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Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected CD4+ T cells. We engineered an anti-PD-1 chimeric antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239-infected rhesus macaques (RMs). Adoptive transfer of anti-PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti-PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of PD-1+ memory T cells in blood and tissues, including lymph node CD4+ follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of CD8+ memory T cells. These data indicate anti-PD-1 CAR T cells depleted PD-1+ T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary.

Allogeneic transplantation (allo-HCT) has led to the cure of HIV in one individual, raising the question of whether transplantation can eradicate the HIV reservoir. To test this, we here present a model of allo-HCT in SHIV-infected, cART-suppressed nonhuman primates. We infect rhesus macaques with SHIV-1157ipd3N4, suppress them with cART, then transplant them using MHC-haploidentical allogeneic donors during continuous cART. Transplant results in ~100% myeloid donor chimerism, and up to 100% T-cell chimerism. Between 9 and 47 days post-transplant, terminal analysis shows that while cell-associated SHIV DNA levels are reduced in the blood and in lymphoid organs post-transplant, the SHIV reservoir persists in multiple organs, including the brain. Sorting of donor-vs.-recipient cells reveals that this reservoir resides in recipient cells. Moreover, tetramer analysis indicates a lack of virus-specific donor immunity post-transplant during continuous cART. These results suggest that early post-transplant, allo-HCT is insufficient for recipient reservoir eradication despite high-level donor chimerism and GVHD. Allogeneic hematopoietic cell transplantation (allo-HCT) has led to the cure of HIV in one individual, but the underlying mechanisms are unclear. Here, the authors present a model of allo-HCT in SHIV-infected nonhuman primates and show that the SHIV reservoir persists in multiple tissues early after transplantation.

Two gammaherpesviruses, Epstein-Barr virus (EBV) (Lymphocryptovirus genus) and Kaposi's sarcoma-associated herpesvirus (KSHV) (Rhadinovirus genus) have been implicated in the etiology of AIDS-associated lymphomas. Homologs of these viruses have been identified in macaques and other non-human primates. In order to assess the association of these viruses with non-human primate disease, archived lymphoma samples were screened for the presence of macaque lymphocryptovirus (LCV) homologs of EBV, and macaque rhadinoviruses belonging to the RV1 lineage of KSHV homologs or the more distant RV2 lineage of Old World primate rhadinoviruses. Viral loads were determined by QPCR and infected cells were identified by immunolabeling for different viral proteins. The lymphomas segregated into three groups. The first group (n = 6) was associated with SIV/SHIV infections, contained high levels of LCV (1-25 genomes/cell) and expressed the B-cell antigens CD20 or BLA.36. A strong EBNA-2 signal was detected in the nuclei of the neoplastic cells in one of the LCV-high lymphomas, indicative of a type III latency stage. None of the lymphomas in this group stained for the LCV viral capsid antigen (VCA) lytic marker. The second group (n = 5) was associated with D-type simian retrovirus-2 (SRV-2) infections, contained high levels of RV2 rhadinovirus (9-790 genomes/cell) and expressed the CD3 T-cell marker. The third group (n = 3) was associated with SIV/SHIV infections, contained high levels of RV2 rhadinovirus (2-260 genomes/cell) and was negative for both CD20 and CD3. In both the CD3-positive and CD3/CD20-negative lymphomas, the neoplastic cells stained strongly for markers of RV2 lytic replication. None of the lymphomas had detectable levels of retroperitoneal fibromatosis herpesvirus (RFHV), the macaque RV1 homolog of KSHV. Our data suggest etiological roles for both lymphocryptoviruses and RV2 rhadinoviruses in the development of simian AIDS-associated lymphomas and indicate that the virus-infected neoplastic lymphoid cells are derived from different lymphocyte lineages and differentiation stages.

Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected [CD4.sup.+] T cells. We engineered an anti-PD-1 chimeric antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239-infected rhesus macaques (RMs). Adoptive transfer of anti-PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti-PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of [PD- 1.sup.+] memory T cells in blood and tissues, including lymph node [CD4.sup.+] follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of [CD8.sup.+] memory T cells. These data indicate anti-PD-1 CAR T cells depleted [PD-1.sup.+] T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary.

Three juvenile male Micronesian kingfishers (Halcyon cinnamomina cinnamomina) housed in the same enclosure presented with rapid weight gain and coelomic distension. Physical examination and radiography revealed marked enlargement of the ventriculus and a single, large foreign body within the ventriculus in each individual. Surgical removal by ventriculotomy was attempted in one individual, which died during the procedure. A second individual was treated with natural peanut butter 0.5 ml p.o. b.i.d. for 14 days and recovered, casting the foreign material. The third bird was similarly treated without success and subsequently died during attempts at endoscopic removal of the foreign body. In all three birds, the foreign bodies proved to be phytobezoars. The birds had been observed stripping leaf fragments from live corn plants (Dracaena fragrans) used in the enclosure. Plant fibers from the phytobezoars were compared with D. fragrans leaves and were considered identical. Medical treatment of phytobezoars with peanut butter or similar oil-containing substances in birds should be considered as an alternative to surgical extraction.

Abstarct Ovine GM-1 gangliosidosis is an inherited lysosomal storage disease. Nine lambs affected with the disease were studied to characterize clinical signs and to determine if there were any pathognomonic clinicopathologic abnormalities. Evaluation included physical, ophthalmic, and neurologic examinations, complete blood counts, serum enzyme and electrolyte analyses, urinalyses, cerebrospinal fluid analyses, blood gas analyses, roentgenograms, electromyograms, and electrocardiograms. Two affected lambs had clinicopathologic tests performed before and after the onset of clinical signs. The only consistent abnormalities recognized were nonspecific signs referable to the central nervous system; predominantly ataxia, conscious proprioceptive deficit most severe in the hind limbs, blindness, and recumbency. Lambs continued to eat and drink, though at diminished levels and with loss of body condition. It was concluded that there are no pathognomonic clinicopathologic abnormalities associated with ovine GM-1 gangliosidosis, and antemortem diagnosis requires enzyme assay of leukocytes or cultured fibroblasts, or lectin histochemistry of tissues obtained by biopsy. Lysosomal storage diseases should be considered among the differential diagnoses in young animals presenting with early neonatal death or with nonspecific neurological signs, in concert with an absence of diagnostic clinicopathologic findings.

One male of a group of seven Pacific white-sided dolphins (Lagenorhynchus obliquidens) died after a brief period of nonspecific clinical signs. Four beluga whales (Delphinapterus leucas) and four harbor seals (Phoca vitulina) were managed in the same water system. Gross examination of the dolphin revealed only moderately enlarged mesenteric lymph nodes. Histopathology revealed small to massive numbers of gram-positive bacilli, usually intravascular, in all tissues. Bacteria were both extracellular and present in macrophages, monocytes, and neutrophils. Aerobic bacterial culture of lung, liver, kidney, and spleen yielded pure cultures of Erysipelothrix rhusiopathiae. Based on clinical course, histopathology, and bacteriology, a diagnosis of acute erysipelas septicemia was made. None of the other cetaceans or pinnipeds exhibited clinical signs.

Nine small cats, including one bobcat (Felis rufus), one Pallas cat (F. manul), one Canada lynx (F. lynx canadensis), two fishing cats (F. viverrina), two margays (F. wiedii), and two sand cats (F. margarita), necropsied between June 1995 and March 1997 had large numbers of gastric spiral bacteria, whereas five large cats, including one African lion (Panthera leo), two snow leopards (P. uncia), one Siberian tiger (P. tigris altaica), and one jaguar (P. onca), necropsied during the same period had none. All of the spiral organisms from the nine small cats were histologically and ultrastructurally similar. Histologically, the spiral bacteria were 5-14 μm long with five to nine coils per organism and were located both extracellularly within gastric glands and surface mucus, and intracellularly in parietal cells. Spiral bacteria in gastric mucosal scrapings from the Canada lynx, one fishing cat, and the two sand cats were gram negative and had corkscrewlike to tumbling motility when viewed with phase contrast microscopy. The bacteria were 0.5-0.7 μm wide, with a periodicity of 0.65-1.1 μm in all cats. Bipolar sheathed flagella were occasionally observed, and no periplasmic fibrils were seen. The bacteria were extracellular in parietal cell canaliculi and intracellular within parietal cells. Culture of mucosal scrapings from the Canada lynx and sand cats was unsuccessful. Based on morphology, motility, and cellular tropism, the bacteria were probably Helicobacter-like organisms. Although the two margays had moderate lymphoplasmacytic gastritis, the other cats lacked or had only mild gastric lymphoid infiltrates, suggesting that these organisms are either commensals or opportunistic pathogens.

Two captive California sea lions (Zalophus californianus) from different facilities were diagnosed with disseminated blastomycosis. The first, a 12-yr-old male, died after a 3-wk history of progressive anorexia and lethargy. Gross examination revealed acute jejunitis with focal perforation and associated peritonitis, along with severe purulent bronchopneumonia. The second, a 15-yr-old female, was euthanized after a 2-wk history of severe cutaneous ulceration and declining clinical condition. Gross examination revealed severe pyogranulomatous bronchopneumonia and ulcerative dermatitis. Histopathologic examination in both individuals revealed severe multifocal subacute to chronic pyogranulomatous pneumonia associated with massive numbers of fungal organisms morphologically compatible with Blastomyces sp. Fungal organisms were 8–20-µm-diameter broad-based budding yeasts with thick, refractile, double-contoured walls. The male sea lion had multifocal transmural Blastomyces-induced enteritis with subsequent rupture and peritonitis. The organism was also present in the liver, with minimal associated inflammation. The female had severe multifocal pyogranulomatous ulcerative dermatitis associated with large numbers of intralesional fungal organisms. Dissemination to the spleen had occurred in both animals. A serologic immunodiffusion test for Blastomyces dermatitidis was positive in the male. The presumptive primary pathogen in both cases was Blastomyces dermatitidis.

An adult male mountain chameleon (Chameleo montium), one of 92 individuals recently caught in the wild and transported, died after a 28-day history of anorexia. Gross examination revealed marked emaciation and enteric nematodiasis. Histopathologic examination of the small intestine revealed moderate numbers of enterocytes containing 2-15 μm-diameter round to ellipsoid, basophilic, intranuclear inclusions. Ultrastructurally, the inclusions consisted of crystalline arrays of hexagonal viral particles 67-76 nm in diameter with electron-dense cores. The viral particles were consistent with an adenovirus. No pathologic changes were associated with the adenoviral infection.