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Simian immunodeficiency viruses (SIVs) share a number of biological and structural features with human immunodeficiency virus (HIV), making SIVs powerful tools for studying HIV infection. SIVs are the sources of the HIV pandemic (71), and SIV infection of nonhuman primates (NHPs) is at the origin of animal models of AIDS research (16, 28, 70, 74). Rhesus macaques (RMs; Macaca mulatta) infected with SIVmac, SIVsmm, and several chimeric simian-human immunodeficiency viruses (SHIVs) are the most widely used animal models of AIDS and provide essential insights into HIV/SIV immunopathogenesis and vaccine research (43, 65). The Indian RM (IndRM) is the best-characterized and most commonly studied model; however, significant expansion of AIDS research in recent years has resulted in limited availability of IndRM and a renewed interest in alternative animal models for pathogenic SIV infection (15, 47), such as Chinese RMs, cynomolgus macaques (Macaca fascicularis), and pigtailed macaques (PTMs; Macaca nemestrina) (15, 65). Chinese RMs and cynomolgus macaques show somewhat less pathogenic courses of SIVmac239, SIVmac251, and SHIV89.6P infections than IndRMs (36, 61). SIV and SHIV strains, as well as HIV type 2 (HIV-2), have also been used to infect PTMs (2, 12, 38, 48). Attempts have been also made to infect PTMs with HIV-1, but no persistent infection resulted (1, 18, 19). Several groups now primarily study PTMs as an animal model for HIV (28), and there are growing data on the common major histocompatibility complex molecules expressed by PTMs and the SIV epitopes they present (2, 12, 38, 48), thus enabling detailed immunopathogenic studies in PTMs similar to those originally pioneered with IndRMs. One of the most important applications of the use of PTMs as animal models for AIDS research is the study of cross-species SIV transmission from the natural hosts. It is widely acknowledged that African NHPs that are natural hosts of SIV generally do not progress to AIDS when infected with their species-specific virus despite high levels of viral replication (51, 54, 55, 62). In striking contrast to the pacific SIV-host interactions observed in natural hosts, HIV-1 and HIV-2 infections in humans are highly pathogenic, being characterized by progression to AIDS in a variable time frame (27). Both HIV-1 and HIV-2 originated by cross-species transmission of the SIVcpz from chimpanzees (Pan troglodytes troglodytes) and SIVsmm from sooty mangabeys (Cercocebus atys), respectively (71). SIVs have a high propensity for cross-species transmission, which is not a rare event, having been documented in the wild (8, 31, 72). However, unlike cross-species transmission of SIVs to humans and macaques that resulted in the emergence of highly pathogenic viruses, cross-species transmission of SIVs to new African NHP hosts generally does not result in increases in SIV pathogenicity (71). Therefore, understanding the mechanisms behind the spectacular increase in pathogenicity of SIVs transmitted across species to humans is a high priority in the field, especially considering the high exposure of humans to a plethora of viruses naturally infecting African NHP hosts in sub-Saharan Africa (59). A systematic approach of the events driving the increase in pathogenicity upon SIV cross-species transmission will need appropriate NHP models. For these types of studies RMs are probably not an appropriate host as studies carried out thus far demonstrated that RMs can control the majority of cross-species-transmitted SIV infections. Thus, SIVmnd-2 from mandrills (Mandrillus sphinx) (68), SIVrcm from red-capped mangabeys (RCMs; Cercocebus torquatus torquatus) (37, 64), SIVagm from African green monkeys (genus Chlorocebus) (52), SIVsyk from Syke's monkey (Cercopithecus albogularis) (26), and SIVtal from talapoins (Myopithecus talapoin) (49) are minimally pathogenic or controlled when transmitted to RMs. The only exception is the cross-species transmission of SIVsmm from sooty mangabeys (Cercocebus atys), which is pathogenic in RMs upon direct cross-species transmission (41, 62). Note that the emergence of SIVmac and SIVsmm reference strains currently used for pathogenesis and vaccine studies occurred through accidental transmission of SIVsmm from sooty mangabeys to different species of macaques in primate centers in the United States (4, 5, 34, 44) and that the high pathogenicity of these reference strains might have resulted as an effect of serial passages (5, 24). This conclusion is also supported by the recent observation that the intrinsic pathogenicity of primary SIVsmm isolates is significantly lower than previously believed (C. Apetrei, unpublished observations). In contrast to RMs, PTMs appear to be more susceptible to cross-species-transmitted SIV, with cases of AIDS reported to occur in PTMs after experimental infection with SIVsmm (17), SIVagm from different species of African green monkeys (SIVagm.ver and SIVagm.sab) (22, 25) (I. Pandrea, unpublished observations), SIVlhoest from l'hoest monkeys (Cercopithecus lhoesti) (6), and SIVsun from sun-tailed monkeys (Cercopithecus solatus) (6). This higher susceptibility of PTMs to cross-species-transmitted viruses may be explained by peculiarities of the TRIM5 genes in PTMs. The TRIM5 gene encodes Trim5α, a protein that blocks infection of the cell by retroviruses through the inhibition of reverse transcription immediately after viral entry into the cell (67). An aberrant splicing of TRIM5 mRNA resulting in TRIM5α isoform transcripts was described in PTMs (46). These isoforms (TRIM5η or TRIM5θ) are incapable of restricting either HIV-1 or SIV infection (11), thus explaining the high susceptibility of PTMs to different retroviral pathogens. The RCMs are found along the Atlantic forest coastal area of west and central Africa (9) and are naturally infected with a specific lentivirus, SIVrcm (7, 13, 21, 64). Since the RCMs were identified by genus and species previously (two paragraphs above), the identification was deleted from the sentence beginning “The RCMs are found.”− SIVrcm is a unique primate lentivirus in that it uses chemokine receptor CCR2 as a coreceptor for entry (13, 76) in contrast to the majority of HIV and SIV strains that use CCR5 and CXCR4 as the main coreceptors (14, 35). This peculiar coreceptor usage pattern is due to a deletion of 24 bp in the RCM CCR5 (Δ24 CCR5) gene that prevents expression of CCR5 on the surface of CD4+ T cells. This Δ24 CCR5 allele has a high frequency in RCM populations (13). Thus, SIVrcm is an example of a primate lentivirus that has adapted its coreceptor usage to allow productive replication and persistence in its natural host species. Given the unique coreceptor usage, along with the observation that the CCR2 coreceptor is expressed mainly on macrophages and only at very low levels on CD4+ T cells, SIVrcm may be ideal for pathogenesis studies of macrophage-tropic viruses. To date, there is no available data on SIVrcm replication in its natural host, but it is believed that SIVrcm rarely causes disease in RCMs, suggesting that it has been associated with its natural host for a long time. Previous studies on experimental infection of cynomolgus macaques and RMs reported that SIVrcm replicated in both macaque species during acute infection, but the replication was completely controlled by day 60 postinfection (p.i.) (21, 64). This controlled pattern of infection was maintained even after serial passage of SIVrcm in RMs (37). In order to develop an animal model for the in vivo study of SIVrcm pathogenesis and to confirm that this virus can be used as a model of macrophage-tropic SIV infection, we infected PTMs with SIVrcm and monitored the dynamics of viral loads (VLs), changes in lymphocyte subsets, antibody responses, and clinical and pathological features over a period of 27 months. Surprisingly, the patterns of SIVrcm replication and memory CD4+ T-cell depletion in PTMs were similar to those observed in lymphotropic SIV infections. Following inoculation in PTMs, SIVrcm expanded its coreceptor usage, becoming able to use CCR4 in vivo in addition to CCR2. This result indicates that lentiviral adaptation to a new host may occur rapidly through strain selection and involve new pathogenic pathways, pointing to the need for in vivo studies to characterize the pathogenesis of primate lentiviruses.

The mechanisms underlying the lack of disease progression in natural simian immunodeficiency virus (SIV) hosts are still poorly understood. To test the hypothesis that SIV-infected African green monkeys (AGMs) avoid AIDS due to virus replication occurring in long-lived infected cells, we infected six animals with SIVagm and treated them with potent antiretroviral therapy [ART; 9-R-(2-phosphonomethoxypropyl) adenine (tenofovir) and beta-2,3-dideoxy-3-thia-5-fluorocytidine (emtricitabine)]. All AGMs showed a rapid decay of plasma viremia that became undetectable 36 h after ART initiation. A significant decrease of viral load was observed in peripheral blood mononuclear cells and intestine. Mathematical modeling of viremia decay post-ART indicates a half-life of productively infected cells ranging from 4 to 9.5 h, i.e., faster than previously reported for human immunodeficiency virus and SIV. ART induced a slight but significant increase in peripheral CD4+T-cell counts but no significant changes in CD4+T-cell levels in lymph nodes and intestine. Similarly, ART did not significantly change the levels of cell proliferation, activation, and apoptosis, already low in AGMs chronically infected with SIVagm. Collectively, these results indicate that, in SIVagm-infected AGMs, the bulk of virus replication is sustained by short-lived cells; therefore, differences in disease outcome between SIVmac infection of macaques and SIVagm infection of AGMs are unlikely due to intrinsic differences in the in vivo cytopathicities between the two viruses.

Dialysis tubing containing spent culture media, when placed in a lake, was colonized by a low diversity of bacteria, whereas abiotic controls had considerable diversity. Changes were seen in the presence and absence of acylated homoserine lactones, suggesting that these molecules and other factors may influence adherent-population composition.

Bitterness is a flavor defect in Cheddar cheese that limits consumer acceptance, and specificity of the Lactococcus lactis extracellular proteinase (lactocepin) is widely believed to be a key factor in the development of bitter cheese. To better define the contribution of this enzyme to bitterness, we investigated peptide accumulation and bitterness in 50% reduced-fat Cheddar cheese manufactured with single isogenic strains of Lactococcus lactis as the only starter. Four isogens were developed for the study; one was lactocepin negative, and the others produced a lactocepin with group a, e, or h specificity. Analysis of cheese aqueous extracts by reversed-phase high-pressure liquid chromatography confirmed that accumulation of α S1 -casein (f 1-23)-derived peptides f 1-9, f 1-13, f 1-16, and f 1-17 in cheese was directly influenced by lactocepin specificity. Trained sensory panelists demonstrated that Cheddar cheese made with isogenic starters that produced group a, e, or h lactocepin was significantly more bitter than cheese made with a proteinase-negative isogen and that propensity for bitterness was highest in cells that produced group h lactocepin. These results confirm the role of starter proteinase in bitterness and suggest that the propensity of some industrial strains for production of the bitter flavor defect in cheese could be altered by proteinase gene exchange or gene replacement.