Effective Antiretroviral Treatment Research Articles

Gastrointestinal Bleeding as a Clinical Manifestation of Strongyloides stercoralis Hyperinfection in a Patient with HIV: A Case Report

AbstractStrongyloidiasis, caused by the nematode Strongyloides stercoralis, is an often neglected parasitic disease, with deeper prevalence in tropical and subtropical regions. This parasitic infection can range from asymptomatic to symptomatic, with nonspecific manifestations, including gastrointestinal symptoms. Herein, we reported the case of an human immunodeficiency virus (HIV)-positive patient, under effective antiretroviral treatment with a normal CD4 count, who was hospitalized due to gastrointestinal bleeding. The diagnosis of strongyloidiasis hyperinfection was confirmed following endoscopic biopsies of both the gastric and duodenal mucosa. Subsequently, a treatment regimen of ivermectin at a dosage of 200 mcg/kg/day for a duration of 14 days was initiated, leading to notable amelioration in the patient's clinical presentation. In considering the differential diagnosis of gastrointestinal bleeding, it is crucial to explore various possibilities, including peptic ulcers, portal hypertension, and cancer. Among immunocompromised individuals like those with HIV, chronic infection can compromise the Th2 immune response, which is pivotal in combating helminthic infections. This underscores the importance of remembering intestinal parasitosis, particularly strongyloidiasis, in such cases. Even in patients with preserved CD4 counts, careful evaluation for opportunistic infections in HIV-positive individuals is paramount. Early initiation of treatment is essential to mitigate the risk of serious complications.

CRISPR/CAS as a Powerful Tool for Human Immunodeficiency Virus Cure: A Review.

Despite care and the availability of effective antiretroviral treatment, some human immunodeficiency virus (HIV)-infected individuals suffer from neurocognitive disorders associated with HIV (HAND) that significantly affect their quality of life. The different types of HAND can be divided into asymptomatic neurocognitive impairment, mild neurocognitive disorder, and the most severe form known as HIV-associated dementia. Little is known about the mechanisms of HAND, but it is thought to be related to infection of astrocytes, microglial cells, and macrophages in the human brain. The formation of a viral reservoir that lies dormant as a provirus in resting CD4+ T lymphocytes and in refuge tissues such as the brain contributes significantly to HIV eradication. In recent years, a new set of tools have emerged: the gene editing based on the clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 system, which can alter genome segments by insertion, deletion, and replacement and has great therapeutic potential. This technology has been used in research to treat HIV and appears to offer hope for a possible cure for HIV infection and perhaps prevention of HAND. This approach has the potential to directly impact the quality of life of HIV-infected individuals, which is a very important topic to be known and discussed.

Frailty assessment: An emerging concept in aged People Living with HIV (PLHIV).

As the life expectancy of People Living with HIV (PLHIV) has improved with effective antiretroviral treatment (ART), they now face the challenges of accelerated ageing. Frailty is an emerging concept in the management of PLHIV and up to 28% of PLHIV are identified as frail. Frailty is a determinant of adverse clinical outcomes and is a complex clinical endpoint that has not been studied in India. This exploratory study was done to evaluate frailty and its determinants among PLHIV in India. This was a cross-sectional study in 76 PLHIV aged 50 years or more. All the study subjects underwent a comprehensive clinical assessment. The Fried's criteria and Veterans Aging Cohort Study (VACS) Index were used to evaluate for frailty. Socio-demographic, clinical, immunological, and virological variables were assessed for their association with frailty. The study was registered under Clinical Trials Registry-India (ICMR-NIMS): REF/2019/05/025616. The mean age of the subjects was 56.05 ± 5.8 years (range 50-76), and males constituted 81.57% (62/76) of the subjects and majority (60.53%) were underweight. On frailty assessment, 57.89% of the PLHIV were identified as prefrail/frail. Frailty had a significant association with low CD4 count (P = 0.0001) and number of comorbidities (P = 0.017) especially when comorbidities ≥2 (P = 0.04) and polypharmacy (P = 0.033). VACS index, polypharmacy, and low CD4 count ≤200 cells/mm3 were strong predictors of frailty. On multivariate regression analysis, CD4 count ≤200 emerged as the strongest independent predictor of frailty. The study highlighted the high prevalence of frailty and under nutrition among aged PLHIV. The study emphasizes the need for a shift away from traditional clinical endpoints to other outcome measures for a holistic approach to PLHIV.

Molecular Evaluation of HIV-1 HAART Efficacy, Comparison of TDF+3TC+EFV and AZT+3TC+NVP Regimens

Context: The UNAIDS goal of ending the HIV epidemic by 2030 will be achieved primarily through the success of the three “95s” by 2030, and in particular the third “95 », which consists of achieving an undetectable viral load thanks to effective antiretroviral treatment. Achieving and maintaining viral suppression is the goal of ART and a good knowledge of the effectiveness of triple ARV therapies can help national HIV programs. Thus, the objective of this study was to evaluate and compare the effectiveness of the two ARTs, Tenovofir + Lamivudine +Efavirenz (TDF+3TC+EFV) and Zidovudine+Lamivudine+ Efavirenz (AZT+3TC+NVP) in their abilities to make the plasma viral load of HIV+ patients under treatment undetectable. 
 
 Material and method: This is a retrospective study of the management of HIV-1 seropositive patients, followed at the Military Hospital of Ouakam (HMO) Molecular Biology laboratory from 2014 to 2021. The main criterion for evaluating the effectiveness of the treatment was the proportions of patients whose Viral load values were undetectable, VL< 50 copies/ml depending on duration of antiretroviral therapy (ART). Plasma viral load tests were carried out on Abbott Real Time HIV-1® (m2000sp/rt) and COBAS®AmpliPrep/COBAS®TaqMan® (Roche) version 2.0. Variables with p<0.05 were considered statistically significant for all comparisons between groups.
 
 Results: 3,335 patients met the inclusion criteria, including 2,078 on TDF+3TC+EFV, 445 on AZT+3TC+NVP and 812 were excluded due to death, transfer or loss to follow-up. At 6 months of ART, VL was undetectable in 7.3% of patients on TDF+3TC+EFV and 6.7% of patients on AZT+3TC+NVP (P=0.67). 78.2% versus 73.4% of patients had an undetectable VL respectively for TDF+3TC+EFV and AZT+3TC+NVP at 12 months of ART (p=0.03). TDF+3TC+EFV had significantly higher virological success rates than AZT+3TC+NVP (85.7% versus 80.2%) and virological failure (VL>1000 copies/ml) was significantly greater in patients taking AZT+3TC+NVP (13% versus 7.2%) after 18 months (P=0.001). Gender and age had a significant relationship in treatment success.
 
 Conclusion: TDF+3TC+EFV was superior in terms of virological suppression at the end of the study period. These results support the WHO recommendation to use TDF+3TD+EFV as an alternative first-line regimen.

Subacute myoclonic measles encephalitis - An opportunistic HIV-associated infection.

An unusual cluster of myoclonic epilepsy was observed in a Romanian pediatric HIV cohort concurrent with measles outbreaks. We describe this particular form of subacute measles encephalitis (SME) in a group of HIV-infected children and adolescents with severe immunosuppression. This is a single-center study, starting in 1997 and covering 4 measles outbreaks in Romania. The presumptive diagnosis of subacute myoclonic measles encephalitis (SMME) was based on: (1) epidemiological data, previous measles episode or presumed contact with measles virus (MV), (2) clinical presentation with initial localized myoclonic jerks with rapid extension and subsequent motor deficit with preserved mental status, and (3) neuroimaging studies revealing cortical gray matter lesions. Definitive diagnosis was based on a neuropathological exam and immunohistochemistry of brain tissues, and measles RNA detection in the cerebrospinal fluid (CSF). Thirty-six patients were diagnosed with a particular form of SME during consecutive measles outbreaks in Romania: 1996-1998 (22); 2005-2008 (12); 2010-2011 (1) and 2016-2018 (1). Most children were born in the late 80s and had parenterally acquired HIV infection in early childhood. Before the episode of SMME, 11 patients had confirmed measles, while the rest, without typical rash, had a respiratory tract infection and/or presumed previous measles contact. In all patients, the clinical onset was sudden, with unilateral myoclonus. MRI findings revealed mainly focal cortical gray matter lesions. Neurologic symptoms progressed rapidly to coma and death in most patients. Three patients survived SMME, they had higher CD4 count at onset, slower progression of neurological symptoms, and benefit of immune recovery with cART. Immunocytochemistry studies revealed MV in the brain with a pattern suggesting an ascending viral neural infection. MV was isolated from CSF in 7 out of 8 patients. Sequence analysis of MV RNA from both nasopharyngeal swabs and CSF was available for one patient with similar N-450 strain characteristics. During an outbreak of measles, neurological manifestations, especially myoclonus in immunosuppressed patients, can be related to measles even in the absence of an acute episode. This particular form of subacute myoclonic measles encephalitis is an opportunistic fatal disease. Immune recovery due to effective antiretroviral treatment might increase survival.

The new profile of psychiatric disorders in patients with HIV infection.

Nowadays, HIV infection is largely considered as a chronic condition rather than a deadly disease, given that effective antiretroviral treatment allows almost complete and persistent suppression of viral replication and restoration of nearly normal CD4+ T-cell counts. Being HIV a "condition", we imply that other illnesses are more frequently seen in persons living with HIV (PLHIV), among which mental health disorders are particularly common. Despite very successful antiretroviral therapy, HIV infection may still cause a wide range of neurocognitive dysfunctions and accelerated brain ageing. Beyond direct viral effects, at least another five causes of neurological damage are more frequent among PLHIV. First, the use of neurochemical substances as sexual boosters (chemsex) has become popular in this population. Second, the rate of sexually transmitted infections as syphilis, which may affect the central nervous system, is more prevalent among PLHIV. Third, the use of certain antiretroviral drugs, such as efavirenz, has been associated with changes in mood and/or psychotic symptoms. Fourth, an increased rate of mental disorders has been reported in PLHIV, either as predisposing conditions or following the recognition of HIV diagnosis (i.e., major depression). Finally, psychosocial factors such as loneliness, isolation and stigmatization are more frequent in PLHIV and worsen their mental health. Given that the life expectancy of PLHIV has increased significantly, a new and much broader spectrum of psychiatric disorders has emerged in PLHIV. Early diagnosis and adequate management, including education and preventative interventions are warranted.

Long-term evolution of comorbidities and their disease burden in individuals with and without HIV as they age: analysis of the prospective AGEhIV cohort study

People with HIV generally have more ageing-associated comorbidities than those without HIV. We aimed to establish whether the difference in comorbidities and their disease burden changes with ageing. In this prospective, longitudinal cohort study, we assessed comorbidities commonly associated with ageing every 2 years in 596 HIV-positive and 550 HIV-negative participants. HIV-positive participants were recruited from the HIV outpatient clinic of the Amsterdam University Medical Centres (Amsterdam, Netherlands). HIV-negative participants were recruited from the sexual health clinic and the Amsterdam Cohort Studies at the Public Health Service of Amsterdam (Amsterdam, Netherlands). Inclusion criteria were participants aged 45 years or older and, for HIV-negative participants, a documented HIV-negative antibody test. The mean number of comorbidities present over time was compared between groups by use of Poisson regression, accounting for dropout and death through joint survival models. Mean disability-adjusted life-years (DALYs) accrued during 2-year intervals were compared between groups by use of an exponential hurdle model. Between Oct 29, 2010, and Oct 9, 2012, participants were enrolled and then prospectively followed up until their last visit before Oct 1, 2018. 1146 participants were followed up for a median 5·9 years (IQR 5·7-6·0), during which 231 participants (20·2%) dropped out: 145 (24·3%) of 596 HIV-positive and 86 (15·6%) of 550 HIV-negative. 38 (3·3%) of 1146 participants died: 31 (5·2%) of 596 HIV-positive and seven (1·3%) of 550 HIV-negative. 24 HIV-positive and two HIV-negative participants died from ageing-associated comorbidities. 15 HIV-positive participants versus one HIV-negative participant died from non-AIDS malignancies. At inclusion, mean number of comorbidities was higher in HIV-positive participants (0·65) than in HIV-negative participants (0·32; p<0·0001). Mean number of comorbidities increased at similar rates over time: rate ratio (RR) per year for HIV-positive participants 1·04 (95% CI 1·00-1·08), RR per year for HIV-negative participants 1·05 (1·01-1·08; pinteraction=0·78). Number of comorbidities was associated with an increased risk of death (hazard ratio 3·33 per additional comorbidity, 95% CI 2·27-4·88; p<0·0001). HIV-positive participants had higher increases in mean DALYs than HIV-negative participants (0·209 per year, 95% CI 0·162-0·256 vs 0·091 per year, 0·025-0·157; pinteraction=0·0045). This difference was reduced when deaths were excluded in establishing DALYs (0·127, 0·083-0·171 vs 0·066, 0·005-0·127; pinteraction =0·11). The larger comorbidity prevalence in HIV-positive participants aged 50-55 years on effective antiretroviral treatment than in HIV-negative participants increased similarly as participants aged and was associated with an increased risk of death, particularly of non-AIDS malignancies. Our findings reinforce the need for strategies to optimise prevention, screening, and early intervention. Netherlands Organization for Health Research and Development, Aidsfonds, Gilead Sciences, ViiV Healthcare, Janssen Pharmaceuticals, and Merck & Co. For the Dutch translation of the abstract see Supplementary Materials section.

Longitudinal characterization of circulating extracellular vesicles and small RNA during simian immunodeficiency virus infection and antiretroviral therapy.

Latent infection by HIV hinders viral eradication despite effective antiretroviral treatment (ART). Among proposed contributors to viral latency are cellular small RNAs that have also been proposed to shuttle between cells in extracellular vesicles. Thus, we profiled extracellular vesicle small RNAs during different infection phases to understand the potential relationship between these extracellular vesicle associated small RNAs and viral infection. A well characterized simian immunodeficiency virus (SIV)/macaque model of HIV was used to profile extracellular vesicle enriched blood plasma fractions harvested during preinfection, acute infection, latent infection/ART treatment, and rebound after ART interruption. Measurement of extracellular vesicle concentration, size distribution, and morphology was complemented with qPCR array for small RNA expression, followed by individual qPCR validations. Iodixanol density gradients were used to separate extracellular vesicle subtypes and virions. Plasma extracellular vesicle particle counts correlated with viral load and peaked during acute infection. However, SIV gag RNA detection showed that virions did not fully explain this peak. Extracellular vesicle microRNAs miR-181a, miR-342-3p, and miR-29a decreased with SIV infection and remained downregulated in latency. Interestingly, small nuclear RNA U6 had a tight association with viral load peak. This study is the first to monitor how extracellular vesicle concentration and extracellular vesicle small RNA expression change dynamically in acute viral infection, latency, and rebound in a carefully controlled animal model. These changes may also reveal regulatory roles in retroviral infection and latency.

Double-Negative T Cell Number and Phenotype Alterations Before and After Effective Antiretroviral Treatment in Persons Living with HIV.

Double-negative (DN) T cells represent a small and phenotypically heterogeneous population that display regulatory functions. In HIV infection, DN T cells are decreased in peripheral blood and have been negatively associated with T cell activation. This study was aimed at describing the dynamics and phenotypic characteristics of DN T cells in peripheral blood of people living with HIV (PLHIV) before and after antiretroviral therapy (ART) initiation. We included 41 newly diagnosed, ART-naive individuals with advanced HIV infection, who were followed up for 6 months after ART initiation. The control group included 34 people without HIV (PWHIV), on preexposure prophylaxis for HIV infection. DN T cells in peripheral blood were characterized by flow cytometry. The absolute counts of DN T cells were lower in PLHIV than in PWHIV (p = 0.0223), and were particularly low in individuals with advanced HIV disease (p = 0.0311). Activation of DN T cells before ART initiation was directly associated with viral load (VL) (p = 0.0081, r = 0.4083) and inversely associated with CD4+ T cell counts (p = 0.0004, r = -0.4041). Compared with PWHIV, DN T cells of PLHIV expressed higher levels of CD57 (p = 0.0019), Ki67 (p = 0.0065), PD-1 (p = 0.0187), and CD38/HLA-DR (p < 0.0001). After 6 months on ART, expression of Ki67, PD-1, and CD38/HLA-DR on DN T cells returned to similar levels to those observed in PWHIV (p > 0.05 in all cases). However, expression of CD57 decreased only in individuals that start ART with high VL (p = 0.0127). DN T cell counts are decreased in HIV infection. Low DN T cell counts remained despite ART-induced immune reconstitution and viremia control. DN T cell phenotype is altered during chronic untreated infection with a high proportion of proliferating, activated, exhausted, and senescent cells. Most markers return to levels similar to those observed in PWHIV after ART. The impact of altered phenotype of DN T and their regulatory functions warrants further exploration.

Cardiovascular Disease Among Persons Living With HIV: New Insights Into Pathogenesis and Clinical Manifestations in a Global Context

Widespread use of contemporary antiretroviral therapy globally has transformed HIV disease into a chronic illness associated with excess risk for disorders of the heart and circulatory system. Current clinical care and research has focused on improving HIV-related cardiovascular disease outcomes, survival, and quality of life. In high-income countries, emphasis on prevention of atherosclerotic coronary artery disease over the past decade, including aggressive management of traditional risk factors and earlier initiation of antiretroviral therapy, has reduced risk for myocardial infarction among persons living with human immunodeficiency virus-1 infection. Still, across the globe, persons living with human immunodeficiency virus-1 infection on effective antiretroviral therapy treatment remain at increased risk for ischemic outcomes such as myocardial infarction and stroke relative to the persons without HIV. Unique features of HIV-related cardiovascular disease, in part, include the pathogenesis of coronary disease characterized by remodeling ectasia and unusual plaque morphology, the relative high proportion of type 2 myocardial infarction events, abnormalities of the aorta such as aneurysms and diffuse aortic inflammation, and HIV cerebrovasculopathy as a contributor to stroke risk. Literature over the past decade has also reflected a shift in the profile and prevalence of HIV-associated heart failure, with a reduced but persistent risk of heart failure with reduced ejection fraction and a growing risk of heart failure with preserved ejection fraction. Cardiac magnetic resonance imaging and autopsy data have emphasized the central importance of intramyocardial fibrosis for the pathogenesis of both heart failure with preserved ejection fraction and the increase in risk of sudden cardiac death. Still, more research is needed to better characterize the underlying mechanisms and clinical phenotype of HIV-associated myocardial disease in the current era. Across the different cardiovascular disease manifestations, a common pathogenic feature is that HIV-associated inflammation working through different mechanisms may amplify underlying pathology because of traditional risk and other host factors. The prevalence and phenotype of individual cardiovascular disease manifestations is ultimately influenced by the degree of injury from HIV disease combined with the profile of underlying cardiometabolic factors, both of which may differ substantially by region globally.

Dysregulation of iron metabolism modulators in virologically suppressed HIV-infected patients.

Iron metabolism plays an essential role in cellular functions. Since virologically suppressed chronic HIV-infected subjects under effective antiretroviral treatment (ART) exhibit a persistent immune dysfunction that leads to comorbidities, iron homeostasis may be relevant in this context. We aimed to explore iron metabolism in virologically suppressed chronic HIV infected subjects under a successful ART. In this retrospective study, traditional iron metabolism biomarkers (total iron, ferritin, transferrin, and transferrin saturation index), as well as soluble transferrin receptor (sTfR), hepcidin, and inflammatory markers were determined in virologically suppressed chronic HIV-infected subjects under at least 2 years of ART (HIV) who also had >350 CD4-T-cells/mm3 (N=92) from Spain. As controls, we collected non-HIV age-matched healthy donors (Young, N=25) and elderly subjects (>65 years old; Elderly; N=25). Additionally, an external group of non-HIV patients with ferritin<50 ng/mL diagnosed with absolute iron deficiency (Ferropenic group; N=84) was included. Comparisons between groups were performed using Kruskal-Wallis or Mann-Whitney U-tests, while associations between variables were explored by Spearman's rho correlation coefficient. We selected samples from HIV-infected subjects (aged 42[34-47], 95% males), young age-matched (aged 40[30-58], 60% males), and elderly controls (aged 82[78-88], 100% males). Compared to both healthy (Young and Elderly) groups, HIV exhibited decreased iron, transferrin saturation, and sTfR, and increased ferritin, but similar hepcidin levels. Notably, associations between sTfR and iron (Young, r=-0.587, p=0.002; Elderly, r=-0.496, p=0.012) or transferrin saturation index (Young, r=-0.581, p=0.002; Elderly, r=-0.489, p=0.013) were negative in both controls while positive in HIV (r=0.464, p<0.0001 and r=0.421, p<0.0001, respectively). Moreover, the expected negative correlation between hepcidin and sTfR, observed in controls (Young, r=-0.533, p=0.006; Elderly, r=-0.473, p=0.017), was absent in HIV (r=0.082; p=0.438). Interestingly, the HIV inflammatory profile differed from the Elderly one, who despite their inflammaging-related profile, succeed in maintaining these associations. Furthermore, subjects from the ferropenic group (aged 42[32-51], 5% males), showing significantly lower levels of hepcidin and higher sTfR, as expected, reflected similar correlations as those Young and Elderly, in contrast to HIV. Virologically suppressed chronic HIV-infected patients under successful ART exhibit altered levels of iron metabolism modulators suggesting a complex functional iron deficiency.

Prevalence of intestinal parasites and associated risk factors in HIV positive and negative patients in Northwest Region, Cameroon

Epidemiological understanding of intestinal parasitic infections is essential for the effective management of HIV infection. Therefore, this study was designed to assess the burden of intestinal parasites and associated risk factors. A cross-sectional study was conducted from May to December 2020 during which 200 HIV positive and 200 HIV negative participants were recruited. A total of 400 stool and venous blood samples were collected and used to identify the different intestinal parasites and for HIV diagnosis and viral load determination respectively. Results obtained revealed that the overall prevalence of intestinal parasites was 11% (44/400). Intestinal parasitosis was significantly (p = 0.025) higher in HIV-positive individuals 14.5% (29/200). Similarly, the prevalence of multiple parasitic infection 4.5% (18/400) and opportunistic helminths 3% (6/400) were insignificantly (p > 0.05) higher among HIV-positive individuals. Furthermore, prevalence of intestinal parasites was significantly (p = 0.004) greater in patients with viral load of > 1000 copies/mL 24.3% (13/46). Age group > 65 years, self-employment, living in Sub-urban areas, being HIV positive, primary level of education, use of potable tap water, and the use of water system toilets for faeces disposal were identified as associated risk factors to intestinal parasites. Intestinal parasites remain public health concern among patients with HIV. Prompt and effective antiretroviral treatment is required to reduce the intensity of the parasite.

Functional Restoration of Exhausted CD8 T Cells in Chronic HIV-1 Infection by Targeting Mitochondrial Dysfunction.

CD8 T cell exhaustion is a hallmark of HIV-1 infection, characterized by phenotypic and functional CD8 T cell abnormalities that persist despite years of effective antiretroviral treatment (ART). More recently, the importance of cellular metabolism in shaping T cell antiviral function has emerged as a crucial aspect of immunotherapeutics aimed at re-invigorating exhausted CD8 T cells but remains under-investigated in HIV-1 infection. To gain a better insight into this process and identify new targets for effective CD8 T cell restoration we examined the metabolic profile of exhausted CD8 T cells in HIV-1 infection. We show that relative to HIV-1 elite controllers (EC) and HIV-1 seronegative donors, CD8 T cells from HIV-1 viraemic individuals are skewed toward a PD-1hiEOMEShiT-betlowTIGIT+ phenotype that is maintained during ART. This exhausted signature is enriched in HIV-specific CD8 T cells, compared to CMV-specific CD8 T cell populations, and further delineated by higher expression of the glucose transporter, Glut-1, impaired mitochondrial function and biogenesis, reflecting underlying metabolic defects. A notable improvement in antiviral HIV-specific CD8 T cell function was elicited via mitochondrial antioxidant treatment in combination with pharmacological modulation of mitochondrial dynamics and IL-15 treatment. These findings identify mitochondria as promising targets for combined reconstitution therapies in HIV-1 infection.

Inositol‐requiring enzyme 1 alpha (IRE1α) regulates astrocyte metabolic and inflammatory phenotypes: Implications in (METH)amphetamine use disorder and HIV‐associated neurocognitive disorders

Human immunodeficiency virus 1 (HIV‐1) invades the central nervous system (CNS) early during infection and can persist in the CNS for life despite effective antiretroviral treatment. Infection and activation of residential glial cells leads to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV‐associated neurocognitive disorders (HAND). Astrocytes are the most numerous glial cells in the CNS and provide essential support to neurons. During a neuropathological challenge, such as HIV‐1 infection, astrocytes can shift their neurotrophic functions to become neurotoxic and even serve as latent reservoirs for HIV‐1 infection. Notably, substance use disorders, including methamphetamine (METH) are disproportionately elevated among people living with HIV‐1. METH use can induce neurotoxic and neurodegenerative consequences, which can increase one’s risk and severity of HAND. Thus, a better understanding of HIV‐1 infection and METH exposure both alone and in combination on astrocyte function could help identify key cellular or molecular targets that can regulate astrocyte neuroprotective versus neurotoxic phenotypes to optimize astrocyte and neuronal coupling and combat CNS pathology.Direct contact sites between the endoplasmic reticulum (ER) and the mitochondria, termed mitochondria‐associated ER membranes (MAMs), are central hubs for regulating several cellular processes, including inflammation and mitochondrial function and dynamics. In fact, the transfer of calcium from the ER to mitochondria is essential for mitochondrial bioenergetics. Interestingly, increasing evidence supports that the three arms of the unfolded protein response (UPR) are key cell signaling messengers within the ER‐mitochondrial interface, beyond their classical ER stress functions. Briefly, protein kinase RNA‐like endoplasmic reticulum kinase (PERK) has been determined as a regulator for MAM tethering and mitochondrial morphology. Inositol‐requiring enzyme 1 alpha (IRE1α) is implicated in regulating MAM‐mediated calcium transfer. Activating transcription factor 6 (ATF6) is suspected to participate in MAM formation as it is known to mediate ER elongation and lipid homeostasis. However, these regulatory mechanisms have not yet been fully elucidated.Our studies specifically highlight IRE1α as a key regulator of astrocyte metabolic and inflammatory phenotypes. Using primary human astrocytes infected with pseudotyped HIV and/or exposed to low doses of METH for seven days, astrocytes have increased protein expression of select UPR/MAM mediators. Under the same paradigms, we see increased cytosolic calcium flux and mitochondrial oxygen consumption rate, which were associated with increased mitochondria calcium uptake. Manipulation of IRE1α using both pharmacological inhibitors and an overexpression plasmid, confirms IRE1α modulates astrocyte calcium signaling, metabolic activity, glutamate clearance, and cytokine release. These findings identify a novel target for regulating astrocyte metabolic and inflammatory phenotypes, which could help combat astrocyte‐mediated neurotoxicity and potentially promote a neurotrophic phenotype during CNS pathologies.

Factors Influencing Immune Restoration in People Living with HIV/AIDS.

Introduction: Immune restoration is a key clinical aspect that is pursued in the care of human immunodeficiency virus (HIV)-infected patients. Despite effective antiretroviral treatment and undetectable viremia, immune recovery is often incomplete. Materials and methods: Data from 311 Caucasian patients were collected. SNP in CCR2(rs1799864), CX3CR1(rs3732378), HLAC-35(rs9264942), and CCR5(promoter, rs1799988); a 32bp deletion(Δ32) in CCR5; and HLA-B*5701 genotypes were correlated with clinical data and selected endpoints. Kaplan–Meier and Cox proportional hazards models were used to analyze the effects of genetic factors over time. Results: For HLA-B*5701, the effect on the CD4+/CD8+ >0.8 cell ratio was lost within 48 months (HR = 2.04, 95% CI: 1.04–4.03), and the effect on the CD4+ cell count >500 cells/µL was lost within 12 months (HR = 2.12, CI: 1.11–4.04). The effect of CCR2 GG on the CD4+/CD8+ >0.8 cell ratio was lost within 36 months (HR = 1.7, CI: 1.05–2.75). For CCR5 wt/Δ32, the effect on the CD4+/CD8+ >1.0 cell ratio was lost within 24 months (HR = 2.0, CI: 1.08–3.69), and the effect on the CD4+ >800 cells/µL cell count was lost within 18 months (HR = 1.98, CI: 1.14–4.73). Conclusions: Selected genetic polymorphisms, namely CCR2 GG and CCR5 Δ32, and the presence of the HLA-B*5701 allele positively influenced immune restoration in cART-treated patients with HIV/AIDS.

From Undetectable Equals Untransmittable (U=U) to Breastfeeding: Is the Jump Short?

Background: Vertical transmission of HIV infection may occur during pregnancy, at childbirth or through breastfeeding. Recommendations on the safety of breastfeeding of HIV-infected women on effective antiretroviral treatment are not univocal among international guidelines (WHO 2010, EACS 2017, DHHS 2017), leaving space for variability at the patient’s level. Methods: We collected clinical, laboratory and outcome data from 13 HIV-infected pregnant women who, between March 2017 and June 2021, elected to breastfeed their children against specific medical advice. All mothers were on antiretroviral therapy with darunavir or raltegravir plus emtricitabine/tenofovir disoproxil and remained HIV-RNA undetectable and >400 cells/mmc CD4+ lymphocytes during pregnancy and breastfeeding. Prophylactic antiretroviral therapy (zidovudine for 4 weeks) was started immediately after birth in all newborns. The mean duration of breastfeeding was 5.4 months. Newborns were tested for HIV-RNA multiple times: at birth, 1, 3, and 6 months after birth, and 1, 3 and 6 months after the end of breastfeeding. Results: None of the infants were infected by HIV. Conclusions: Our experience, gathered in the setting of freedom of choice on the patient’s side, while insufficient to address the eventual safety of breastfeeding in HIV-infected mothers since the represented cohort is numerically irrelevant, supports the extension of the U=U (Undetectable Equals Untransmittable) paradigm to this setting. Since breastfeeding is often requested by women with HIV planning pregnancy, more extensive comparative studies should be performed.

Enhancing well-being and alleviating depressive symptoms in people with HIV/AIDS: An intervention based on if-then plans with self-affirming cognitions.

Effective antiretroviral treatment has increased the life expectancy of people living with HIV, and currently, the challenges of prominent importance appear to be mental health issues. This preregistered study among adults living with HIV/AIDS investigated the effectiveness of a brief self‐affirmation intervention framed in terms of if–then plans (i.e. self‐affirming implementation intentions [S‐AII]) against both active and non‐active control conditions, forming non‐affirming implementation intentions and mere goal intentions, respectively. The primary outcomes were defined as a reduction of depressive symptoms and enhancement of well‐being, along with secondary outcomes as positive other‐ and self‐directed feelings. A total of 162 individuals were assessed for eligibility, and 130 (aged 18–74 years) were randomized to the study conditions. Intervention effects were estimated through intention‐to‐treat analysis, using linear mixed models. The S‐AII intervention yielded improvements in overall well‐being over 2 weeks (d = .23), primarily driven by positive changes in emotional (d = .24) and social (d = .30) dimensions of well‐being. There were no significant differences in depression or secondary outcomes. Based on a minimal clinically important difference index, the S‐AII intervention resulted in improvement in well‐being in approximately 40 percent of participants. Nevertheless, further systematic research is needed to optimize self‐affirmation‐interventions, before their application in real‐life contexts.

SARS-CoV-2 transmission: time to rethink public health strategy

SARS-CoV-2 transmission: time to rethink public health strategy

Management of a human immunodeficiency virus case with discordant antiviral drug resistance profiles in cerebrospinal fluid compared with plasma: a case report

BackgroundHuman immunodeficiency virus-1-associated neurocognitive disorder is a known complication in individuals treated with antiretroviral therapy. Cerebrospinal fluid escape, which is defined as discordant higher cerebrospinal fluid viremia than plasma, may occur in antiretroviral therapy-experienced individuals. Different cerebrospinal fluid versus plasma mutation patterns have been observed in individuals with cerebrospinal fluid escape.Case presentationA 46-year-old adult African male with human immunodeficiency virus-1 infection and acquired immunodeficiency syndrome based on cerebral toxoplasmosis and a chronic hepatitis B virus infection developed cerebrospinal fluid escape. A different human immunodeficiency virus-1 genotypic drug resistance profile was observed in plasma compared with cerebrospinal fluid. Brain biopsy and cerebral magnetic resonance imaging indicated the development of human immunodeficiency virus encephalopathy. A discordant protease inhibitor mutation/wild-type T74PT in plasma but not in cerebrospinal fluid indicated poor central nervous system penetration due to the selective pressure of drug therapy. An intensified antiretroviral therapy regimen including dolutegravir with good central nervous system penetration improved conditions.ConclusionsThis case shows the importance of measuring human immunodeficiency virus drug resistance in cerebrospinal fluid, which might differ from resistance detected in plasma samples and target effective antiretroviral therapy treatment accordingly.

Randomized, Blinded, Placebo-Controlled Trial of De Simone Formulation Probiotic During HIV-Associated Suboptimal CD4+ T Cell Recovery.

To assess whether probiotic supplementation may reduce disease-linked systemic immune activation in people living with HIV with the immunologic nonresponder phenotype. Phase 2b, randomized, double-blind, placebo-controlled pilot trial. HIV-positive individuals with blood CD4+ T-cell counts <350/mm3 despite viral suppression were randomized to 2:1 to receive De Simone Formulation Probiotic (DSFP; "Visbiome" commercially) or placebo for 48 weeks; target enrollment was 36 patients. The primary endpoint was the change in blood CD8+ T-cell coexpression of human leukocyte antigen-DR isotype and CD38 ("CD8 activation"). Secondary endpoints included biomarkers of inflammation, immune reconstitution, bacterial translocation, and gut permeability. Adjusted linear regression and linear mixed regression methods evaluated the differences between study arms from baseline to week 48. Study monitoring was performed by the CIHR Canadian HIV Trials Network Data Safety Monitoring Committee. Nineteen patients received DSFP, whereas 10 received placebo. One probiotic arm patient withdrew early. Blood CD8 activation increased 0.82 percentage points (pp) in the probiotic arm (95% confidence interval: -1.23 to 2.87;) and decreased by 2.06 pp in the placebo arm (-4.81 to 0.70; between arms P = 0.097). CD4+ T-cell activation (%HLA-DR+) decreased in the placebo arm [-3.79 pp (-7.32 to -0.26)] but increased in the probiotic arm [1.64 (-0.98 to 4.26); between arms P = 0.018]. No differences were observed in plasma or urine biomarkers of inflammation or microbial translocation. Blood immune activation markers in immunologic nonresponder individuals on effective antiretroviral treatment were not reduced by supplementation with DSFP; CD4+ T-cell activation may have been increased.