Caribbean-born African green monkeys (AGMs) were classified as .). CD4 ؉ T-cell counts in the blood showed a transient depletion at the peak of VL, and then returned to near preinfection values by day 28 p.i. and remained relatively stable during the chronic infection. Preservation of CD4 T cells was also found in lymph nodes (LNs) of chronic SIVagm.sab-infected Caribbean AGMs. No activation of CD4؉ T cells was detected in the periphery in SIV-infected Caribbean AGMs. These virological and immunological profiles from peripheral blood and LNs were identical to those previously reported in African-born AGMs infected with the same viral strain (SIVagm.sab92018). Due to these similarities, we conclude that Caribbean AGMs are a useful alternative to AGMs of African origin as a model for the study of SIV infection in natural African hosts.

Nonhuman primate models are increasingly used in the screening of candidate AIDS vaccine and immunization strategies for advancement to large-scale human trials. The predictive value of such macaque studies is largely dependent upon the fidelity of the model system in mimicking human immunodeficiency virus (HIV) type 1 infection in terms of viral transmission, replication, and pathogenesis. Herein, we describe the efficient mucosal transmission of a CCR5-specific chimeric simian/human immunodeficiency virus, SHIV SF162P3 . Female rhesus macaques were infected with SHIV SF162P3 after a single atraumatic application to the cervicovaginal mucosa. The disease course of SHIV SF162P3 -infected monkeys is similar and as varied as natural HIV infection in terms of viral replication, gradual loss of CD4؉ peripheral blood mononuclear cells, and the development of simian AIDS-defining opportunistic infections. The SHIV SF162P3 /macaque model should facilitate direct preclinical assessment of HIV vaccine strategies in addition to antiviral compounds directed towards envelope target cell interactions. Furthermore, this controlled model provides the setting to investigate immunologic responses and putative host-specific susceptibility factors that alter viral transmission and subsequent disease progression.

In contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4 ؉ T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, sun-tailed monkeys, and chimpanzees) but is absent in 5 nonnatural/recent hosts (humans, rhesus, pigtail, cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts IntroductionIt is now clear that human immunodeficiency virus type 1 (HIV-1) evolved from a closely related virus of chimpanzees (Pan troglodytes) named simian immunodeficiency virus (SIVcpz). [1][2][3] Similarly, HIV-2 originated from a related virus, SIVsmm, which naturally infects sooty mangabeys (SMs). [4][5][6] In marked contrast to HIV infection, which almost invariably progresses to AIDS unless treated with antiretrovirals, natural SIVcpz infection of chimpanzees and SIVsmm infection in SMs rarely result in clinical symptoms. [7][8][9][10][11][12] Similarly, other natural hosts for SIV, such as African green monkeys (AGMs), mandrills, and several other African nonhuman primate (NHP) species, generally live normal lifespans despite many years of infection with a highly replicating virus. [13][14][15][16][17][18][19][20][21][22][23] Importantly, the inoculation of SIV, which naturally infects African monkeys, into NHPs that are not natural hosts for SIV, such as macaques and baboons, may result in chronic infection that eventually progresses to a disease closely resembling AIDS. 16,[24][25][26][27][28] Given that the earliest documented exposure of a human to HIV-1 infection was in 1959, 29 it is thought that the introduction of primate lentiviruses into a new host species results in AIDS because of the inability of a naive immune system to cope with a virus recently transmitted from another species. Although it is agreed that the rarity of disease likely reflects a pacific coevolution between SIV and its natural hosts resulting from many thousands of years of endemic infection, the exact mechanisms underlying this absence of disease are still poorly understood. It should be noted, however, that the preservation of the immune system in natural SIV hosts does not simply result from immune control of viral replication, a task obviously not achieved in these animals given their high level of viral load (VL). 7,8,12,14,[19][20][21][22][23] In addition, the differences in virulence between the SIVs naturally infecting African NHP hosts and the pathogenic HIV/SIV strains are not related to differences in virus biology. As do most HIV/SIVmac/ SIVsmm strains, SIVs from African species use CD4 as a receptor 30 and CCR5 as a major coreceptor ...

SARS-CoV-2 induces a wide range of disease severity ranging from asymptomatic infection, to a life-threating illness, particularly in the elderly and persons with comorbid conditions. Among those persons with serious COVID-19 disease, acute respiratory distress syndrome (ARDS) is a common and often fatal presentation. Animal models of SARS-CoV-2 infection that manifest severe disease are needed to investigate the pathogenesis of COVID-19 induced ARDS and evaluate therapeutic strategies. Here we report ARDS in two aged African green monkeys (AGMs) infected with SARS-CoV-2 that demonstrated pathological lesions and disease similar to severe COVID-19 in humans. We also report a comparatively mild COVID-19 phenotype characterized by minor clinical, radiographic and histopathologic changes in the two surviving, aged AGMs and four rhesus macaques (RMs) infected with SARS-CoV-2. We found dramatic increases in circulating cytokines in three of four infected, aged AGMs but not in infected RMs. All of the AGMs showed increased levels of plasma IL-6 compared to baseline, a predictive marker and presumptive therapeutic target in humans infected with SARS-CoV-2 infection. Together, our results show that both RM and AGM are capable of modeling SARS-CoV-2 infection and suggest that aged AGMs may be useful for modeling severe disease manifestations including ARDS.

GSK1265744 (GSK744) is an integrase strand-transfer inhibitor that has been formulated as a long-acting (LA) injectable suitable for monthly to quarterly clinical administration. GSK744 LA was administered at two time points 4 weeks apart beginning 1 week before virus administration, and macaques were challenged weekly for 8 weeks. GSK744 LA, at plasma concentrations achievable with quarterly injections in humans, protected all animals against repeated low-dose challenges. In a second experiment, macaques were given GSK744 LA 1 week before virus administration and challenged repeatedly until infection occurred. Protection decreased over time and correlated with the plasma drug levels. With a quarterly dosing schedule in humans, our results suggest that GSK744 LA could potentially decrease adherence problems associated with daily preexposure prophylaxis (PrEP).

Chronic enterocolitis is the leading cause of morbidity in colonies of captive rhesus macaques (Macaca mulatta). This study's aim was to identify the common enteric pathogens frequently associated with chronic enterocolitis in normal, immunocompetent rhesus monkeys and to elucidate the influence of this clinical syndrome on the host immune system. We analyzed the fecal specimens from 100 rhesus macaques with or without clinical symptoms of chronic diarrhea. Retrospective analysis revealed an increased incidence of Campylobacter spp. (Campylobacter coli and Campylobacter jejuni), Shigella flexneri, Yersinia enterocolitica, adenovirus, and Strongyloides fulleborni in samples collected from animals with chronic diarrhea (P < 0.05). The presence of additional enteric pathogens, such as Escherichia coli, carrying the eaeA intimin or Stx2c Shiga toxin virulence genes, Balantidium coli, Giardia lamblia, Enterocytozoon bieneusi, and Trichuris trichiura was found in all animals regardless of whether diarrhea was present. In addition, the upregulation of interleukin-1␣ (IL-1␣), IL-3, and tumor necrosis factor alpha cytokine genes, accompanied by an increased presence of activated (CD4 ؉ CD69 ؉ ) T lymphocytes was found in gut-associated lymphoid tissues collected from animals with chronic enterocolitis and diarrhea in comparison with clinically healthy controls (P < 0.05). These data indicate that chronic enterocolitis and diarrhea are associated, in part, with a variety of enteric pathogens and highlight the importance of defining the microbiological status of nonhuman primates used for infectious disease studies. The data also suggest that chronic colitis in rhesus macaques may have potential as a model of inflammatory bowel disease in humans.

No abstract

Neurological manifestations are a significant complication of coronavirus disease (COVID-19), but underlying mechanisms aren’t well understood. The development of animal models that recapitulate the neuropathological findings of autopsied brain tissue from patients who died from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are critical for elucidating the neuropathogenesis of infection and disease. Here, we show neuroinflammation, microhemorrhages, brain hypoxia, and neuropathology that is consistent with hypoxic-ischemic injury in SARS-CoV-2 infected non-human primates (NHPs), including evidence of neuron degeneration and apoptosis. Importantly, this is seen among infected animals that do not develop severe respiratory disease, which may provide insight into neurological symptoms associated with “long COVID”. Sparse virus is detected in brain endothelial cells but does not associate with the severity of central nervous system (CNS) injury. We anticipate our findings will advance our current understanding of the neuropathogenesis of SARS-CoV-2 infection and demonstrate SARS-CoV-2 infected NHPs are a highly relevant animal model for investigating COVID-19 neuropathogenesis among human subjects.