Exosome-mediated PROTAC delivery for treatment of RNA viral infections and zoonosis.

The increase in diseases caused by RNA viruses, such as influenza, severe acute respiratory syndrome-coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS), and Ebola, presents a growing global health challenge as well as the threat of zoonosis. Traditional antiviral treatments are often undermined by fast-mutating viruses, drug resistance, and newly emerging pathogens. Here, we explore proteolysis-targeting chimeras (PROTACs), a novel protein degradation machinery that has the potential to reshape the way in which RNA viral infections can be managed. PROTACs excel at specifically degrading pathogenic proteins, offering a targeted and efficient antiviral strategy. We also investigate the potential of exosome-based diagnostic technologies, which harness cell-derived nanovesicles for non-invasive sampling and early viral infection detection. Addressing the challenge of PROTAC delivery, we introduce a groundbreaking strategy utilizing exosomes to deliver PROTACs with improved precision and as a targeted delivery vehicle. Integrating these innovative strategies provides a novel approach to combat RNA zoonotic viral diseases, paving the way for a new era in antiviral therapy.

Dual RNA-seq Analysis of Patients' Cells and Viral Genome After Measles Infection.

During the infection of a host cell by an infectious agent, a series of gene expression changes occurs as a consequence of host-pathogen interactions. Unraveling this complex interplay is the key for understanding of microbial virulence and host response pathways, thus providing the basis for new molecular insights into the mechanisms of pathogenesis and the corresponding immune response. Dual RNA sequencing (dual RNA-seq) has been developed to simultaneously determine pathogen and host transcriptomes enabling both differential and coexpression analyses between the two partners as well as genome characterization in the case of RNA viruses. Here, we provide a detailed laboratory protocol and bioinformatics analysis guidelines for dual RNA-seq experiments focusing on - but not restricted to - measles virus (MeV) as a pathogen of interest. The application of dual RNA-seq technologies in MeV-infected patients can potentially provide valuable information on the structure of the viral RNA genome and on cellular innate immune responses and drive the discovery of new targets for antiviral therapy.

Host species and geography impact bee-associated RNA virus communities with evidence for isolation by distance in viral populations.

Virus symbionts are important mediators of ecosystem function, yet we know little of their diversity and ecology in natural populations. The alarming decline of pollinating insects in many regions of the globe, especially the European honey bee, Apis mellifera, has been driven in part by worldwide transmission of virus pathogens. Previous work has examined the transmission of known honey bee virus pathogens to wild bee populations, but only a handful of studies have investigated the native viromes associated with wild bees, limiting epidemiological predictors associated with viral pathogenesis. Further, variation among different bee species might have important consequences in the acquisition and maintenance of bee-associated virome diversity. We utilized comparative metatranscriptomics to develop a baseline description of the RNA viromes associated with wild bee pollinators and to document viral diversity, community composition, and structure. Our sampling includes five wild-caught, native bee species that vary in social behavior as well as managed honey bees. We describe 26 putatively new RNA virus species based on RNA-dependent RNA polymerase phylogeny and show that each sampled bee species was associated with a specific virus community composition, even among sympatric populations of distinct host species. From 17 samples of a single host species, we recovered a single virus species despite over 600 km of distance between host populations and found strong evidence for isolation by distance in associated viral populations. Our work adds to the small number of studies examining viral prevalence and community composition in wild bees.

PZR suppresses innate immune response to RNA viral infection by inhibiting MAVS activation in interferon signaling mediated by RIG-I and MDA5.

RNA viral infections seriously endanger human health. Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) suppresses innate immunity against influenza A virus, and pharmacological inhibition of SHP2 provokes hepatic innate immunity. SHP2 binds and catalyzes tyrosyl dephosphorylation of protein zero-related (PZR), but the regulatory effect of PZR on innate immune response to viral infection is unclear. In this study, the transcription and protein level of PZR in host cells were found to be decreased with RNA viral infection, and high level of PZR was uncovered to inhibit interferon (IFN) signaling mediated by RIG-I and MDA5. Through localizing in mitochondria, PZR targeted and interacted with MAVS (also known as IPS-1/VISA/Cardif), suppressing the aggregation and activation of MAVS. Specifically, Y263 residue in ITIM is critical for PZR to exert immunosuppression under RNA viral infection. Moreover, the recruited SHP2 by PZR that modified with tyrosine phosphorylation under RNA viral infection might inhibit phosphorylation activation of MAVS. In conclusion, PZR and SHP2 suppress innate immune response to RNA viral infection through inhibiting MAVS activation. This study reveals the regulatory mechanism of PZR-SHP2-MAVS signal axis on IFN signaling mediated by RIG-I and MDA5, which may provide new sight for developing antiviral drugs.

Gynaecologic and breast cancers in women living with HIV in South Africa: A record linkage study.

Breast and gynaecologic cancers account for approximately half of all cancers diagnosed amongst women in South Africa, many of whom also live with HIV. We aimed to determine the incidence of and risk factors for developing breast and gynaecologic cancers in women living with HIV (WLHIV) in South Africa. This is a longitudinal analysis of the South African HIV Cancer Match study including women aged ≥15 years with two or more HIV-related laboratory tests. We used Cox proportional hazard models to determine the association of Human Papilloma Virus (HPV)-related and hormone-related gynaecologic cancer with patient- and municipal-level characteristics. From 3 447 908 women and 10.5 million years of follow-up, we identified 11 384 incident and 7612 prevalent gynaecologic and breast cancers. The overall crude incidence rate was 108/1 00 000 person-years (pyears) (95% confidence interval [CI]: 106-110), with the highest incidence observed for cervical cancer (70/1 00 000 pyears; 95% CI: 68.5-71.7). Low CD4 cell counts and high HIV RNA viral loads increased the risk of cervical and other HPV-related cancers. Age was associated with both HPV-related and hormone-related cancers. Women accessing health facilities in high socioeconomic position (SEP) municipalities were more likely to be diagnosed with HPV-related cancers and breast cancer than women accessing care in low SEP municipalities. It is important to improve the immunologic status of WLHIV as part of cancer prevention strategies in WLHIV. Cancer prevention and early detection programmes should be tailored to the needs of women ageing with HIV. In addition, SEP disparities in cancer diagnostic services have to be addressed.

Patient Living with Human Immunodeficiency Virus and Depression with High HIV Viral Load Presenting for Evaluation of Root Caries.

A 26-year-old man living with HIV and depression presents with symptoms of tooth sensitivity. His laboratory studies are all within normal limits except for a high viral load. The patient does not require any special dental management protocol and should be treated like other patients, with his laboratory studies reviewed every 6 months to 1 year. HIV is now a chronic medical conditions, with most patients having stable disease if they are compliant with their medications. Universal infection control protocols should be followed for all patients regardless of their HIV status.

Stroke After SARS-CoV-2 mRNA Vaccine: A Nationwide Registry Study.

BACKGROUND: Whether the SARS-CoV-2 mRNA vaccines may cause a transient increased stroke risk is uncertain. METHODS: In a registry-based cohort of all adult residents at December 27, 2020, in Norway, we linked individual-level data on COVID-19 vaccination, positive SARS-CoV-2 test, hospital admissions, cause of death, health care worker status, and nursing home resident status extracted from the Emergency Preparedness Register for COVID-19 in Norway. The cohort was followed for incident intracerebral bleeding, ischemic stroke, and subarachnoid hemorrhage within the first 28 days after the first/second or third dose of mRNA vaccination until January 24, 2022. Stroke risk after vaccination relative to time not exposed to vaccination was assessed by Cox proportional hazard ratio, adjusted for age, sex, risk groups, health care personnel, and nursing home resident. RESULTS: The cohort included 4 139 888 people, 49.8% women, and 6.7% were ≥80 years of age. During the first 28 days after an mRNA vaccine, 2104 people experienced a stroke (82% ischemic stroke, 13% intracerebral hemorrhage, and 5% subarachnoid hemorrhage). Adjusted hazard ratios (95% CI) after the first/second and after the third mRNA vaccine doses were 0.92 (0.85-1.00) and 0.89 (0.73-1.08) for ischemic stroke, 0.81 (0.67-0.98) and 1.05 (0.64-1.71) for intracerebral hemorrhage, and 0.64 (0.46-0.87) and 1.12 (0.57-2.19) for subarachnoid hemorrhage, respectively. CONCLUSIONS: We did not find increased risk of stroke during the first 28 days after an mRNA SARS-CoV-2 vaccine.

Genetic variation characteristics of HA gene of influenza A virus (H3N2) in Guizhou province from 2017 to 2019 / 中国基层医药

Objective:To analyze the genetic variation characteristics of the HA gene of influenza A virus (H3N2) in Guizhou province from 2017 to 2019. Methods:Twenty strains of influenza A virus (H3N2) were randomly selected from 10 network laboratories in Guizhou province for RNA extraction. Reverse transcriptase-polymerase chain reaction and sequencing were performed. The products were analyzed using bioinformatics software.Results:The nucleotide homology of the HA gene of the 20 strains was 97.7%-100%, which was highly homologous to the vaccine strains A/Hong-Kong/4801/2014 recommended by WHO in 2017 and A/Singapore-INFIMH/16-0019/2016 recommended by WHO in 2018, but they were significantly different from the vaccine strain A/Kansas/14/2017 recommended by WHO in 2019. Genetic analysis showed that the 20 strains were divided into two branches, and the strains that were prevalent in 2019 were located in different branches, with marked genetic differences. Key site analysis showed mutations in antigenic determinants A, B, C, and E and mutations in the anterior and posterior walls of receptor binding sites. Key site analysis also showed that there was an increase in the number of glycosylation sites compared with the vaccine strains prevalent in the same year. Genetic distance, antigen sites, and glycosylation sites were slightly different between virus strains prevalent in 2017-2018 and virus strains prevalent in 2019. Conclusion:The HA gene of the influenza A virus subtype H3N2 in Guizhou province from 2017 to 2019 showed heterogeneity and gene mutation, especially in 2019. Therefore, close monitoring of the genetic evolution of the influenza A virus subtype H3N2 is necessary.

Identifying Potential Factors Associated with High HIV viral load in KwaZulu-Natal, South Africa using Multiple Correspondence Analysis and Random Forest Analysis.

BACKGROUND: Sustainable Human Immunodeficiency Virus (HIV) virological suppression is crucial to achieving the Joint United Nations Programme of HIV/AIDS (UNAIDS) 95-95-95 treatment targets to reduce the risk of onward HIV transmission. Exploratory data analysis is an integral part of statistical analysis which aids variable selection from complex survey data for further confirmatory analysis. METHODS: In this study, we divulge participants' epidemiological and biological factors with high HIV RNA viral load (HHVL) from an HIV Incidence Provincial Surveillance System (HIPSS) sequential cross-sectional survey between 2014 and 2015 KwaZulu-Natal, South Africa. Using multiple correspondence analysis (MCA) and random forest analysis (RFA), we analyzed the linkage between socio-demographic, behavioral, psycho-social, and biological factors associated with HHVL, defined as ≥400 copies per m/L. RESULTS: Out of 3956 in 2014 and 3868 in 2015, 50.1% and 41% of participants, respectively, had HHVL. MCA and RFA revealed that knowledge of HIV status, ART use, ARV dosage, current CD4 cell count, perceived risk of contracting HIV, number of lifetime HIV tests, number of lifetime sex partners, and ever diagnosed with TB were consistent potential factors identified to be associated with high HIV viral load in the 2014 and 2015 surveys. Based on MCA findings, diverse categories of variables identified with HHVL were, did not know HIV status, not on ART, on multiple dosages of ARV, with less likely perceived risk of contracting HIV and having two or more lifetime sexual partners. CONCLUSION: The high proportion of individuals with HHVL suggests that the UNAIDS 95-95-95 goal of HIV viral suppression is less likely to be achieved. Based on performance and visualization evaluation, MCA was selected as the best and essential exploration tool for identifying and understanding categorical variables' significant associations and interactions to enhance individual epidemiological understanding of high HIV viral load. When faced with complex survey data and challenges of variables selection in research, exploratory data analysis with robust graphical visualization and reliability that can reveal divers' structures should be considered.

SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells.

BACKGROUND: Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysiology due to difficulty in isolating and culturing human SAN cells. Embryonic stem cells (ESCs) can be a source to derive human SAN-like pacemaker cells for disease modeling. METHODS: We used both a hamster model and human ESC (hESC)-derived SAN-like pacemaker cells to explore the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pacemaker cells of the heart. In the hamster model, quantitative real-time polymerase chain reaction and immunostaining were used to detect viral RNA and protein, respectively. We then created a dual knock-in SHOX2:GFP;MYH6:mCherry hESC reporter line to establish a highly efficient strategy to derive functional human SAN-like pacemaker cells, which was further characterized by single-cell RNA sequencing. Following exposure to SARS-CoV-2, quantitative real-time polymerase chain reaction, immunostaining, and RNA sequencing were used to confirm infection and determine the host response of hESC-SAN-like pacemaker cells. Finally, a high content chemical screen was performed to identify drugs that can inhibit SARS-CoV-2 infection, and block SARS-CoV-2-induced ferroptosis. RESULTS: Viral RNA and spike protein were detected in SAN cells in the hearts of infected hamsters. We established an efficient strategy to derive from hESCs functional human SAN-like pacemaker cells, which express pacemaker markers and display SAN-like action potentials. Furthermore, SARS-CoV-2 infection causes dysfunction of human SAN-like pacemaker cells and induces ferroptosis. Two drug candidates, deferoxamine and imatinib, were identified from the high content screen, able to block SARS-CoV-2 infection and infection-associated ferroptosis. CONCLUSIONS: Using a hamster model, we showed that primary pacemaker cells in the heart can be infected by SARS-CoV-2. Infection of hESC-derived functional SAN-like pacemaker cells demonstrates ferroptosis as a potential mechanism for causing cardiac arrhythmias in patients with COVID-19. Finally, we identified candidate drugs that can protect the SAN cells from SARS-CoV-2 infection.

A Versatile Expression Platform in Insects and Cereals Based on a Cytorhabdovirus.

In recent years, plant virus-based vectors have been widely applied to express heterologous proteins for genomic studies and commercial production. Among these versatile RNA viral vectors, the barley yellow striate mosaic virus (BYSMV)-based expression vector system has outstanding capability to express large and multiple heterologous proteins. Here we describe a detailed protocol for expression of heterologous proteins using BYSMV expression systems in monocot plants and insects.

Modeling nonsegmented negative-strand RNA virus (NNSV) transcription with ejective polymerase collisions and biased diffusion.

Infections by non-segmented negative-strand RNA viruses (NNSV) are widely thought to entail gradient gene expression from the well-established existence of a single promoter at the 3' end of the viral genome and the assumption of constant transcriptional attenuation between genes. But multiple recent studies show viral mRNA levels in infections by respiratory syncytial virus (RSV), a major human pathogen and member of NNSV, that are inconsistent with a simple gradient. Here we integrate known and newly predicted phenomena into a biophysically reasonable model of NNSV transcription. Our model succeeds in capturing published observations of respiratory syncytial virus and vesicular stomatitis virus (VSV) mRNA levels. We therefore propose a novel understanding of NNSV transcription based on the possibility of ejective polymerase-polymerase collisions and, in the case of RSV, biased polymerase diffusion.

Atypical Prolonged Viral Shedding With Intra-Host SARS-CoV-2 Evolution in a Mildly Affected Symptomatic Patient.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is caused by a respiratory virus with a wide range of manifestations, varying from asymptomatic to fatal cases, with a generally short outcome. However, some individuals present long-term viral shedding. We monitored 38 individuals who were mildly affected by the SARS-CoV-2 infection. Out of the total studied population, three (7.9%) showed atypical events regarding the duration of positivity for viral RNA detection. In one of these atypical cases, a previously HIV-positive male patient presented a SARS-CoV-2 RNA shedding and subgenomic RNA (sgRNA) detected from the upper respiratory tract, respectively, for 232 and 224 days after the onset of the symptoms. The SARS-CoV-2 B.1.1.28 lineage, one of the most prevalent in Brazil in 2020, was identified in this patient in three serial samples. Interestingly, the genomic analyses performed throughout the infectious process showed an increase in the genetic diversity of the B.1.1.28 lineage within the host itself, with viral clearance occurring naturally, without any intervention measures to control the infection. Contrasting widely spread current knowledge, our results indicate that potentially infectious SARS-CoV-2 virus might be shed by much longer periods by some infected patients. This data call attention to better adapted non-pharmacological measures and clinical discharge of patients aiming at preventing the spread of SARS-CoV-2 to the population.

RNA Viral Vectors for Accelerating Plant Synthetic Biology.

The tools of synthetic biology have enormous potential to help us uncover the fundamental mechanisms controlling development and metabolism in plants. However, their effective utilization typically requires transgenesis, which is plagued by long timescales and high costs. In this review we explore how transgenesis can be minimized by delivering foreign genetic material to plants with systemically mobile and persistent vectors based on RNA viruses. We examine the progress that has been made thus far and highlight the hurdles that need to be overcome and some potential strategies to do so. We conclude with a discussion of biocontainment mechanisms to ensure these vectors can be used safely as well as how these vectors might expand the accessibility of plant synthetic biology techniques. RNA vectors stand poised to revolutionize plant synthetic biology by making genetic manipulation of plants cheaper and easier to deploy, as well as by accelerating experimental timescales from years to weeks.

Evaluation of a rapid antigen detection test (Panbio™ COVID-19 Ag Rapid Test Device) as a point-of-care diagnostic tool for COVID-19 in a pediatric emergency department.

We evaluated the Panbio™ COVID-19 Ag Rapid Test Device as a point-of-care diagnostic tool for COVID-19 in 357 patients at a pediatric emergency department. Thirty-four patients tested positive by reverse transcription polymerase chain reaction, of which 24 were positive by the antigen assay. The sensitivity and specificity of the assay were 70.5% and 100%, respectively.

Natural killer cells associated with SARS-CoV-2 viral RNA shedding, antibody response and mortality in COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is a novel infectious viral disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two consecutively negative SARS-CoV-2 viral RNA test ( interval ≥ 24 hours), improved respiratory symptoms and obvious absorption of inflammation in pulmonary imaging are the discharge criteria for COVID-19 patients. The clearance profile of viral RNA in the upper respiratory tract specimens, including nasopharyngeal swab and/or oropharyngeal swabs, is related to innate immune cells such as Natural Killer cells. A total of 168 patients were included for the study. In this cohort, non-severe and severe groups showed significant differences in white blood cells, neutrophils, lymphocytes, basophils and platelets counts, as well as in infection related parameters such as CRP and serum cytokine IL-6. For lymphocyte subsets tests at admission, the severe group displayed significantly lower cell counts than the non-severe group. Higher counts of total T cells, CD4 + T cells, CD8 + T cells, and NK cells in peripheral blood showed a significant correlation with the shorter time taken to obtain the first negative viral RNA test and first positive IgM/ IgG antibody test. The number of B cells was only correlated with time to achieve the first positive IgM/IgG test. The count of NK cells was also correlated with a higher level of IgG antibody (p = 0.025). The lymphocytopenia group had a significantly worse survival rate (p = 0.022) and a longer duration (p = 0.023) of viral shedding than the normal lymphocyte count group. A lower NK cell count correlates the most with the worse survival rate (p<0.001) and a longer duration (p<0.001) of viral shedding. This study suggests the potential value of allo-Natural Killer cell therapy as an universal COVID-19 treatment strategy.

Expression level of serum HBV RNA in HBeAg-positive chronic hepatitis B patients at different periods and its value of measurement / 临床肝胆病杂志

Objective To investigate the expression level and potential clinical value of serum HBV RNA in HBeAg-positive chronic hepatitis B (CHB) patients at different periods. Methods A total of 61 CHB patients who attended the outpatient and inpatient services of Department of Hepatology, Hangzhou Xixi Hospital, from August 2019 to December 2020 were enrolled, and according to the antiviral therapy for HBeAg-positive CHB patients, they can be divided into group A with untreated HBeAg-positive CHB (HBeAg+ and HBV DNA+) patients, group B with treatment-experienced patients before HBeAg seroconversion (HBeAg+ and HBV DNA-), and group C with treatment-experienced patients after HBeAg seroconversion (HBeAg- and HBV DNA-). Peripheral blood HBV RNA load was measured at different periods, and its correlation with HBsAg and HBV DNA was analyzed. The t -test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between groups; a Pearson or Spearman correlation analysis was used to describe the correlation between two variables. Results The positive rates of HBV RNA in these three groups were 100% (22/22), 88.2% (15/17), and 22.7% (6/22), respectively. In group A, HBV RNA was positively correlated with HBsAg and HBV DNA ( r =0.612 and 0.922, both P < 0.01), while in groups B and C, there was no correlation between HBV RNA and HBsAg. Group B had significantly higher levels of HBV RNA and HBsAg than group C ( Z =-4.44 and -2.41, both P < 0.05). The HBV DNA-positive group had a significantly higher level of HBV RNA than the HBV DNA-negative group ( Z =-6.16, P < 0.01). Conclusion After HBV DNA clearance achieved by antiviral therapy with nucleos(t)ide analogues in CHB patients, serum HBV RNA can still be detected in some of these patients. Since HBV RNA only comes from cccDNA in the liver, it can better reflect viral replication activity in the liver than HBV DNA and thus has a certain clinical value in the management of CHB patients.

Accuracy of quantitative HIV-1 RNA test methods at 1000 copies/mL and the potential impact of differences in assay calibration on therapy monitoring of patients.

The World Health Organization (WHO) recommends the clinical use of a human immunodeficiency virus 1 (HIV-1) viral load (VL) threshold level of 1000 copies (cp)/mL in patients on antiretroviral therapy (ART) to distinguish between viral control (VL < 1000 cp/mL) and viral failure or poor adherence (VL > 1000 cp/mL). The accuracy of five quantitative HIV-1 RNA assays at this level was compared by replicate testing (n = 24) of 1000 cp/mL samples prepared from the Viral Quality Control (VQC) HIV-1 subtype B standard, which is in use for validation of nucleic acid testing methods since 1995. Until 2004 the VL assays reported geometric mean (95% confidence interval [CI]) values ranging between 449 (188-1067) and 3162 (3057-2367) cp/mL when using the Siemens bDNA 3.0 assay as reference method for an assigned value of 1000 (962-1038) cp/mL. In 2018, the following values (95% CI) were found by 24 replicate tests in each of the VL assays on the 1000 cp/mL samples: Abbott RealTime 1084 (784-1572), BioMerieux EasyQ 1110 (533-2230), Roche CAP/CTM 1277 (892-1828), Hologic Aptima 1616 (1324-1973), and Cepheid GeneXpert 2502 (1713-3655) cp/mL. Calibration studies involving three consecutive WHO replacement standards showed a significant drift in the amount of RNA copies per International Unit overtime. Heat inactivation of HIV-1 standards was found to cause a destandardizing effect. Our study underlines the limitations in HIV-1 RNA assay calibration based on frequently replaced WHO international standards. It is therefore proposed that clinicians interpret the recommended 1000 cp/mL alert level in therapy monitoring with an inaccuracy range of 500 to 2000 cp/mL.

Early HIV infection is associated with reduced proportions of gamma delta T subsets as well as high creatinine and urea levels.

Renal dysfunctions are major predictors of co-morbidities and mortality in HIV-infected individuals. Unconventional T cells have been shown to regulate kidney functions. However, there is dearth of information on the effect of HIV-associated nephropathies on γδ and DN T cells. It is also not clear whether γδ T cell perturbations observed during the early stages of HIV infection occur before immune activation. In this study, we investigated the relationship between creatinine and urea on the number of unconventional T cells in HIV-infected individuals at the early and chronic stages of infection. Persons in the chronic stage of infection were divided into treatment naïve and exposed groups. Treatment exposed individuals were further subdivided into groups with undetectable and detectable HIV-1RNA in their blood. Creatinine and urea levels were significantly higher among persons in the early HIV infection compared with the other groups. Proportions of γδ T, γδ + CD8, γδ + CD16 cells were also significantly reduced in the early stage of HIV infection (P < .01). Markers of immune activation, CD4 + HLA-DR and CD8 + HLA-DR, were also significantly reduced during early HIV infection (P < .01). Taken together, our findings suggest that high levels of renal markers as well as reduced proportions of gamma delta T cells are associated with the early stages of HIV infection. This event likely occurs before systemic immune activation reaches peak levels. This study provides evidence for the need for early HIV infection diagnosis and treatment.

Association of Immunosuppression and Human Immunodeficiency Virus (HIV) Viremia With Anal Cancer Risk in Persons Living With HIV in the United States and Canada.

BACKGROUND: People living with human immunodeficiency virus (HIV; PLWH) have a markedly elevated anal cancer risk, largely due to loss of immunoregulatory control of oncogenic human papillomavirus infection. To better understand anal cancer development and prevention, we determined whether recent, past, cumulative, or nadir/peak CD4+ T-cell count (CD4) and/or HIV-1 RNA level (HIV RNA) best predict anal cancer risk. METHODS: We studied 102 777 PLWH during 1996-2014 from 21 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. Using demographics-adjusted, cohort-stratified Cox models, we assessed associations between anal cancer risk and various time-updated CD4 and HIV RNA measures, including cumulative and nadir/peak measures during prespecified moving time windows. We compared models using the Akaike information criterion. RESULTS: Cumulative and nadir/peak CD4 or HIV RNA measures from approximately 8.5 to 4.5 years in the past were generally better predictors for anal cancer risk than their corresponding more recent measures. However, the best model included CD4 nadir (ie, the lowest CD4) from approximately 8.5 years to 6 months in the past (hazard ratio [HR] for <50 vs ≥500 cells/µL, 13.4; 95% confidence interval [CI], 3.5-51.0) and proportion of time CD4 <200 cells/µL from approximately 8.5 to 4.5 years in the past (a cumulative measure; HR for 100% vs 0%, 3.1; 95% CI, 1.5-6.6). CONCLUSIONS: Our results are consistent with anal cancer promotion by severe, prolonged HIV-induced immunosuppression. Nadir and cumulative CD4 may represent useful markers for identifying PLWH at higher anal cancer risk.