Innate Immune Mechanisms Research Articles

Latent gammaherpesvirus infection enhances type I IFN response and reduces virus spread in an influenza A virus co-infection model.

Infections with persistent or latent viruses alter host immune homeostasis and have potential to affect the outcome of concomitant acute viral infections such as influenza A virus (IAV). Gammaherpesviruses establish life-long infections and require an on-going immune response to control reactivation. We have used a murine model of co-infection to investigate the response to IAV infection in mice latently infected with the gammaherpesvirus MHV-68. Over the course of infection, latently infected BALB/c mice showed less weight loss, clinical signs, pulmonary cellular infiltration and expression of inflammatory mediators than naïve mice infected with IAV and had significantly more activated CD8+ T cells in the lungs. Four days after IAV infection, virus spread in the lungs of latently infected animals was significantly lower than in naïve animals. By 7 days after IAV infection latently infected lungs express elevated levels of cytokines and chemokines indicating they are primed to respond to the secondary infection. Investigation at an early time point showed that 24 h after IAV infection co-infected animals had higher expression of IFNβ and Ddx58 (RIG-I) and a range of ISGs than mice infected with IAV alone suggesting that the type I IFN response plays a role in the protective effect. This effect was mouse strain dependent and did not occur in 129/Sv/Ev mice. These results offer insight into innate immune mechanisms that could be utilized to protect against IAV infection and highlight on-going and persistent viral infections as a significant factor impacting the severity of acute respiratory infections.

Integrative Molecular Structure Elucidation and Construction of an Extended Metabolic Pathway Associated with an Ancient Innate Immune Response in COVID-19 Patients.

We present compelling evidence for the existence of an extended innate viperin-dependent pathway, which provides crucial evidence for an adaptive response to viral agents, such as SARS-CoV-2. We show the in vivo biosynthesis of a family of novel endogenous cytosine metabolites with potential antiviral activities. Two-dimensional nuclear magnetic resonance (NMR) spectroscopy revealed a characteristic spin-system motif, indicating the presence of an extended panel of urinary metabolites during the acute viral replication phase. Mass spectrometry additionally enabled the characterization and quantification of the most abundant serum metabolites, showing the potential diagnostic value of the compounds for viral infections. In total, we unveiled ten nucleoside (cytosine- and uracil-based) analogue structures, eight of which were previously unknown in humans allowing us to propose a new extended viperin pathway for the innate production of antiviral compounds. The molecular structures of the nucleoside analogues and their correlation with an array of serum cytokines, including IFN-α2, IFN-γ, and IL-10, suggest an association with the viperin enzyme contributing to an ancient endogenous innate immune defense mechanism against viral infection.

Implications of metabolism on multi-systems healthy aging across the lifespan.

Aging is increasingly thought to involve dysregulation of metabolism in multiple organ systems that culminate in decreased functional capacity and morbidity. Here, we seek to understand complex interactions among metabolism, aging, and systems-wide phenotypes across the lifespan. Among 2469 adults (mean age 74.7 years; 38% Black) in the Health, Aging and Body Composition study we identified metabolic cross-sectionally correlates across 20 multi-dimensional aging-related phenotypes spanning seven domains. We used LASSO-PCA and bioinformatic techniques to summarize metabolome-phenome relationships and derive metabolic scores, which were subsequently linked to healthy aging, mortality, and incident outcomes (cardiovascular disease, disability, dementia, and cancer) over 9 years. To clarify the relationship of metabolism in early adulthood to aging, we tested association of these metabolic scores with aging phenotypes/outcomes in 2320 participants (mean age 32.1, 44% Black) of the Coronary Artery Risk Development in Young Adults (CARDIA) study. We observed significant overlap in metabolic correlates across the seven aging domains, specifying pathways of mitochondrial/cellular energetics, host-commensal metabolism, inflammation, and oxidative stress. Across four metabolic scores (body composition, mental-physical performance, muscle strength, and physical activity), we found strong associations with healthy aging and incident outcomes, robust to adjustment for risk factors. Metabolic scores for participants four decades younger in CARDIA were related to incident cardiovascular, metabolic, and neurocognitive performance, as well as long-term cardiovascular disease and mortality over three decades. Conserved metabolic states are strongly related to domain-specific aging and outcomes over the life-course relevant to energetics, host-commensal interactions, and mechanisms of innate immunity.

Gut complement induced by the microbiota combats pathogens and spares commensals

Canonically, the complement system is known for its rapid response to remove microbes in the bloodstream. However, relatively little is known about a functioning complement system on intestinal mucosal surfaces. Herein, we report the local synthesis of complement component 3 (C3) in the gut, primarily by stromal cells. C3 is expressed upon commensal colonization and is regulated by the composition of the microbiota in healthy humans and mice, leading to an individual host's specific luminal C3 levels. The absence of membrane attack complex (MAC) components in the gut ensures that C3 deposition does not result in the lysis of commensals. Pathogen infection triggers the immune system to recruit neutrophils to the infection site for pathogen clearance. Basal C3 levels directly correlate with protection against enteric infection. Our study reveals the gut complement system as an innate immune mechanism acting as a vigilant sentinel that combats pathogens and spares commensals.

Persistent complement dysregulation with signs of thromboinflammation in active Long Covid.

Long Covid is a debilitating condition of unknown etiology. We performed multimodal proteomics analyses of blood serum from COVID-19 patients followed up to 12 months after confirmed severe acute respiratory syndrome coronavirus 2 infection. Analysis of >6500 proteins in 268 longitudinal samples revealed dysregulated activation of the complement system, an innate immune protection and homeostasis mechanism, in individuals experiencing Long Covid. Thus, active Long Covid was characterized by terminal complement system dysregulation and ongoing activation of the alternative and classical complement pathways, the latter associated with increased antibody titers against several herpesviruses possibly stimulating this pathway. Moreover, markers of hemolysis, tissue injury, platelet activation, and monocyte-platelet aggregates were increased in Long Covid. Machine learning confirmed complement and thromboinflammatory proteins as top biomarkers, warranting diagnostic and therapeutic interrogation of these systems.

A systematic review of the role of surfactants in bronchial asthma: Implications for pathogenesis and treatment of the disease

The study aims to examine existing literature and highlight the significance of surfactants as a factor in pathogenesis and a potential therapeutic target in bronchial asthma. A systematic search is conducted in Scopus, Web of Science, and PubMed/Medline, utilizing specific keywords related to surfactants and bronchial asthma. The findings demonstrate that surfactants, a unique mixture of lipids and proteins, play a crucial role in the mechanisms of innate and adaptive immunity in the lungs. They act as a mechanical barrier, modulate inflammatory responses, and interact with pathogens. Changes in surfactant composition and levels have been associated with various lung diseases, including bronchial asthma

Effect of dietary supplementation of probiotic on growth, survival, and immune-related biomarkers in Chinook Salmon (Oncorhynchus tshawytscha) challenged with Vibrio anguillarum

Chinook salmon is a native species of the Canadian Pacific coast with potential economic and environmental benefits for aquaculture. However, its production is jeopardized by low tolerance to high densities and disease susceptibility. Due to this, Chinook salmon represents a great candidate for evaluating the effect of non-polluting alternatives to vaccines and antibiotics, such as probiotics. Preliminary studies have suggested that certain probiotic strains may be able to enhance fish growth, antioxidant activity, food digestibility, modulate the host microbial community in the digestive tract, and prevent bacterial infections. However, there is currently no evidence of its effects in Chinook salmon. Here, we used the commercially available, low-cost multi-strain probiotic used by humans, to determine the impact on Chinook salmon growth, survival, immune response, and gut barrier integrity. Fish were randomly assigned to four netpens and given either regular (control) feed or supplemented with probiotics for 4, 10, or 14 months. After this, fish were transferred to troughs and challenged with Vibrio anguillarum. Probiotic supplementation for 14 months decreased mortality by ∼10% compared to the control treatment. However, no positive effects of this probiotic supplementation on fish growth occurred. Despite the improvement in survival associated to long-term probiotic supplementation, the expression of the immune genes il1b, il8, il10, tnfa, camp, hamp, and transferrin in head kidney, spleen, and hindgut tissues did not fully provide the specific innate immune mechanisms that could be associated with a better protection. Decreased expression of cldn1 and ocln in fish supplemented for 14 months compared to 4- and 10-months suggested that probiotic treatment during the freshwater and saltwater cycle confers a better protection and intestinal integrity, resulting in an improved survival. Although it was not possible to observe differences in IgM and IgT protein levels between probiotic-supplemented fish and the control treatment in plasma, head kidney, spleen, and hindgut, this study represents the first measurement of total IgT protein levels in Chinook salmon. In summary, probiotic supplementation modulated the early inflammatory response against V. anguillarum infection and helped improve the survival of Chinook salmon aquaculture in an environmentally sustainable manner when applied in freshwater and up to the transition to saltwater growth phase.

The Role of Innate Immunity in Osteoarthritis and the Connotation of "Immune-joint" Axis: A Narrative Review.

Osteoarthritis (OA) is a degenerative disease that results in constriction of the joint space due to the gradual deterioration of cartilage, alterations in subchondral bone, and synovial membrane. Recently, scientists have found that OA involves lesions in the whole joint, in addition to joint wear and tear and cartilage damage. Osteoarthritis is often accompanied by a subclinical form of synovitis, which is a chronic, relatively low-grade inflammatory response mainly mediated by the innate immune system. The "immune-joint" axis refers to an interaction of an innate immune response with joint inflammation and the whole joint range. Previous studies have underestimated the role of the immune-joint axis in OA, and there is no related research. For this reason, this review aimed to evaluate the existing evidence on the influence of innate immune mechanisms on the pathogenesis of OA. The innate immune system is the body's first line of defense. When the innate immune system is triggered, it instantly activates the downstream inflammatory signal pathway, causing an inflammatory response, while also promoting immune cells to invade joint synovial tissue and accelerate the progression of OA. We have proposed the concept of the "immune-joint" axis and explored it from two aspects of Traditional Chinese Medicine (TCM) theory and modern medical research, such as the innate immunity and OA, macrophages and OA, complement and OA, and other cells and OA, to enrich the scientific connotation of the "immune-joint" axis.

C-C chemokine receptor type 7 (CCR7) regulates hepatic CD8 + T cell homeostasis and response to acute liver injury.

Acute liver failure (ALF) is a rare but life-threatening condition, and DILI, particularly acetaminophen toxicity, is the leading cause of ALF. Innate immune mechanisms further perpetuate liver injury, while the role of the adaptive immune system in DILI-related ALF is unclear. We analyzed liver tissue from 2 independent patient cohorts with ALF and identified hepatic T cell infiltration as a prominent feature in human ALF. CD8 + T cells were characterized by zonation toward necrotic regions and an activated gene expression signature. In murine acetaminophen-induced liver injury, intravital microscopy revealed zonation of CD8 + but not CD4 + T cells at necrotic areas. Gene expression analysis exposed upregulated C-C chemokine receptor 7 (CCR7) and its ligand CCL21 in the liver as well as a broadly activated phenotype of hepatic CD8 + T cells. In 2 mouse models of ALF, Ccr7-/- mice had significantly aggravated early-phase liver damage. Functionally, CCR7 was not involved in the recruitment of CD8 + T cells, but regulated their activation profile potentially through egress to lymphatics. Ccr7-/- CD8 + T cells were characterized by elevated expression of activation, effector, and exhaustion profiles. Adoptive transfer revealed preferential homing of CCR7-deficient CD8 + T cells to the liver, and depletion of CD8 + T cells attenuated liver damage in mice. Our study demonstrates the involvement of the adaptive immune system in ALF in humans and mice. We identify the CCR7-CCL21 axis as an important regulatory pathway, providing downstream protection against T cell-mediated liver injury.

Comparative Study to Assess the Effectiveness and Safety of Etoricoxib & Aceclofenac in Osteoarthritis Patients

Osteoarthritis (OA) is defined as a disorder that involves the movement of limbs characterized by cellular stress and a deterioration of the outer matrix that trigger malignant remodelling responses that include inflammatory mechanisms of natural immunity. Non-steroidal anti-inflammatory (NSAID) drugs are the first choice of treatment, since they reduce pain, improve functional ability. So, by comparing the effectiveness and safety of NSAID used in the treatment of OA can enhance the quality of life of patients. The goal of the study was to compare the effectiveness and safety of Aceclofenac and Etoricoxib in OA patients as well as to assess the quality of life (QOL) and medication adherence among subjects. It is an observational study conducted in the selected Orthopaedics clinics in T. Dasarahalli, Bengaluru District for a period of 6 months, based on various inclusion and exclusion criteria. Standardized questionnaire used in the study were Western Ontario and McMaster Universities Arthritis Index, Medical Outcomes Study 36-Item Short-Form Health Survey and Morisky Medication-Taking Adherence Scale. The collected data were entered in Microsoft Excel and appropriate descriptive and inferential statistical analysis was performed. On comparing Aceclofenac and Etoricoxib in terms of WOMAC score Etoricoxib (28.42) was found to be more effective than Aceclofenac (31.61) while comparing Etoricoxib 60 mg and 90mg, 90 mg (26.22) was found to be more effective. Regarding the safety of these drugs, Etoricoxib was found to be safer than Aceclofenac in terms of side effects. On associating the QOL scores in both the groups, it was found that the subjects belonging to the Aceclofenac group had the highest overall mean score 57.68. Investigation of medication adherence in the study population revealed that out of 68 subject’s majority of them had shown low adherence (n=38). Because of its enhanced safety profile, Etoricoxib is a better option than Aceclofenac for treating .....

Current update on dermatomyositis

Dermatomyositis (DM) is arare autoimmune disease with involvement of skin and muscle that is classified as an idiopathic inflammatory myopathy. In addition to cutaneous lesions as well as weakness and atrophy of muscles, the heart and lungs are the major affected organs. DM occurs in association with malignant tumors in 20% of affected adults. The pathogenesis of the disease is not completely understood. DM is amultifactorial disease influenced by genetic, environmental and immunological factors. The immune response is characterized by activation of innate and adaptive immune mechanisms and astrong activation of the typeI interferon pathway. Myositis-specific antibodies are characteristic of DM and allow differential diagnosis. Therapies include corticosteroids, antimalarials, immunoglobulins, biologics such as rituximab or JAK inhibitors. Early diagnosis and treatment are essential for the prognosis.

Mapping the interaction sites of human and avian influenza A viruses and complement factor H.

The complement system is an innate immune mechanism against microbial infections. It involves a cascade of effector molecules that is activated via classical, lectin and alternative pathways. Consequently, many pathogens bind to or incorporate in their structures host negative regulators of the complement pathways as an evasion mechanism. Factor H (FH) is a negative regulator of the complement alternative pathway that protects "self" cells of the host from non-specific complement attack. FH has been shown to bind viruses including human influenza A viruses (IAVs). In addition to its involvement in the regulation of complement activation, FH has also been shown to perform a range of functions on its own including its direct interaction with pathogens. Here, we show that human FH can bind directly to IAVs of both human and avian origin, and the interaction is mediated via the IAV surface glycoprotein haemagglutinin (HA). HA bound to common pathogen binding footprints on the FH structure, complement control protein modules, CCP 5-7 and CCP 15-20. The FH binding to H1 and H3 showed that the interaction overlapped with the receptor binding site of both HAs, but the footprint was more extensive for the H3 HA than the H1 HA. The HA - FH interaction impeded the initial entry of H1N1 and H3N2 IAV strains but its impact on viral multicycle replication in human lung cells was strain-specific. The H3N2 virus binding to cells was significantly inhibited by preincubation with FH, whereas there was no alteration in replicative rate and progeny virus release for human H1N1, or avian H9N2 and H5N3 IAV strains. We have mapped the interaction between FH and IAV, the in vivo significance of which for the virus or host is yet to be elucidated.

RNA m5C methylation: a potential modulator of innate immune pathways in hepatocellular carcinoma.

RNA 5-methylcytosine (m5C) methylation plays a crucial role in hepatocellular carcinoma (HCC). As reported, aberrant m5C methylation is closely associated with the progression, therapeutic efficacy, and prognosis of HCC. The innate immune system functions as the primary defense mechanism in the body against pathogenic infections and tumors since it can activate innate immune pathways through pattern recognition receptors to exert anti-infection and anti-tumor effects. Recently, m5C methylation has been demonstrated to affect the activation of innate immune pathways including TLR, cGAS-STING, and RIG-I pathways by modulating RNA function, unveiling new mechanisms underlying the regulation of innate immune responses by tumor cells. However, research on m5C methylation and its interplay with innate immune pathways is still in its infancy. Therefore, this review details the biological significance of RNA m5C methylation in HCC and discusses its potential regulatory relationship with TLR, cGAS-STING, and RIG-I pathways, thereby providing fresh insights into the role of RNA methylation in the innate immune mechanisms and treatment of HCC.

Construction of a hydrophilic porphyrin-based MOF@COF hybrid via post-synthetic modification for N-glycopeptides analysis in human serum.

A hybrid material, M@C-Br@GMA@Glu, consisting of a porphyrin-based metal-organic framework-covalent organic framework (MOF@COF), has been meticulously synthesized using a post-synthetic modification approach. This advanced material has demonstrated exceptional effectiveness in glycopeptide enrichment, characterized by an impressively low detection limit (0.2 fmol μL-1), high selectivity (1 : 2000), and loading capacity for glycopeptides (100 mg g-1). In practical applications with complex biological samples, 210 glycopeptides associated with 87 glycoproteins from the serum of the healthy group, and 156 glycopeptides related to 85 glycoproteins from the serum of cervical cancer were identified after enrichment with M@C-Br@GMA@Glu. Subsequent genetic ontology analysis has elucidated the relationship between cervical cancer and glycosylation, focusing on biological processes such as complement activation, innate immune response mechanisms, and the structural dynamics of the extracellular matrix. The collective findings not only validate the material's proficiency in the sensitive and selective enrichment of glycopeptides, but also underscore its potential in biomarker discovery applications.

How underappreciated autoinflammatory (innate immunity) mechanisms dominate disparate autoimmune disorders.

Historically inflammation against self was considered autoimmune which stems back to the seminal observations by Ehrlich who described serum factors, now known to be autoantibodies produced by B lineage cells that mediate "horror autotoxicus". The 20th century elucidation of B- and T-cell adaptive immune responses cemented the understanding of the key role of adaptive immune responses in mediating pathology against self. However, Mechnikov shared the Nobel Prize for the discovery of phagocytosis, the most rudimentary aspect of innate immunity. Fast forward some 100 years and an immunogenetic understanding of innate immunity led to the categorising of innate immunopathology under the umbrella term 'auto inflammation' and terminology such as "horror autoinflammaticus" to highlight the schism from the classical adaptive immune understanding of autoimmunity. These concepts lead to calls for a two-tiered classification of inflammation against self, but just as innate and adaptive immunity are functionally integrated, so is immunopathology in many settings and the concept of an autoimmune to autoinflammation continuum emerged with overlaps between both. Herein we describe several historically designated disorders of adaptive immunity where innate immunity is key, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) where the immunopathology phenotype is strongly linked to major histocompatibility complex (MHC) class II associations and responds to drugs that target T-cells. We also consider MHC-I-opathies including psoriasis and Behcet's disease(BD) that are increasingly viewed as archetype CD8 T-cell related disorders. We also briefly review the key role of barrier dysfunction in eczema and ulcerative colitis (UC) where innate tissue permeability barrier dysfunction and microbial dysbiosis contributes to prominent adaptive immune pathological mechanisms. We also highlight the emerging roles of intermediate populations of lymphocytes including gamma delta (γδ) and mucosal-associated invariant T (MAIT) cells that represent a blend of adaptive immune plasticity and innate immune rapid responders that may also determine site specific patterns of inflammation.

Lipoteichoic Acids Are Essential for Pneumococcal Colonization and Membrane Integrity.

The hydrophilic, polymeric chain of the lipoteichoic acid (LTA) of the Gram-positive pathobiont Streptococcus pneumoniae is covalently linked to the glycosylglycerolipid α-<sc>d</sc>-glucopyranosyl-(1,3)-diacylglycerol by the LTA ligase TacL, leading to its fixation in the cytoplasmic membrane. Pneumococcal LTA, sharing identical repeating units with the wall teichoic acids (WTA), is dispensable for normal growth but required for full virulence in invasive infections. Mutants deficient in TacL and complemented strains constructed were tested for their growth, resistance against oxidative stress, and susceptibility against antimicrobial peptides. Further, the membrane fluidity of pneumococci, their capability to adhere to lung epithelial cells, and virulence in a Galleria mellonella as well as intranasal mouse infection model were assessed. In the present study, we indicate that LTA is already indispensable for pneumococcal adherence to human nasopharyngeal cells and colonization in an intranasal mouse infection model. Mutants deficient for TacL did not show morphological defects. However, our analysis of pneumococcal membranes in different serotypes showed an altered membrane fluidity and surface protein abundance of lipoproteins in mutants deficient for LTA but not WTA. These mutants had a decreased membrane fluidity, exhibited higher amounts of lipoproteins, and showed an increased susceptibility to antimicrobial peptides. In complemented mutant strains, this defect was fully restored. Taken together, LTA is crucial for colonization and required to effectively protect pneumococci from innate immune defence mechanisms by maintaining the membrane integrity.

Proteomic analysis of crocodile white blood cells reveals insights into the mechanism of the innate immune system

Crocodiles have a particularly powerful innate immune system because their blood contains high levels of antimicrobial peptides. They can survive injuries that would be fatal to other animals, and they are rarely afflicted with diseases. To better understand the crocodile’s innate immune response, proteomic analysis was performed on the white blood cells (WBC) of an Aeromonas hydrophila-infected crocodile. Levels of WBC and red blood cells (RBC) rapidly increased within 1 h. In WBC, there were 109 up-regulated differentially expressed proteins (DEP) that were up-regulated. Fifty-nine DEPs dramatically increased expression from 1 h after inoculation, whereas 50 up-regulated DEPs rose after 24 h. The most abundant DEPs mainly had two biological functions, 1) gene expression regulators, for example, zinc finger proteins and histone H1 family, and 2) cell mechanical forces such as actin cytoskeleton proteins and microtubule-binding proteins. This finding illustrates the characteristic effective innate immune response mechanism of crocodiles that might occur via boosted transcription machinery proteins to accelerate cytoskeletal protein production for induction of phagocytosis, along with the increment of trafficking proteins to transport essential molecules for combating pathogens. The findings of this study provide new insights into the mechanisms of the crocodile’s innate immune system.

Immunomodulatory properties of bacteriophage derived dsRNA of different size and their use as anticancer vaccine adjuvants

Dendritic cell (DC) based immunotherapy is one of the strategies to combat cancer invoking a patient's immune system. This form of anticancer immunotherapy employs adjuvants to enhance the immune response, triggering mechanisms of innate immunity and thus increase immunotherapeutic efficiency. A conventional adjuvant for DCs maturation during production of anticancer vaccines is bacterial LPS. Nevertheless, synthetic dsRNAs were also shown to stimulate different receptors on innate immune cells and to activate immune responses through induction of cytokines via toll-like receptors. In our study we investigated the potential of Larifan as dsRNA of natural origin to stimulate maturation of DCs with proinflammatory (possible antitumoral) activity and to compare these immunostimulatory properties between Larifan’s fractions with different molecular lengths. To explore the suitability of this product for therapy, it is necessary to study the properties of its different fractions and compare them to standard adjuvants. We investigated the effect of Larifan’s fractions on immune system stimulation in vivo by monitoring the survival time of tumor-bearing mice. Murine DCs produced in vitro using Larifan and its fractions together with tumor antigens during production were also characterized. All Larifan fractions resulted in inducing high expression of immunogenic markers CD40, CD80, CD86, CCR7, MHC II and lower secretion of the immunosuppressive cytokine IL-10, compared to the maturation with LPS in mDCs. The lowest expression of tolerogenic gene Ido1 and highest expression of the immunogenic genes Clec7a, Tnf, Icosl, Il12rb2, Cd209a were characteristic to the unfractionated dsRNA and short fraction FR15. In the mouse model the best overall survival rate was observed in mice treated with medium-length FR9 and FR15. We can state that both Larifan and its fractions were superior to LPS as vaccine adjuvants in stimulating phenotype and functional activity of mature DCs. DCs maturation using these factors induces a valuable anticancer immune response.

Dynamics and Regulatory Mechanisms of Innate Immunity and CD8 T Cells Synergy in Response to Viral Infections

Dynamics and Regulatory Mechanisms of Innate Immunity and CD8 T Cells Synergy in Response to Viral Infections

Adaptation of SIVmac to baboon primary cells results in complete absence of in vivo baboon infectivity.

While simian immunodeficiency virus (SIV) infection is non-pathogenic in naturally infected African nonhuman primate hosts, experimental or accidental infection in rhesus macaques often leads to AIDS. Baboons, widely distributed throughout Africa, do not naturally harbor SIV, and experimental infection of baboons with SIVmac results in transient low-level viral replication. Elucidation of mechanisms of natural immunity in baboons could uncover new targets of antiviral intervention. We tested the hypothesis that an SIVmac adapted to replicate in baboon primary cells will gain the capacity to establish chronic infections in vivo. Here, we generated SIVmac variants in baboon cells through serial passage in PBMC from different donors (SIVbn-PBMC s1), in PBMC from the same donors (SIVbn-PBMC s2), or in isolated CD4 cells from the same donors used for series 2 (SIVbn-CD4). While SIVbn-PBMC s1 and SIVbn-CD4 demonstrated increased replication capacity, SIVbn-PBMC s2 did not. Pharmacological blockade of CCR5 revealed SIVbn-PBMC s1 could more efficiently use available CCR5 than SIVmac, a trait we hypothesize arose to circumvent receptor occupation by chemokines. Sequencing analysis showed that all three viruses accumulated different types of mutations, and that more non-synonymous mutations became fixed in SIVbn-PBMC s1 than SIVbn-PBMC s2 and SIVbn-CD4, supporting the notion of stronger fitness pressure in PBMC from different genetic backgrounds. Testing the individual contribution of several newly fixed SIV mutations suggested that is the additive effect of these mutations in SIVbn-PBMC s1 that contributed to its enhanced fitness, as recombinant single mutant viruses showed no difference in replication capacity over the parental SIVmac239 strain. The replicative capacity of SIVbn-PBMC passage 4 (P4) s1 was tested in vivo by infecting baboons intravenously with SIVbn-PBMC P4 s1 or SIVmac251. While animals infected with SIVmac251 showed the known pattern of transient low-level viremia, animals infected with SIVbn-PBMC P4 s1 had undetectable viremia or viral DNA in lymphoid tissue. These studies suggest that adaptation of SIV to grow in baboon primary cells results in mutations that confer increased replicative capacity in the artificial environment of cell culture but make the virus unable to avoid the restrictive factors generated by a complex multicellular organism.