Persistent immune activation and inflammation despite sustained antiretroviral therapy (ART)-mediated viral suppression has emerged as a major challenge of the modern HIV treatment era. While immune ...activation, inflammatory, and coagulation markers typically decline during suppressive ART, they remain abnormally elevated in many HIV-infected individuals and predict subsequent mortality and non-AIDS morbidities including cardiovascular disease. The goal of this review is to summarize the current state of our knowledge regarding the underlying causes of persistent immune activation during ART-mediated viral suppression as well as the link between persistent immune activation and morbidity and mortality in this setting. Several recent studies have linked surrogate markers of this persistent inflammatory state to clinical outcomes, validating persistent immune activation as a viable therapeutic target. Other recent studies have helped clarify the roles of persistent HIV expression and/or replication, microbial translocation, and co-infections in driving this persistent inflammatory state, identifying targets for novel interventions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, ...whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression.
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•In HIV-infected Ugandans, low CD4 T cells were linked to enteric adenovirus expansion•Low CD4 T cell numbers were also associated with alterations in the bacterial microbiome•These changes in the virome and bacterial microbiome were independent of ART treatment•These changes may contribute to AIDS-associated enteropathy and disease progression
Monaco et al. characterize the enteric virome and bacterial microbiome in an HIV-infected Ugandan patient cohort. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and bacterial microbiome alterations, including increases in Enterobacteriaceae, each of which may contribute to AIDS-associated enteropathy and disease progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
IMPORTANCE: The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary ...because the majority of the patients had estrogen receptor–positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology). OBJECTIVE: To determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women treated with axillary dissection. DESIGN, SETTING, AND PARTICIPANTS: The ACOSOG Z0011 phase 3 randomized clinical trial enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011 (Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases. INTERVENTIONS: All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was disease-free survival. RESULTS: Among 891 women who were randomized (median age, 55 years), 856 (96%) completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median follow-up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was 86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 1-sided 95% CI, 0-1.16; noninferiority P = .02). The 10-year disease-free survival was 80.2% in the SLND alone group and 78.2% in the ALND group (HR, 0.85 95% CI, 0.62-1.17; P = .32). Between year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups. CONCLUSIONS AND RELEVANCE: Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003855
Although invasive cytomegalovirus (CMV) disease is uncommon in the era of antiretroviral therapy (ART), asymptomatic CMV coinfection is nearly ubiquitous in HIV infected individuals. While microbial ...translocation and gut epithelial barrier dysfunction may promote persistent immune activation in treated HIV infection, potentially contributing to morbidity and mortality, it has been unclear whether CMV replication in individuals with no symptoms of CMV disease might play a role in this process. We hypothesized that persistent CMV replication in the intestinal epithelium of HIV/CMV-coinfected individuals impairs gut epithelial barrier function. Using a combination of state-of-the-art in situ hybridization technology (RNAscope) and immunohistochemistry, we detected CMV DNA and proteins and evidence of intestinal damage in rectosigmoid samples from CMV-positive individuals with both untreated and ART-suppressed HIV infection. Two different model systems, primary human intestinal cells differentiated in vitro to form polarized monolayers and a humanized mouse model of human gut, together demonstrated that intestinal epithelial cells are fully permissive to CMV replication. Independent of HIV, CMV disrupted tight junctions of polarized intestinal cells, significantly reducing transepithelial electrical resistance, a measure of monolayer integrity, and enhancing transepithelial permeability. The effect of CMV infection on the intestinal epithelium is mediated, at least in part, by the CMV-induced proinflammatory cytokine IL-6. Furthermore, letermovir, a novel anti-CMV drug, dampened the effects of CMV on the epithelium. Together, our data strongly suggest that CMV can disrupt epithelial junctions, leading to bacterial translocation and chronic inflammation in the gut and that CMV could serve as a target for therapeutic intervention to prevent or treat gut epithelial barrier dysfunction during HIV infection.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite marked improvements in the modern treatment era, human immunodeficiency virus (HIV)-infected individuals, particularly those who initiated antiretroviral therapy (ART) at advanced disease ...stages, continue to have increased age-related morbidity and mortality, compared with the general population. Immune activation and inflammation persist despite suppressive ART and predict many of these morbidities. The goal of this review is to examine the evidence suggesting a link between the persistent inflammatory state and morbidity and mortality in this setting, to describe the impact of early ART initiation on these factors, and to highlight important unanswered questions for the field. We also advance a hypothesis to explain why some morbidities—and their root inflammatory drivers—may be prevented more than others by early ART initiation.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Translational research is often conceptualized with an implicit directionality, taking an idea generated in the laboratory (ie, the "bench") and applying it at the point of care (ie, the "bedside"). ...This role is often played by physician-scientists who work both in the laboratory and in the clinic. Less well appreciated is the valuable role a physician-scientist can play by using compelling observations from clinical research studies to guide basic scientists toward clinically important problems and even novel scientific concepts. The goal of this editorial is to highlight this often overlooked role that clinical-translational physician-scientists can play in translating observations at the bedside to efforts at the bench, highlighting their importance for scientific progress and discussing the type of research training and scientific environments that can help these individuals flourish. The importance of cohort studies and multidisciplinary team science in this context will also be highlighted.
The source and dynamics of persistent HIV-1 during long-term combinational antiretroviral therapy (cART) are critical to understanding the barriers to curing HIV-1 infection. To address this issue, ...we isolated and genetically characterized HIV-1 DNA from naïve and memory T cells from peripheral blood and gut-associated lymphoid tissue (GALT) from eight patients after 4–12 y of suppressive cART. Our detailed analysis of these eight patients indicates that persistent HIV-1 in peripheral blood and GALT is found primarily in memory CD4 ⁺ T cells CD45RO ⁺/CD27(⁺/⁻). The HIV-1 infection frequency of CD4 ⁺ T cells from peripheral blood and GALT was higher in patients who initiated treatment during chronic compared with acute/early infection, indicating that early initiation of therapy results in lower HIV-1 reservoir size in blood and gut. Phylogenetic analysis revealed an HIV-1 genetic change between RNA sequences isolated before initiation of cART and intracellular HIV-1 sequences from the T-cell subsets after 4–12 y of suppressive cART in four of the eight patients. However, evolutionary rate analyses estimated no greater than three nucleotide substitutions per gene region analyzed during all of the 4–12 y of suppressive therapy. We also identified a clearly replication-incompetent viral sequence in multiple memory T cells in one patient, strongly supporting asynchronous cell replication of a cell containing integrated HIV-1 DNA as the source. This study indicates that persistence of a remarkably stable population of infected memory cells will be the primary barrier to a cure, and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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•Haemonchus contortus has significantly changed its distribution in Australia over the past 70years.•Inhibition of H. contortus L4s over winter has largely been abolished by more ...effective anthelmintics.•Inhibition of H. contortus L4s over winter has resulted in the advent of yearly rather than seasonal haemonchosis.•Customised on-farm control and monitoring programmes should arise from rapid advances in H. contortus genomics.
Haemonchus contortus (Barber’s pole worm or “BPW”) is the nematode “nemesis” of small ruminant production systems in tropical and subtropical regions of the world. Its reputation derives from a combination of high fecundity and a short generational interval that provides an enviable developmental plasticity for adaptation or resistance to control measures. This review critically examines the historical and current literature on the host–parasite–environment interaction for H. contortus, particularly in sheep, to highlight changes in parasite distribution and ecology on pasture, changes to the seasonal inhibition of fourth stage larvae and the most appropriate models to identify protective responses and assess vaccines. The review also proposes pathways to bring host genetics to fruition and avenues where advances in the parasite genome may complement control measures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
BACKGROUNDThe presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized ...postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.METHODSIn a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.RESULTSWe observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).CONCLUSIONOverall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.TRIAL REGISTRATIONLong-term Impact of Infection with Novel Coronavirus; ClinicalTrials.gov NCT04362150.FUNDINGThis work was supported by NIH/National Institute of Allergy and Infectious Diseases grants (3R01AI141003-03S1, R01AI158013, and K24AI145806); the Zuckerberg San Francisco General Hospital Department of Medicine and Division of HIV, Infectious Diseases, and Global Medicine; and the UCSF-Bay Area Center for AIDS Research (P30-AI027763).
The American College of Surgeons Oncology Group trial Z0011 was a prospective, randomized, multicenter trial comparing overall survival between patients with positive sentinel lymph nodes (SLNs) who ...did and did not undergo axillary lymph node dissection (ALND). The current study compares complications associated with SLN dissection (SLND) plus ALND, versus SLND alone.
From May 1999 to December 2004, 891 patients were randomly assigned to SLND + ALND (n = 445) or SLND alone (n = 446). Information on wound infection, axillary seroma, paresthesia, brachial plexus injury (BPI), and lymphedema was available for 821 patients.
Adverse surgical effects were reported in 70% (278 of 399) of patients after SLND + ALND and 25% (103 of 411) after SLND alone (P <or= .001). Patients in the SLND + ALND group had more wound infections (P <or= .0016), seromas (P <or= .0001), and paresthesias (P <or= .0001) than those in the SLND-alone group. At 1 year, lymphedema was reported subjectively by 13% (37 of 288) of patients after SLND + ALND and 2% (six of 268) after SLND alone (P <or= .0001). The difference between the two groups' lymphedema, assessed by arm measurements at 30 days (P = .36), 6 months (P = .22), and 1 year (P = .078), although close to the cutoff for significance at 1 year, was not significant. BPIs occurred in less than 1% of patients.
In trial Z0011, the use of SLND + ALND resulted in more wound infections, axillary seromas, and paresthesias than SLND alone. Lymphedema was more common after SLND + ALND but was significantly different only by subjective report. The use of SLND alone resulted in fewer complications.
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