with a localized accumulation of stromal eosinophils, which is rapidly followed by epithelial plaque formation in the basal cells of the luminal epithelium and gland necks. Plaque cells hypertrophy, develop marginal dense granules, and accumulate glycogen. They form a pad underlying the margins but not the central zone of the implantation site. However, some degenerating plaque cells are found as early as day 15; and little more than a region of leukocytic infiltration remains of the plaque by day 35. Shortly after the plaque response is initiated there is a striking subepithelial edema surrounding the plaque, and the venular capillaries enlarge by engorgement and by endothelial hyperplasia. The endothelial cells subsequently hypertrophy, resulting in a largely columnar endothelium. There is a localized decidual cell response, consisting of an increase in rough endoplasmic reticulum and in filaments, but only a moderate amount of hypertrophy of these cells. Endometrial granular cells become more conspicuous in the area as they accumulate glycogen. Patches of large pale cells appear in the lumen and walls of arterioles subjacent to the implantation site, but the cytology of these cells provided insufficient clues to their origin (cytotrophoblast?). Although the endometrial responses described are impressive and diverse, their advantages to the organism are not obvious. The hypertrophy of the anastomotic capillary bed that accompanies plaque formation may well provide an extensive vascular network available to the developing trophoblastic lacunae. The role of endometrial granular cells, decidual cells, and even plaque cells may be more related to their largely unexplored secretory activity than to their physical contribution to the formation of the basal plate.     

Intestinal schwannoma in a rhesus monkey

An intestinal schwannoma (neurilemmoma) was found in an aged female rhesus monkey culled from a research colony. The neoplasm was characterized principally by palisades of spindle-shaped cells (Antoni type A) surrounded by thick argyrophilic fibres, while plump cells with areas of vacuolation (Antoni type B) were observed to a lesser extent. Thick hyalinized perivascular cuffs were prominent and multifocal thromboses were present in cavernous vascular channels. Electron microscopic examination of the intercellular matrix between Antoni type A cells revealed long-spacing (100 to 120 nm) collagen fibrils. Although the mass had expanded beyond the confines of the muscularis externa, the cytological features of the neoplasm appeared benign.     

Adrenergic and dopaminergic response to chronic chair restraint in the rhesus monkey.

Prolonged chair restraint and social isolation in the rhesus monkey led to a reduction in the urinary excretion of HVA (4-hydroxy-3-methoxyphenylacetic acid), DOPAC (3,4-dihydroxyphenylacetic acid), VMA methoxy-4-hydroxymandelic acid), and MHPG (3-methoxy-4-hydroxyphenylethylglycol) over a 3 week period. This adaptation to a chronically "stressful" situation corresponds to earlier studies on the rhesus monkey indicating a gradual reduction in the urinary excretion of norepinephrine and epinephrine after initiation of restraint. The following basic information on the urinary excretion of catecholamine metabolites was obtained: (1) the rate of excretion of the dopamine metabolites (HVA and DOPAC) is about four times higher than the rate of excretion of adrenergic metabolites (VMA and MHPG): (2) MHPG is the major adrenergic metabolite in the rhesus monkey; and (3) the excretion rates of the urinary metabolites varied considerably between animals.