Suboptimal response to tumor necrosis factor antagonists in inflammatory bowel disease in Latin America: EXPLORE LATAM study.

OBJECTIVE: Data on anti-tumor necrosis factor (anti-TNF) treatment and suboptimal response (SOR) among patients with inflammatory bowel diseases (IBD) in Latin America (LATAM) are scarce. This study evaluated the incidence and indicators of SOR to anti-TNF therapy in patients with ulcerative colitis (UC) and Crohn's disease (CD) from Argentina, Colombia and Mexico. PATIENTS AND METHODS: We performed retrospective analysis of data from LATAM patients of the EXPLORE study (NCT03090139) including adult patients with IBD who initiated anti-TNF therapy between March 2010 to March 2015. The cumulative incidence of SOR to first-line anti-TNF therapy was assessed. A physician survey to assess barriers to anti-TNF therapies was also carried out. RESULTS: We included 185 IBD patients (UC/CD: 99/86) treated with first-line anti-TNF from Argentina (38 UC; 40 CD), Colombia (21 UC; 25 CD) and Mexico (40 UC; 21 CD). 36.4% of patients with UC and 46.5% of patients with CD experienced SOR to anti-TNF therapy during the median (interquartile range) observational period: 49.0 months (37.2-60.1) in UC, and 50.0 months (40.9-60.1) in CD. The most common indicator of SOR among patients was augmentation of non-biologic therapy (UC: 41.7%; CD: 35.0%). Affordability and late referral to IBD specialist care centers were the most common barriers to anti-TNF therapies. CONCLUSIONS: SOR to anti-TNF therapy was common in LATAM IBD patients, where augmentation with non-biologic therapy represented the most frequent indicator of SOR across indications. Our findings contribute to the current evidence on the unmet needs associated with anti-TNF in LATAM.

Real-world experience of vedolizumab use in Colombian patients with inflammatory bowel disease-EXVEDOCOL.

BACKGROUND: Real-world studies about the effectiveness and safety of vedolizumab (VDZ) in the treatment of inflammatory bowel disease (IBD) in Latin America are scarce. Our study describes the effectiveness and safety of VDZ in Colombian patients with IBD. METHODS: EXVEDOCOL (EXperience of VEDOlizumab in COLombia) was a retrospective, multicenter, observational study. Adults with IBD receiving a first dose of VDZ between July 2016 and October 2018 were included. The co-primary outcomes clinical response, and remission, were determined at week 14 and last visit during the maintenance phase (LVMP). The secondary outcomes, deep remission and loss of response were recorded at LVMP. RESULTS: Thirty-one patients (25 ulcerative colitis (UC), 6 Crohn's disease (CD)) were included. At week 14, clinical response was achieved by 87.1% (27/31) of the patients treated with VDZ, while loss of response was reported in 6.7% (2/30). The remission rate at week 14 was 65.5% (19/29) and 75.9% (22/29) at LVMP. Prior anti-TNF exposure was reported in 61.3% (19 patients) of whom 84.2% (16/19) achieved clinical response at week 14 and 89.5% (17/19) at LVMP. For anti-TNF naïve patients, clinical response was recorded in 91.7% (11/12) at week 14 and 100% (12/12) at LVMP. CONCLUSIONS: High clinical remission rates and safety profile highlight VDZ as a valuable treatment option for IBD patients. Anti-TNF naïve patients may derive greater benefit from therapy. Studies with larger cohorts could confirm these findings.

Herpes Simplex Virus 1 Spread in Oligodendrocytic Cells Is Highly Dependent on MAL Proteolipid.

Myelin and lymphocyte protein (MAL) is a tetraspan integral membrane protein that resides in detergent-insoluble membrane fractions enriched in condensed membranes. MAL is expressed in oligodendrocytes, in Schwann cells, where it is essential for the stability of myelin, and at the apical membrane of epithelial cells, where it has a critical role in transport. In T lymphocytes, MAL is found at the immunological synapse and plays a crucial role in exosome secretion. However, no involvement of MAL in viral infections has been reported so far. Here, we show that herpes simplex virus 1 (HSV-1) virions travel in association with MAL-positive structures to reach the end of cellular processes, which contact uninfected oligodendrocytes. Importantly, the depletion of MAL led to a significant decrease in infection, with a drastic reduction in the number of lytic plaques in MAL-silenced cells. These results suggest a significant role for MAL in viral spread at cell contacts. The participation of MAL in the cell-to-cell spread of HSV-1 may shed light on the involvement of proteolipids in this process.IMPORTANCE Herpes simplex virus 1 (HSV-1) is a neurotropic pathogen that can infect many types of cells and establish latent infections in neurons. HSV-1 may spread from infected to uninfected cells by two main routes: by cell-free virus or by cell-to-cell spread. In the first case, virions exit into the extracellular space and then infect another cell from the outside. In the second case, viral transmission occurs through cell-to-cell contacts via a mechanism that is still poorly understood. A third mode of spread, using extracellular vesicles, also exists. In this study, we demonstrate the important role for a myelin protein, myelin and lymphocyte protein (MAL), in the process of cell-to-cell viral spread in oligodendrocytes. We show that MAL is involved in trafficking of virions along cell processes and that MAL depletion produces a significant alteration in the viral cycle, which reduces cell-to cell spread of HSV-1.

Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3.

PURPOSE: Variants in genes encoding sarcomeric proteins are the most common cause of inherited cardiomyopathies. However, the underlying genetic cause remains unknown in many cases. We used exome sequencing to reveal the genetic etiology in patients with recessive familial cardiomyopathy. METHODS: Exome sequencing was carried out in three consanguineous families. Functional assessment of the variants was performed. RESULTS: Affected individuals presented with hypertrophic or dilated cardiomyopathy of variable severity from infantile- to early adulthood-onset and sudden cardiac death. We identified a homozygous missense substitution (c.170C>A, p.[Ala57Asp]), a homozygous translation stop codon variant (c.106G>T, p.[Glu36Ter]), and a presumable homozygous essential splice acceptor variant (c.482-1G>A, predicted to result in skipping of exon 5). Morpholino knockdown of the MYL3 orthologue in zebrafish, cmlc1, resulted in compromised cardiac function, which could not be rescued by reintroduction of MYL3 carrying either the nonsense c.106G>T or the missense c.170C>A variants. Minigene assay of the c.482-1G>A variant indicated a splicing defect likely resulting in disruption of the EF-hand Ca2+ binding domains. CONCLUSIONS: Our data demonstrate that homozygous MYL3 loss-of-function variants can cause of recessive cardiomyopathy and occurrence of sudden cardiac death, most likely due to impaired or loss of myosin essential light chain function.

Are There Ideal Small Bowel Limb Lengths for One-Anastomosis Gastric Bypass (OAGB) to Obtain Optimal Weight Loss and Remission of Comorbidities with Minimal Nutritional Deficiencies?

BACKGROUND: Ideal jejunal and ileal lengths in bariatric/metabolic procedures to be left in alimentary continuity still remain unclear. We aimed to evaluate different lengths of biliopancreatic limb (BPL) and common limb (CL) performed in a series of patients submitted to OAGB, and correlate them with weight loss and nutritional deficits. PATIENTS AND METHODS: A prospective observational study of 350 consecutive morbidly obese patients undergoing OAGB was performed. BPL and CL lengths were determined intraoperatively; BPL/TBL and CL/TBL ratios were then calculated. Anthropometric variables, remission of comorbidities and specific supplementation needs were recorded at 1, 2 and 5 years after surgery. RESULTS: Three hundred patients were included for final analysis. BPL length and BPL/TBL ratio directly correlated with Units of BMI lost (UBMIL). Conversely, CL length and CL/TBL ratio showed an inverse correlation with UBMIL. Establishing a BMI ≤ 25 kg/m2 as ideal, the most accurate AUC, to predict achieving an ideal BMI at 1, 2 and 5 years after surgery, was obtained for the CL/TBL ratio, followed by the CL length at 1, 2 and 5 years. An ideal range was established between 0.40 and 0.43 for the CL/TBL ratio, and 200 to 220 cm for the CL length. Among these ranges, there were no cases of protein or calorie malnutrition. CONCLUSION: TBL measurement is essential to obtain optimal outcomes after OAGB, both in terms of excellent weight loss and remission/improvement of comorbidities, as well as with a low risk of nutritional deficiencies. The CL/TBL ratio, followed by CL length, are the most accurate parameters to predict a 5-year postoperative BMI ≤ 25 kg/m2.

[Endoscopic-radiologic rendezvous for biliary obstruction management. Case report and literature review]. / Rendezvous radiológico-endoscópico para manejo de obstrucción biliar. Reporte de casos y revisión de la literatura.

Biliary obstruction of different origin is a common clinical problem, with significant impact on the patients quality of life and poses a permanent risk of cholangitis. The management of these patients has evolved over time, makes collection of various technological developments and involve clinicians, surgeons, gastroenterologists, and interventional radiologists. Were port four cases of biliary obstruction that despite the significant demographic and clinical differences between them could be successfully managed approach in the biliary tract with the technique of radiological endoscopic Rendezvous.

[Colonic metastases from carcinoma of the lung, an unusual presentation. Case report and literature review]. / Metástasis a colon de un carcinoma de pulmón, una presentación inusual. Reporte de un caso y revisión de la literatura.

The symptomatic metastasis of the colon from a pulmonary cancer is rare; however, the global incidence of pulmonary cancer is 12.9%. It is an infrequent site of metastasis, with a prevalence of less than 0.5% in patients with pulmonary cancer. One of the most common manifestation is intestinal obstruction. We present a case report of a patient with an acute lower intestinal bleeding from multiple metastasis lesion of the colon as the initial manifestation of a non-small cell lung carcinoma.

Weight loss and improvement of lipid profiles in morbidly obese patients after laparoscopic one-anastomosis gastric bypass: 2-year follow-up.

BACKGROUND: Obesity is the most frequent chronic metabolic disease globally. There is a direct correlation between increasing body mass index (BMI) and elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL), and triglycerides (Tg), and an inverse correlation with high-density lipoprotein cholesterol (HDL); all these lipid derangements are associated with an increased risk of cardiovascular disease. Our aim was to evaluate lipid profiles in morbidly obese patients before and after one-anastomosis gastric bypass (OAGB) performed at a single-center during a 2-year follow-up. PATIENTS AND METHODS: A prospective, observational and descriptive study was carried out, including morbidly obese patients with at least one lipid abnormality, who underwent laparoscopic OAGB. Lipid profiles were evaluated preoperatively and at different intervals during a 2-year follow-up. RESULTS: A total of 150 patients were included (73 % females and 27 % males). Mean age was 45.83 ± 10.65 years, mean BMI was 42.82 kg/m2 ± 6.43, and mean weight was 116.23 kg ± 22.70; 2 years after surgery, the latter two decreased to 24.73 ± 4.43 (p < 0.001) and 67.34 ± 13.35 (p < 0.001), respectively, thus leading to a mean weight loss (WL) of 48.85 kg ± 15.64 and mean %excess WL of 71.87 ± 13.41. Tg, TC and LDL levels significantly decreased: 123.60 ± 56.34 versus 84.79 ± 33.67, 194.33 ± 43.90 versus 173.65 ± 34.84, and 124.47 ± 36.07 versus 97.36 ± 25.05, respectively (p < 0.001); HDL levels significantly increased: 43.61 ± 9.85 versus 61.56 ± 12.63 (p < 0.001). CONCLUSION: OAGB leads to substantial and durable WL in morbidly obese patients after a 2-year follow-up. Postoperative lipid profiles significantly improved; these changes translate into theoretical relevant cardiovascular risk benefits.

Identification and spontaneous immune targeting of an endogenous retrovirus K envelope protein in the Indian rhesus macaque model of human disease.

BACKGROUND: Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections that have invaded the germ line of both humans and non-human primates. Most ERVs are functionally crippled by deletions, mutations, and hypermethylation, leading to the view that they are inert genomic fossils. However, some ERVs can produce mRNA transcripts, functional viral proteins, and even non-infectious virus particles during certain developmental and pathological processes. While there have been reports of ERV-specific immunity associated with ERV activity in humans, adaptive immune responses to ERV-encoded gene products remain poorly defined and have not been investigated in the physiologically relevant non-human primate model of human disease. FINDINGS: Here, we identified the rhesus macaque equivalent of the biologically active human ERV-K (HML-2), simian ERV-K (SERV-K1), which retains intact open reading frames for both Gag and Env on chromosome 12 in the macaque genome. From macaque cells we isolated a spliced mRNA product encoding SERV-K1 Env, which possesses all the structural features of a canonical, functional retroviral Envelope protein. Furthermore, we identified rare, but robust T cell responses as well as frequent antibody responses targeting SERV-K1 Env in rhesus macaques. CONCLUSIONS: These data demonstrate that SERV-K1 retains biological activity sufficient to induce cellular and humoral immune responses in rhesus macaques. As ERV-K is the youngest and most active ERV family in the human genome, the identification and characterization of the simian orthologue in rhesus macaques provides a highly relevant animal model in which to study the role of ERV-K in developmental and disease states.

Tertiary mutations stabilize CD8+ T lymphocyte escape-associated compensatory mutations following transmission of simian immunodeficiency virus.

Compensatory mutations offset fitness defects resulting from CD8(+) T lymphocyte (CD8(TL))-mediated escape, but their impact on viral evolution following transmission to naive hosts remains unclear. Here, we investigated the reversion kinetics of Gag(181-189)CM9 CD8(TL) escape-associated compensatory mutations in simian immunodeficiency virus (SIV)-infected macaques. Preexisting compensatory mutations did not result in acute-phase escape of the SIVmac239 CD8(TL) epitope Gag(181-189)CM9 and instead required a tertiary mutation for stabilization in the absence of Gag(181-189)CM9 escape mutations. Therefore, transmitted compensatory mutations do not necessarily predict rapid CD8(TL) escape.

Reduced systemic levels of IL-10 are associated with the severity of obstructive sleep apnea and insulin resistance in morbidly obese humans.

Obstructive sleep apnea (OSA) has been related to elevation of inflammatory cytokines and development of insulin resistance in morbidly obese (MO) subjects. However, it is still unclear whether the systemic concentration of anti-inflammatory mediators is also affected in MO subjects directly related to the severity of OSA and level of insulin resistance. Normal weight and MO subjects were subjected to overnight polysomnography in order to establish the severity of OSA, according to the apnea-hypopnea index (AHI). Blood samples were obtained for estimation of total cholesterol and triglycerides, insulin, glucose, insulin resistance, tumor necrosis factor alpha (TNF-α), interleukin 12 (IL12), and interleukin 10 (IL-10). Serum levels of IL-10 were significantly lower in MO subjects with OSA than in MO and control individuals without OSA. Besides being inversely associated with serum TNF-α and IL-12, decreased IL-10 levels were significantly related to increased AHI, hyperinsulinemia, and insulin resistance. Serum IL-10 is significantly reduced in morbidly obese subjects with severe OSA while also showing a clear relationship with a state of hyperinsulinemia and insulin resistance probably regardless of obesity in the present sample. It may be of potential clinical interest to identify the stimulatory mechanisms of IL-10 in obese individuals with OSA.

Neutralizing polyclonal IgG present during acute infection prevents rapid disease onset in simian-human immunodeficiency virus SHIVSF162P3-infected infant rhesus macaques.

Simian-human immunodeficiency virus (SHIV) models for human immunodeficiency virus (HIV) infection have been widely used in passive studies with HIV neutralizing antibodies (NAbs) to test for protection against infection. However, because SHIV-infected adult macaques often rapidly control plasma viremia and any resulting pathogenesis is minor, the model has been unsuitable for studying the impact of antibodies on pathogenesis in infected animals. We found that SHIVSF162P3 infection in 1-month-old rhesus macaques not only results in high persistent plasma viremia but also leads to very rapid disease progression within 12 to 16 weeks. In this model, passive transfer of high doses of neutralizing IgG (SHIVIG) prevents infection. Here, we show that at lower doses, SHIVIG reduces both plasma and peripheral blood mononuclear cell (PBMC)-associated viremia and mitigates pathogenesis in infected animals. Moreover, production of endogenous NAbs correlated with lower set-point viremia and 100% survival of infected animals. New SHIV models are needed to investigate whether passively transferred antibodies or antibodies elicited by vaccination that fall short of providing sterilizing immunity impact disease progression or influence immune responses. The 1-month-old rhesus macaque SHIV model of infection provides a new tool to investigate the effects of antibodies on viral replication and clearance, mechanisms of B cell maintenance, and the induction of adaptive immunity in disease progression.

Orofacial Anomalies in Kindler Epidermolysis Bullosa.

Importance: Kindler epidermolysis bullosa is a genetic skin-blistering disease associated with recessive inherited pathogenic variants in FERMT1, which encodes kindlin-1. Severe orofacial manifestations of Kindler epidermolysis bullosa, including early oral squamous cell carcinoma, have been reported. Objective: To determine whether hypoplastic pitted amelogenesis imperfecta is a feature of Kindler epidermolysis bullosa. Design, Settings, and Participants: This longitudinal, 2-center cohort study was performed from 2003 to 2023 at the Epidermolysis Bullosa Centre, University of Freiburg, Germany, and the Special Care Dentistry Clinic, University of Chile in association with DEBRA Chile. Participants included a convenience sampling of all patients with a diagnosis of Kindler epidermolysis bullosa. Main Outcomes and Measures: The primary outcomes were the presence of hypoplastic pitted amelogenesis imperfecta, intraoral wounds, gingivitis and periodontal disease, gingival hyperplasia, vestibular obliteration, cheilitis, angular cheilitis, chronic lip wounds, microstomia, and oral squamous cell carcinoma. Results: The cohort consisted of 36 patients (15 female [42%] and 21 male [58%]; mean age at first examination, 23 years [range, 2 weeks to 70 years]) with Kindler epidermolysis bullosa. The follow-up ranged from 1 to 24 years. The enamel structure was assessed in 11 patients, all of whom presented with enamel structure abnormalities. The severity of hypoplastic pitted amelogenesis imperfecta varied from generalized to localized pitting. Additional orofacial features observed include gingivitis and periodontal disease, which was present in 90% (27 of 30 patients) of those assessed, followed by intraoral lesions (16 of 22 patients [73%]), angular cheilitis (24 of 33 patients [73%]), cheilitis (22 of 34 patients [65%]), gingival overgrowth (17 of 26 patients [65%]), microstomia (14 of 25 patients [56%]), and vestibular obliteration (8 of 16 patients [50%]). Other features included chronic lip ulcers (2 patients) and oral squamous cell carcinoma with lethal outcome (2 patients). Conclusions and Relevance: These findings suggest that hypoplastic pitted amelogenesis imperfecta is a feature of Kindler epidermolysis bullosa and underscore the extent and severity of oral manifestations in Kindler epidermolysis bullosa and the need for early and sustained dental care.

Revision/Conversion Surgeries After One Anastomosis Gastric Bypass-An Experts' Modified Delphi Consensus.

PURPOSE: There is a lack of evidence for treatment of some conditions including complication management, suboptimal initial weight loss, recurrent weight gain, or worsening of a significant obesity complication after one anastomosis gastric bypass (OAGB). This study was designed to respond to the existing lack of agreement and to provide a valuable resource for clinicians by employing an expert-modified Delphi consensus method. METHODS: Forty-eight recognized bariatric surgeons from 28 countries participated in the modified Delphi consensus to vote on 64 statements in two rounds. An agreement/disagreement among ≥ 70.0% of the experts was regarded to indicate a consensus. RESULTS: A consensus was achieved for 46 statements. For recurrent weight gain or worsening of a significant obesity complication after OAGB, more than 85% of experts reached a consensus that elongation of the biliopancreatic limb (BPL) is an acceptable option and the total bowel length measurement is mandatory during BPL elongation to preserve at least 300-400 cm of common channel limb length to avoid nutritional deficiencies. Also, more than 85% of experts reached a consensus on conversion to Roux-en-Y gastric bypass (RYGB) with or without pouch downsizing as an acceptable option for the treatment of persistent bile reflux after OAGB and recommend detecting and repairing any size of hiatal hernia during conversion to RYGB. CONCLUSION: While the experts reached a consensus on several aspects regarding revision/conversion surgeries after OAGB, there are still lingering areas of disagreement. This highlights the importance of conducting further studies in the future to address these unresolved issues.

Production and Characterisation of an Exopolysaccharide by Bacillus amyloliquefaciens: Biotechnological Applications.

The Bacillus amyloliquefaciens RT7 strain was isolated from an extreme acidic environment and identified. The biodegradation capabilities of the strain using different carbon sources (glucose, oleic acid, Tween 80, PEG 200, and the combination of glucose-Tween 80) were evaluated via an indirect impedance technique. The glucose-Tween 80 combination was further studied using nuclear magnetic resonance (NMR). The exopolysaccharide (EPSRT7) that had been produced with the strain when biodegrading glucose-Tween 80 was isolated and characterised using different techniques (GC-MS, HPLC/MSMS, ATR-FTIR, TGA, and DSC), and its molecular weight was estimated. The results show that the average molecular weight of EPSRT7 was approximately 7.0794 × 104 Da and a heteropolysaccharide composed of mannose, glucose, galactose, and xylose (molar ratio, 1:0.5:0.1:0.1) with good thermostability. EPSRT7 showed good emulsifying activity against different natural oils and hydrocarbons at high concentrations (2 mg/mL) and at the studied pH range (3.1-7.2). It also presented good emulsifying activity compared to that of commercial emulsifiers. Lastly, EPSRT7 showed antioxidant capacity for different free radicals, a lack of cytotoxicity, and antioxidant activity at the cellular level. EPSRT7 has promising applications in bioremediation processes and other industrial applications.

Psychometric Correlation of Personality Disorders Along With Defense Mechanisms in Mexican Individuals With Depressive and Anxious Disorders: A Cross-Sectional Study.

Background Personality disorders are a multi-theoretical construct that encompasses predictable and quantifiable behavioral, cognitive, and affective characteristics in individuals. Previous studies underscore the existence of a relationship between personality disorders and defense mechanisms, these being coping styles that arise unconsciously in the face of adversity and that have adaptive purposes. There is evidence that alludes to a connection between pathological personality, defense mechanisms, and their relationship with negative mental health outcomes, such as depressive and anxious symptoms. The objective of this study was to study, psychometrically measure, and associate personality disorders, defense mechanisms, and depressive and anxious symptoms. Methodology A cross-sectional study was conducted on 81 participants with major depressive disorder, generalized anxiety disorder, and panic disorder who received treatment at a tertiary care institution between July 2021 and February 2022. Psychometric instruments were employed to evaluate the study variables, such as the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale (HAM-A), the Personality Diagnostic Questionnaire - Version 4 (PDQ-4) Plus, and the 40-item Defensive Styles Questionnaire (DSQ-40). Results Depressive and anxious symptoms were related to the scores obtained in the Defensive Styles Questionnaire and the Personality Disorders Questionnaire. Some defense mechanisms were positive predictors of the score between these scales. Conclusions There is a relationship between personality traits and defense mechanisms that could influence the development and severity of depressive and anxious psychopathology in this population.

CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller.

BACKGROUND: Virus-specific T cells are critical components in the containment of immunodeficiency virus infections. While the protective role of CD8+ T cells is well established by studies of CD8+ T cell-mediated viral escape, it remains unknown if CD4+ T cells can also impose sufficient selective pressure on replicating virus to drive the emergence of high-frequency escape variants. Identifying a high frequency CD4+ T cell driven escape mutation would provide compelling evidence of direct immunological pressure mediated by these cells. RESULTS: Here, we studied a SIVmac239-infected elite controller rhesus macaque with a 1,000-fold spontaneous increase in plasma viral load that preceded disease progression and death from AIDS-related complications. We sequenced the viral genome pre- and post-breakthrough and demonstrate that CD8+ T cells drove the majority of the amino acid substitutions outside of Env. However, within a region of Gag p27CA targeted only by CD4+ T cells, we identified a unique post-breakthrough mutation, Gag D205E, which abrogated CD4+ T cell recognition. Further, we demonstrate that the Gag p27CA-specific CD4+ T cells exhibited cytolytic activity and that SIV bearing the Gag D205E mutation escapes this CD4+ T cell effector function ex vivo. CONCLUSIONS: Cumulatively, these results confirm the importance of virus specific CD8+ T cells and demonstrate that CD4+ T cells can also exert significant selective pressure on immunodeficiency viruses in vivo during low-level viral replication. These results also suggest that further studies of CD4+ T cell escape should focus on cases of elite control with spontaneous viral breakthrough.

CD8+ T cell escape mutations in simian immunodeficiency virus SIVmac239 cause fitness defects in vivo, and many revert after transmission.

Virus-specific CD8(+) T lymphocytes select for escape mutations in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). To assess the effects of these mutations on viral fitness, we introduced escape mutations into 30 epitopes (bound by five major histocompatibility complex class I [MHC-I] molecules) in three different viruses. Two of these MHC-I alleles are associated with elite control. Two of the three viruses demonstrated reduced fitness in vivo, and 27% of the introduced mutations reverted. These findings suggest that T cell epitope diversity may not be such a daunting problem for the development of an HIV vaccine.

Macaque long-term nonprogressors resist superinfection with multiple CD8+ T cell escape variants of simian immunodeficiency virus.

Human immunodeficiency virus (HIV)-positive individuals can be superinfected with different virus strains. Individuals who control an initial HIV infection are therefore still at risk for subsequent infection with divergent viruses, but the barriers to such superinfection remain unclear. Here we tested long-term nonprogressors' (LTNPs') susceptibility to superinfection using Indian rhesus macaques that express the major histocompatibility complex class I (MHC-I) allele Mamu-B 17, which is associated with control of the pathogenic AIDS virus SIVmac239. The Mamu-B 17-restricted CD8(+) T cell repertoire is focused almost entirely on 5 epitopes. We engineered a series of SIVmac239 variants bearing mutations in 3, 4, or all 5 of these epitopes and used them to serially challenge 2 Mamu-B 17-positive LTNPs. None of the escape variants caused breakthrough replication in LTNPs, although they readily infected Mamu-B 17-negative naive macaques. In vitro competing coculture assays and examination of viral evolution in hosts lacking Mamu-B 17 suggested that the mutant viruses had negligible defects in replicative fitness. Both LTNPs maintained robust immune responses, including simian immunodeficiency virus (SIV)-specific CD8(+) and CD4(+) T cells and neutralizing antibodies. Our results suggest that escape mutations in epitopes bound by "protective" MHC-I molecules may not be sufficient to establish superinfection in LTNPs.