Signatures of immune dysfunction in HIV and HCV infection share features with chronic inflammation in aging and persist after viral reduction or elimination.

Chronic inflammation is thought to be a major cause of morbidity and mortality in aging, but whether similar mechanisms underlie dysfunction in infection-associated chronic inflammation is unclear. Here, we profiled the immune proteome, and cellular composition and signaling states in a cohort of aging individuals versus a set of HIV patients on long-term antiretroviral therapy therapy or hepatitis C virus (HCV) patients before and after sofosbuvir treatment. We found shared alterations in aging-associated and infection-associated chronic inflammation including T cell memory inflation, up-regulation of intracellular signaling pathways of inflammation, and diminished sensitivity to cytokines in lymphocytes and myeloid cells. In the HIV cohort, these dysregulations were evident despite viral suppression for over 10 y. Viral clearance in the HCV cohort partially restored cellular sensitivity to interferon-α, but many immune system alterations persisted for at least 1 y posttreatment. Our findings indicate that in the HIV and HCV cohorts, a broad remodeling and degradation of the immune system can persist for a year or more, even after the removal or drastic reduction of the pathogen load and that this shares some features of chronic inflammation in aging.

Factors Associated with Resilience Among Older People Living with HIV.

Resilience, a measure of stress coping ability, may be important in helping older people (age 50+) living with HIV (PLWH) age successfully, but limited data exist regarding factors that contribute to resilience for this group. This study uses the Connor-Davidson Resilience Scale 2 (CD-RISC2) to assess resilience, based on a cross-sectional analysis of 1047 older PLWH. Bivariate linear regression models were used to identify predictor variables that had a relationship with resilience. Those variables were then included in a multivariable linear regression model, which was pared using backward selection. In the multivariable model, higher income and greater interpersonal support were associated with greater resilience, whereas depression and anxiety were associated with lower resilience. Relevant interventions that address these issues, such as increasing opportunities for social support and increasing screening for and treatment of depression and anxiety, are identified as potential pathways to increase resilience among older PLWH.

Patients With Uncomplicated Coronavirus Disease 2019 (COVID-19) Have Long-Term Persistent Symptoms and Functional Impairment Similar to Patients with Severe COVID-19: A Cautionary Tale During a Global Pandemic.

To assess the prevalence of persistent functional impairment after coronavirus disease (COVID-19), we assessed 118 individuals 3-4 months after their initial COVID-19 diagnosis with a symptom survey, work productivity and activity index questionnaire, and 6-minute walk test. We found significant persistent symptoms and functional impairment, even in non-hospitalized patients with COVID-19.

SARS-CoV-2 Neutralization Resistance Mutations in Patient with HIV/AIDS, California, USA.

We report persistent severe acute respiratory syndrome coronavirus 2 infection in a patient with HIV/AIDS; the virus developed spike N terminal domain and receptor binding domain neutralization resistance mutations. Our findings suggest that immunocompromised patients can harbor emerging variants of severe acute respiratory syndrome coronavirus 2.

Overexpression of the Cdk5 inhibitory peptide in motor neurons rescue of amyotrophic lateral sclerosis phenotype in a mouse model.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor nerve cells in the brain and the spinal cord. Etiological mechanisms underlying the disease remain poorly understood; recent studies suggest that deregulation of p25/Cyclin-dependent kinase 5 (Cdk5) activity leads to the hyperphosphorylation of Tau and neurofilament (NF) proteins in ALS transgenic mouse model (SOD1G37R). A Cdk5 involvement in motor neuron degeneration is supported by analysis of three SOD1G37R mouse lines exhibiting perikaryal inclusions of NF proteins and hyperphosphorylation of Tau. Here, we tested the hypothesis that inhibition of Cdk5/p25 hyperactivation in vivo is a neuroprotective factor during ALS pathogenesis by crossing the new transgenic mouse line that overexpresses Cdk5 inhibitory peptide (CIP) in motor neurons with the SOD1G37R, ALS mouse model (TriTg mouse line). The overexpression of CIP in the motor neurons significantly improves motor deficits, extends survival and delays pathology in brain and spinal cord of TriTg mice. In addition, overexpression of CIP in motor neurons significantly delays neuroinflammatory responses in TriTg mouse. Taken together, these data suggest that CIP may serve as a novel therapeutic agent for the treatment of neurodegenerative diseases.

Risk factors for difficult-to-treat hepatitis C virus genotype 4r in Rwanda and implications for elimination in sub-Saharan Africa.

In sub-Saharan Africa, there exist distinct HCV genotype (GT) subtypes harbouring resistance-associated substitutions to commonly used non-structural protein 5A (NS5A) inhibitor-based direct-acting antiviral (DAA) regimens. In particular, GT4r subtype has demonstrated high rates of treatment failure. In the absence of routine viral sequencing in sub-Saharan Africa, it is important to identify sociodemographic, epidemiologic, and clinical characteristics that may be associated with GT4r infection. Methods: A secondary analysis was performed on data from 300 adults with HCV GT4 enrolled in a prospective trial assessing the safety and efficacy of sofosbuvir-ledipasvir in Rwanda in 2017. The association between characteristics at enrolment and GT subtype was assessed by chi-square analysis and logistic regression. In multivariate analysis, there were a higher proportion of participants with GT4r subtype with age <40 years (OR: 3.6, 95% CI: 1.3-10.5, p = 0.02), previous hospitalization (OR: 2.5, 95% CI: 1.3-5.0, p = 0.006), previous surgery (OR: 2.2, 95% CI: 1.1-4.2, p = 0.03), cirrhosis (OR: 3.2, 95% CI: 1.3-7.5, p = 0.008) and baseline HCV RNA >1 million IU/ml (OR: 3.4, 95% CI: 1.6-6.9, p = 0.001). Rwandan adults with GT4r are more likely to be younger, have a history of hospital admissions and surgeries and have more active or advanced liver disease compared to those with other GT4 subtypes. In the absence of advanced diagnostics to assess GT subtype, patients with these characteristics may warrant closer monitoring for treatment failure or alternative DAA regimens. More treatment experience with diverse DAA regimens is urgently needed for GT subtypes particular to this region.

Improved quality of life following direct-acting antiviral treatment for chronic hepatitis C infection in Rwanda: Results from a clinical trial in sub-Saharan Africa (the SHARED study).

Around 71 million people are living with chronic hepatitis C virus (HCV) infection, with approximately 14% residing in sub-Saharan Africa. Direct-acting antiviral (DAA) therapies offer clear benefits for liver-related morbidity and mortality, and data from high-income settings suggest that DAA treatments also provide significant benefits in terms of health-related quality of life (HRQL). In this study, we assessed the effect of DAA treatment on HRQL for individuals treated for HCV in a clinical trial in Rwanda. We assessed the HRQL of participants using an 83-question composite survey at Day 0 ('baseline') and Week 24 ('endpoint'). Data were analysed in R. A total of 296 participants were included in this analysis. Their ages ranged from 19 to 90, and 184 (62.2%) were female. There were significant improvements from baseline to endpoint median scores for all physical and mental quality of life sub-scales. Additionally, a reduction-before and after treatment-in the proportion of those classified as depressed and needing social support was statistically significant (both P < .001). Economic productivity increased after treatment (P < .001), and households classified as food secure increased from baseline to endpoint (P < .001). These results demonstrate that Rwandans with chronic HCV infection experience both clinical and HRQL benefits, including household-level benefits like substantial gains in workforce stability, economic productivity, and poverty alleviation, from DAA treatment. A stronger demonstration of accurate and broader household-level benefits achieved through treatment of HCV with DAAs will help financing and investment for HCV in resource-constrained settings become an urgent priority.

A systematic review of the genetic mechanisms of dolutegravir resistance.

BACKGROUND: Characterizing the mutations selected by the integrase strand transfer inhibitor (INSTI) dolutegravir and their effects on susceptibility is essential for identifying viruses less likely to respond to dolutegravir therapy and for monitoring persons with virological failure (VF) on dolutegravir therapy. METHODS: We systematically reviewed dolutegravir resistance studies to identify mutations emerging under dolutegravir selection pressure, the effect of INSTI resistance mutations on in vitro dolutegravir susceptibility, and the virological efficacy of dolutegravir in antiretroviral-experienced persons. RESULTS AND CONCLUSIONS: We analysed 14 studies describing 84 in vitro passage experiments, 26 studies describing 63 persons developing VF plus INSTI resistance mutations on a dolutegravir-containing regimen, 41 studies describing dolutegravir susceptibility results, and 22 clinical trials and 16 cohort studies of dolutegravir-containing regimens. The most common INSTI resistance mutations in persons with VF on a dolutegravir-containing regimen were R263K, G118R, N155H and Q148H/R, with R263K and G118R predominating in previously INSTI-naive persons. R263K reduced dolutegravir susceptibility ∼2-fold. G118R generally reduced dolutegravir susceptibility >5-fold. The highest levels of reduced susceptibility occurred in viruses containing Q148 mutations in combination with G140 and/or E138 mutations. Dolutegravir two-drug regimens were highly effective for first-line therapy and for virologically suppressed persons provided dolutegravir's companion drug was fully active. Dolutegravir three-drug regimens were highly effective for salvage therapy in INSTI-naive persons provided one or more of dolutegravir's companion drugs was fully active. However, dolutegravir monotherapy in virologically suppressed persons and functional dolutegravir monotherapy in persons with active viral replication were associated with a non-trivial risk of VF plus INSTI resistance mutations.

Long-term Bone Mineral Density Changes in Antiretroviral-Treated HIV-Infected Individuals.

We compared adjusted bone mineral density (BMD) changes between human immunodeficiency virus (HIV)-infected individuals during the first approximately 7.5 years after antiretroviral therapy (ART) initiation and HIV-uninfected controls. HIV-infected individuals (n = 97) had significantly greater adjusted BMD decline than controls (n = 614) during the first 96 weeks of ART. Subsequently, the rate of BMD decline slowed in HIV-infected individuals but remained greater than the rate of decline in HIV-uninfected individuals at the lumbar spine but not at the hip. In HIV-infected individuals after 96 weeks, no HIV- or treatment-related characteristic was associated with BMD loss, but lower lean body mass was associated with greater BMD loss at both lumbar spine and hip.

Association between latent proviral characteristics and immune activation in antiretrovirus-treated human immunodeficiency virus type 1-infected adults.

UNLABELLED: Generalized immune activation during HIV infection is associated with an increased risk of cardiovascular disease, neurocognitive disease, osteoporosis, metabolic disorders, and physical frailty. The mechanisms driving this immune activation are poorly understood, particularly for individuals effectively treated with antiretroviral medications. We hypothesized that viral characteristics such as sequence diversity may play a role in driving HIV-associated immune activation. We therefore sequenced proviral DNA isolated from peripheral blood mononuclear cells from HIV-infected individuals on fully suppressive antiretroviral therapy. We performed phylogenetic analyses, calculated viral diversity and divergence in the env and pol genes, and determined coreceptor tropism and the frequency of drug resistance mutations. Comprehensive immune profiling included quantification of immune cell subsets, plasma cytokine levels, and intracellular signaling responses in T cells, B cells, and monocytes. These antiretroviral therapy-treated HIV-infected individuals exhibited a wide range of diversity and divergence in both env and pol genes. However, proviral diversity and divergence in env and pol, coreceptor tropism, and the level of drug resistance did not significantly correlate with markers of immune activation. A clinical history of virologic failure was also not significantly associated with levels of immune activation, indicating that a history of virologic failure does not inexorably lead to increased immune activation as long as suppressive antiretroviral medications are provided. Overall, this study demonstrates that latent viral diversity is unlikely to be a major driver of persistent HIV-associated immune activation. IMPORTANCE: Chronic immune activation, which is associated with cardiovascular disease, neurologic disease, and early aging, is likely to be a major driver of morbidity and mortality in HIV-infected individuals. Although treatment of HIV with antiretroviral medications decreases the level of immune activation, levels do not return to normal. The factors driving this persistent immune activation, particularly during effective treatment, are poorly understood. In this study, we investigated whether characteristics of the latent, integrated HIV provirus that persists during treatment are associated with immune activation. We found no relationship between latent viral characteristics and immune activation in treated individuals, indicating that qualities of the provirus are unlikely to be a major driver of persistent inflammation. We also found that individuals who had previously failed treatment but were currently effectively treated did not have significantly increased levels of immune activation, providing hope that past treatment failures do not have a lifelong "legacy" impact.

Patterns of peripheral neuropathy in ART-naïve patients initiating modern ART regimen.

The purpose of this study was to evaluate associations of pre-ART CD4 with peripheral neuropathy (PN) and estimate the prevalence of PN in HIV-positive patients starting modern combination antiretroviral therapy (cART) regimens. ART-naïve subjects initiating cART were followed longitudinally and screened for signs/symptoms of PN. Lower pre-ART CD4 count was associated with post-ART PN. After 7 years (n = 117), the prevalence (95% CI) of PN and SPN were 31% (23, 40%) and 5% (2, 11%) with pre-ART CD4 count >250 copies/µL. PN continues to be identified in HIV-infected individuals on modern cART by targeted assessment but is generally without symptoms.

Comparative effectiveness and cost-effectiveness of antiretroviral therapy and pre-exposure prophylaxis for HIV prevention in South Africa.

BACKGROUND: Antiretroviral therapy (ART) and oral pre-exposure prophylaxis (PrEP) are effective in reducing HIV transmission in heterosexual adults. The epidemiologic impact and cost-effectiveness of combined prevention approaches in resource-limited settings remain unclear. METHODS: We develop a dynamic mathematical model of the HIV epidemic in South Africa's adult population. We assume ART reduces HIV transmission by 95% and PrEP by 60%. We model two ART strategies: scaling up access for those with CD4 counts ≤ 350 cells/µL (Guidelines) and for all identified HIV-infected individuals (Universal). PrEP strategies include use in the general population (General) and in high-risk individuals (Focused). We consider strategies where ART, PrEP, or both are scaled up to 100% of remaining eligible individuals yearly. We measure infections averted, quality-adjusted life-years (QALYs) gained and incremental cost-effectiveness ratios over 20 years. RESULTS: Scaling up ART to 50% of eligible individuals averts 1,513,000 infections over 20 years (Guidelines) and 3,591,000 infections (Universal). Universal ART is the most cost-effective strategy at any scale ($160-$220/QALY versus comparable scale Guidelines ART expansion). General PrEP is costly and provides limited benefits beyond ART scale-up ($7,680/QALY to add 100% PrEP to 50% Universal ART). Cost-effectiveness of General PrEP becomes less favorable when ART is widely given ($12,640/QALY gained when added to 100% Universal ART). If feasible, Focused PrEP is cost saving or highly cost effective versus status quo and when added to ART strategies. CONCLUSIONS: Expanded ART coverage to individuals in early disease stages may be more cost-effective than current guidelines. PrEP can be cost-saving if delivered to individuals at increased risk of infection.

Encephalitis caused by Chikungunya virus in a traveler from the Kingdom of Tonga.

Febrile travelers from countries with unique endemic pathogens pose a significant diagnostic challenge. In this report, we describe the case of a Tongan man presenting with fever, rash, and altered mental status. The diagnosis of Chikungunya encephalitis was made using a laboratory-developed real-time RT-PCR and serologic testing.

A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice.

Alzheimer's disease (AD), one of the leading neurodegenerative disorders of older adults, which causes major socioeconomic burdens globally, lacks effective therapeutics without significant side effects. Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs), it has been reported that cyclin-dependent kinase 5 (Cdk5), a critical neuronal kinase, is hyperactivated in AD brains and is, in part, responsible for the above pathology. Here we show that a modified truncated 24-aa peptide (TFP5), derived from the Cdk5 activator p35, penetrates the blood-brain barrier after intraperitoneal injections, inhibits abnormal Cdk5 hyperactivity, and significantly rescues AD pathology (up to 70-80%) in 5XFAD AD model mice. The mutant mice, injected with TFP5 exhibit behavioral rescue, whereas no rescue was observed in mutant mice injected with either saline or scrambled peptide. However, TFP5 does not inhibit cell cycle Cdks or normal Cdk5/p35 activity, and thereby has no toxic side effects (even at 200 mg/kg), a common problem in most current therapeutics for AD. In addition, treated mice displayed decreased inflammation, amyloid plaques, NFTs, cell death, and an extended life by 2 mo. These results suggest TFP5 as a potential therapeutic, toxicity-free candidate for AD.

Clinical and immunologic predictors of death after an acute opportunistic infection: results from ACTG A5164.

BACKGROUND: In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era. OBJECTIVE: To determine clinical and immunological predictors of death after an OI. METHODS: We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both. RESULTS: The median CD4+ T-cell count in study participants at baseline was 29 cells/µL. Sixty-four percent of subjects had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death. CONCLUSIONS: In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI.

Sex differences and immune correlates of Long COVID development, persistence, and resolution.

Sex differences have been observed in acute COVID-19 and Long COVID (LC) outcomes, with greater disease severity and mortality during acute infection in males and a greater proportion of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to the pathogenesis of LC. To investigate the immunologic underpinnings of LC development and persistence, we used single-cell transcriptomics, single-cell proteomics, and plasma proteomics on blood samples obtained during acute SARS-CoV-2 infection and at 3 and 12 months post-infection in a cohort of 45 patients who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Specifically, males who would develop LC at 3 months had widespread increases in TGF-ß signaling during acute infection in proliferating NK cells. Females who would develop LC demonstrated increased expression of XIST , an RNA gene implicated in autoimmunity, and increased IL1 signaling in monocytes at 12 months post infection. Several immune features of LC were also conserved across sexes. Both males and females with LC had reduced co-stimulatory signaling from monocytes and broad upregulation of NF-κB transcription factors. In both sexes, those with persistent LC demonstrated increased LAG3, a marker of T cell exhaustion, reduced ETS1 transcription factor expression across lymphocyte subsets, and elevated intracellular IL-4 levels in T cell subsets, suggesting that ETS1 alterations may drive an aberrantly elevated Th2-like response in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics. One Sentence Summary: This multi-omic analysis of Long COVID reveals sex differences and immune correlates of Long COVID development, persistence, and resolution.

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review.

BACKGROUND: Dolutegravir (DTG) is a cornerstone of global antiretroviral (ARV) therapy (ART) due to its high efficacy and favorable tolerability. However, limited data exist regarding the risk of emergent integrase strand transfer inhibitor (INSTI) drug-resistance mutations (DRMs) in individuals receiving DTG-containing ART. METHODS: We performed a PubMed search using the term "Dolutegravir", last updated 18 December 2023, to estimate the prevalence of VF with emergent INSTI DRMs in people living with HIV (PLWH) without previous VF on an INSTI who received DTG-containing ART. RESULTS: Of 2131 retrieved records, 43 clinical trials, 39 cohorts, and 6 cross-sectional studies provided data across 6 clinical scenarios based on ART history, virological status, and co-administered ARVs: (1) ART-naïve PLWH receiving DTG plus two NRTIs; (2) ART-naïve PLWH receiving DTG plus lamivudine; (3) ART-experienced PLWH with VF on a previous regimen receiving DTG plus two NRTIs; (4) ART-experienced PLWH with virological suppression receiving DTG plus two NRTIs; (5) ART-experienced PLWH with virological suppression receiving DTG and a second ARV; and (6) ART-experienced PLWH with virological suppression receiving DTG monotherapy. The median proportion of PLWH in clinical trials with emergent INSTI DRMs was 1.5% for scenario 3 and 3.4% for scenario 6. In the remaining four trial scenarios, VF prevalence with emergent INSTI DRMs was ≤0.1%. Data from cohort studies minimally influenced prevalence estimates from clinical trials, whereas cross-sectional studies yielded prevalence data lacking denominator details. CONCLUSIONS: In clinical trials, the prevalence of VF with emergent INSTI DRMs in PLWH receiving DTG-containing regimens has been low. Novel approaches are required to assess VF prevalence with emergent INSTI DRMs in PLWH receiving DTG in real-world settings.

Low baseline CD4+ count is associated with greater bone mineral density loss after antiretroviral therapy initiation.

BACKGROUND: Bone mineral density (BMD) decreases 2%-6% in the 2 years after antiretroviral therapy (ART) initiation. Pre-ART immune deficiency and early immune recovery may contribute to this loss. METHODS: We pooled data from 3 studies of ART initiation in treatment-naive patients in which serial whole-body dual-energy X-ray absorptiometry scans were performed. We used linear regression to evaluate effects of baseline CD4(+) and 16-week CD4(+) change (both absolute and relative) on 96-week total BMD change from baseline. We performed multivariable linear regression to assess associations between baseline variables of age, sex, race/ethnicity, body mass index (BMI), hepatitis C status, parent study, human immunodeficiency virus type 1 (HIV-1) RNA level, and assignment to a protease inhibitor (PI)- or tenofovir-containing regimen on 96-week total BMD change. RESULTS: The included 796 subjects had mean 96-week total BMD loss of 2.0%. In multivariable analysis, baseline CD4(+) cell count was significantly associated with 96-week BMD loss; individuals with baseline CD4(+) <50 cells/µL lost significantly more BMD compared to those with CD4(+) ≥500 cells/µL. A greater relative, but not absolute, 16-week increase in CD4(+) count was significantly associated with greater declines in BMD, but not after controlling for baseline CD4(+) count. In multivariable analysis, older age, female sex, lower BMI, higher HIV-1 RNA levels, and PI and tenofovir assignment were also associated with greater BMD decline. CONCLUSIONS: Low pretreatment CD4(+) count, but not greater CD4(+) count increase, is a strong and independent risk factor for bone loss after ART initiation. ART initiation at higher CD4(+) counts may reduce the burden of osteoporosis and fragility fractures.

Topographic regulation of neuronal intermediate filaments by phosphorylation, role of peptidyl-prolyl isomerase 1: significance in neurodegeneration.

The neuronal cytoskeleton is tightly regulated by phosphorylation and dephosphorylation reactions mediated by numerous associated kinases, phosphatases and their regulators. Defects in the relative kinase and phosphatase activities and/or deregulation of compartment-specific phosphorylation result in neurodegenerative disorders. The largest family of cytoskeletal proteins in mammalian cells is the superfamily of intermediate filaments (IFs). The neurofilament (NF) proteins are the major IFs. Aggregated forms of hyperphosphorylated tau and phosphorylated NFs are found in pathological cell body accumulations in the central nervous system of patients suffering from Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. The precise mechanisms for this compartment-specific phosphorylation of cytoskeletal proteins are not completely understood. In this review, we focus on the mechanisms of neurofilament phosphorylation in normal physiology and neurodegenerative diseases. We also address the recent breakthroughs in our understanding the role of different kinases and phosphatases involved in regulating the phosphorylation status of the NFs. In addition, special emphasis has been given to describe the role of phosphatases and Pin1 in phosphorylation of NFs.