Lack of susceptibility in neonatally infected rhesus macaques to simian immunodeficiency virus-induced encephalitis.

Despite combination antiretroviral therapies making HIV a chronic rather than terminal condition for many people, the prevalence of HIV-associated neurocognitive disorders (HAND) is increasing. This is especially problematic for children living with HIV. Children diagnosed HAND rarely display the hallmark pathology of HIV encephalitis in adults, namely infected macrophages and multinucleated giant cells in the brain. This finding has also been documented in rhesus macaques infected perinatally with simian immunodeficiency virus (SIV). However, the extent and mechanisms of lack of susceptibility to encephalitis in perinatally HIV-infected children remain unclear. In the current study, we compared brains of macaques infected with pathogenic strains of SIV at different ages to determine neuropathology, correlates of neuroinflammation, and potential underlying mechanisms. Encephalitis was not found in the macaques infected within 24 h of birth despite similar high plasma viral load and high monocyte turnover. Macaques developed encephalitis only when they were infected after 4 months of age. Lower numbers of CCR5-positive cells in the brain, combined with a less leaky blood-brain barrier, may be responsible for the decreased virus infection in the brain and consequently the absence of encephalitis in newborn macaques infected with SIV.

Long-term pulmonary complications in perinatally HIV-infected youth.

BACKGROUND: Increased incidence and prevalence of asthma have been documented for perinatally HIV-infected youth 10 to 21 years of age compared with HIV-exposed uninfected (HEU) youth. OBJECTIVE: We sought to perform objective pulmonary function tests (PFTs) in HIV-infected and HEU youth with and without diagnosed asthma. METHOD: Asthma was determined in 370 participants (218 HIV-infected and 152 HEU participants) by means of chart review and self-report at 13 sites. Interpretable PFTs (188 HIV-infected and 132 HEU participants) were classified as obstructive, restrictive, or normal, and reversibility was determined after bronchodilator inhalation. Values for HIV-1 RNA, CD4 and CD8 T cells, eosinophils, total IgE, allergen-specific IgE, and urinary cotinine were measured. Adjusted prevalence ratios (PRs) of asthma and PFT outcomes were determined for HIV-infected participants relative to HEU participants, controlling for age, race/ethnicity, and sex. RESULTS: Current asthma was identified in 75 (34%) of 218 HIV-infected participants and 38 (25%) of 152 HEU participants (adjusted PR, 1.33; P = .11). The prevalence of obstructive disease did not differ by HIV status. Reversibility was less likely in HIV-infected youth than in HEU youth (17/183 [9%] vs 21/126 [17%]; adjusted PR, 0.47; P = .020) overall and among just those with obstructive PFT results (adjusted PR, 0.46; P = .016). Among HIV-infected youth with current asthma, serum IgE levels were inversely correlated with CD8 T-cell counts and positively correlated with eosinophil counts and not associated with CD4 T-cell counts. HIV-infected youth had lower association of specific IgE levels to several inhalant and food allergens compared with HEU participants and significantly lower CD4/CD8 T-cell ratios (suggesting immune imbalance). CONCLUSION: Compared with HEU youth, HIV-infected youth demonstrated decreased reversibility of obstructive lung disease, which is atypical of asthma. This might indicate an early stage of chronic obstructive pulmonary disease. Follow-up into adulthood is warranted to further define their pulmonary outcomes.

Distinct fecal microbial signatures are linked to sex and chronic immune activation in pediatric HIV infection.

Introduction: Our understanding of HIV-associated gut microbial dysbiosis in children perinatally-infected with HIV (CLWH) lags behind that of adults living with HIV. Childhood represents a critical window for the gut microbiota. Any disturbances, including prolonged exposure to HIV, antiretroviral drugs, and antibiotics are likely to have a significant impact on long-term health, resulting in a less resilient gut microbiome. The objective of our study was to characterize the gut microbiota in CLWH, and compare it with HIV-unexposed and -uninfected children. Methods: We enrolled 31 children aged 3 to 15 years; 15 were CLWH and 16 were HUU. We assessed dietary patterns and quality; quantified soluble and cellular markers of HIV disease progression by flow cytometry, enzyme-linked immunosorbent and multiplex-bead assays, and profiled the gut microbiota by 16S rRNA sequencing. We explored relationships between the gut microbiota, antibiotic exposure, dietary habits, soluble and cellular markers and host metadata. Results: Children had a Western-type diet, their median health eating index score was 67.06 (interquartile range 58.76-74.66). We found no discernable impact of HIV on the gut microbiota. Alpha diversity metrics did not differ between CLWH and HUU. Sex impacted the gut microbiota (R-squared= 0.052, PERMANOVA p=0.024). Male children had higher microbial richness compared with female children. Two taxa were found to discriminate female from male children independently from HIV status: Firmicutes for males, and Bacteroides for females. Markers of HIV disease progression were comparable between CLWH and HUU, except for the frequency of exhausted CD4+ T cells (PD-1+) which was increased in CLWH (p=0.0024 after adjusting for confounders). Both the frequency of exhausted CD4+ and activated CD4+ T cells (CD38+ HLADR+) correlated positively with the relative abundance of Proteobacteria (rho=0.568. false discovery rate (FDR)-adjusted p= 0.029, and rho=0.62, FDR-adjusted p=0.0126, respectively). Conclusion: The gut microbiota of CLWH appears similar to that of HUU, and most markers of HIV disease progression are normalized with long-term ART, suggesting a beneficial effect of the latter on the gut microbial ecology. The relationship between exhausted and activated CD4+ T cells and Proteobacteria suggests a connection between the gut microbiome, and premature aging in CLWH.

Highlights from the Inaugural HIV Reservoirs and Immune Control Conference, October 1st-4th 2023, Malahide Ireland.

The inaugural FASEB HIV Reservoirs and Immune Control Conference brought researchers together from across the globe to discuss reservoir dynamics in clinical cohorts. It extended over 4 days in the seaside town of Malahide, Ireland. The scientific sessions covered a broad range of topics, including: 1) HIV pathogenesis and control, 2) reservoirs and viral expression, 3) pediatric reservoirs, 4) innate immunity and B cell responses, 5) environmental factors affecting pathogenesis, 6) loss of virologic control, and 7) HIV-2. The following article provides a brief summary of the meeting proceedings and includes a supplementary document with the meeting abstracts.

Metabolic Changes in Pediatric HIV-Positive Patients and Potential Lifestyle Interventional Strategies.

Metabolic changes in the HIV population have been well-studied, particularly after the advent of antiretroviral therapy. More notably, the emergence of the metabolic syndrome within the HIV population, due to prolonged survival, has led to an increasing rate of cardiovascular occurrence and mortality within the population in adult life. Importance of early intervention in HIV children, particularly lifestyle modifications, is necessary to reduce cardiovascular disease (CVD) risk and mortality in adulthood. Potential clinical interventions include routine anthropometric measurements as a measure of CVD risk, a low saturated fat and high fiber diet, and vigorous aerobic exercise have been shown to decrease CVD risk in the HIV population. The literature review found multiple knowledge gaps due to minimal studies completed on the HIV population and even less on HIV-positive children. Overall, a standardized protocol was required to better care for HIV-positive children and potential future CVD mortality.

Viral Tropism in Human Immunodeficiency Virus Type 1-Infected Children and Adolescents in Thailand.

BACKGROUND: Maraviroc, a C-C chemokine receptor 5 (CCR5) antagonist, has been used as an alternative antiretroviral drug in treatment-experienced adults and children infected by CCR5-tropic human immunodeficiency virus type 1 (HIV-1) isolates. Prior to widespread use of this drug, rates of HIV-1 coreceptor tropism and factors associated with coreceptor tropism had to be determined. METHODS: HIV-1-infected individuals aged <20 years with HIV-1 viral loads >1000 RNA copies/mL who were treatment-experienced or treatment-naive were enrolled. HIV-1 coreceptor tropism was determined using a genotypic test in which V3 sequences were analyzed with GENO2PHENO version 2.5 and a false discovery rate of 5%. RESULTS: Fifty-two HIV-1-infected patients were recruited. The median age of participants was 14.9 years (interquartile range [IQR], 8.9-16.8 years). The median CD4 cell count was 396.0 cells/µL (IQR, 72.0-630.3 cells/µL). The median HIV-1 viral load was 43 339 RNA copies/mL (IQR, 8874-197 055 copies/mL). Thirty-nine patients (75%) were treatment-experienced. The most prevalent HIV-1 subtype in this population was CRF01_AE (36 patients, 69.2%). Based on analyses of V3 loop sequences, 5 of 13 treatment-naive patients (38.5%) and 11 of 39 treatment-experienced patients (28.2%) were infected by R5 viruses, while 7 of 13 treatment-naive patients (53.8%) and 19 of 39 treatment-experienced patients (48.7%) were infected by X4 viruses. The only factor associated with the presence of X4 viruses was HIV-1 subtype CRF01_AE. CONCLUSIONS: X4-tropic viruses are associated with the CRF01_AE subtype. Hence, testing of HIV tropism should be performed before treatment with CCR5 inhibitors in children in areas where CRF01_AE predominates.

Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children.

Pediatric slow progressors (PSP) are rare ART-naïve, HIV-infected children who maintain high CD4 T-cell counts and low immune activation despite persistently high viral loads. Using a well-defined cohort of PSP, we investigated the role of regulatory T-cells (TREG) and of IL-7 homeostatic signaling in maintaining normal-for-age CD4 counts in these individuals. Compared to children with progressive disease, PSP had greater absolute numbers of TREG, skewed toward functionally suppressive phenotypes. As with immune activation, overall T-cell proliferation was lower in PSP, but was uniquely higher in central memory TREG (CM TREG), indicating active engagement of this subset. Furthermore, PSP secreted higher levels of the immunosuppressive cytokine IL-10 than children who progressed. The frequency of suppressive TREG, CM TREG proliferation, and IL-10 production were all lower in PSP who go on to progress at a later time-point, supporting the importance of an active TREG response in preventing disease progression. In addition, we find that IL-7 homeostatic signaling is enhanced in PSP, both through preserved surface IL-7receptor (CD127) expression on central memory T-cells and increased plasma levels of soluble IL-7receptor, which enhances the bioactivity of IL-7. Combined analysis, using a LASSO modeling approach, indicates that both TREG activity and homeostatic T-cell signaling make independent contributions to the preservation of CD4 T-cells in HIV-infected children. Together, these data demonstrate that maintenance of normal-for-age CD4 counts in PSP is an active process, which requires both suppression of immune activation through functional TREG, and enhanced T-cell homeostatic signaling.

Moving forward with treatment options for HIV-infected children.

INTRODUCTION: Current international guidelines recommend to treat all HIV-1 infected patients regardless of CD4 cell count. Despite the remarkable worldwide progress for universal access to antiretroviral during the last decade, the pediatric population remains fragile due to lack of randomized studies, inappropriate antiretroviral formulations, adherence difficulties, drug toxicity and development of resistance. AREAS COVERED: This review summarizes the latest recommendations and advances for the treatment of HIV-infected children and highlights the potential complications of a lifelong antiretroviral treatment initiated early in life. EXPERT OPINION: International guidelines recommend to start combination antiretroviral therapy (cART) as fast as possible in all children diagnosed with HIV-1. The principal goal is to improve survival and reduce mortality as well as rapidly decrease HIV reservoirs. This remains a challenge in resource-limited settings were diagnostic tools and treatment access may be limited. Different new strategies are in the pipeline such as immunotherapy in combination with very early cART initiation to seek remission or functional cure. For the time being and awaiting for long term remission or cure, there is a need for further pharmacokinetics studies, more pediatric formulations with improved palatability and implementation of randomized trials for the newer antiretroviral drugs.

Assessment of neurological soft signs in pediatric patients with HIV infection.

BACKGROUND: Children and adolescents comprise a significant proportion of people living with HIV. The effects of HIV on the growing brain have generated interest among researchers in this field. Deficits arising during this crucial phase of neuromaturation due to HIV infection need to be assessed and addressed. Neurological soft signs (NSSs) can act as a proxy marker for underlying neuropsychological deficits. The present study aims to study the NSSs in pediatric patients with HIV and compare with healthy controls (HCs). MATERIALS AND METHODS: Forty-eight children aged between 6 and 16 years diagnosed with HIV were selected by purposive sampling, and the Physical and Neurological Examination of Soft Signs (PANESS) scale was applied. Fifty children matched by age and sex were recruited from a nearby school, and the PANESS scale was applied. Children were divided into age- and gender-specific groups. The outcome scores of cases and controls groups were compared. RESULTS: Males and females aged 13-16 years with HIV showed more soft signs as compared to HCs, with respect to gait errors, dysrhythmia, impersistence, speed of repetitive and sequenced movements, overflow with gaits, overflow with sequenced movements, total overflow, and overflow in excess of age. The differences in scores were less marked in younger age groups among both the genders. CONCLUSIONS: The persistence of NSSs in older age group in HIV-infected children may point toward the presence of HIV-associated neurological disorder.

High-Frequency, Functional HIV-Specific T-Follicular Helper and Regulatory Cells Are Present Within Germinal Centers in Children but Not Adults.

Broadly neutralizing antibodies (bnAbs) against HIV-1 are an effective means of preventing transmission. To better understand the mechanisms by which HIV-specific bnAbs naturally develop, we investigated blood and lymphoid tissue in pediatric infection, since potent bnAbs develop with greater frequency in children than adults. As in adults, the frequency of circulating effector T-follicular helper cells (TFH) in HIV infected, treatment naïve children correlates with neutralization breadth. However, major differences between children and adults were also observed both in circulation, and in a small number of tonsil samples. In children, TFH cells are significantly more abundant, both in blood and in lymphoid tissue germinal centers, than in adults. Second, HIV-specific TFH cells are more frequent in pediatric than in adult lymphoid tissue and secrete the signature cytokine IL-21, which HIV-infected adults do not. Third, the enrichment of IL-21-secreting HIV-specific TFH in pediatric lymphoid tissue is accompanied by increased TFH regulation via more abundant regulatory follicular T-cells and HIV-specific CXCR5+ CD8 T-cells compared to adults. The relationship between regulation and neutralization breadth is also observed in the pediatric PBMC samples and correlates with neutralization breadth. Matching neutralization data from lymphoid tissue samples is not available. However, the distinction between infected children and adults in the magnitude, quality and regulation of HIV-specific TFH responses is consistent with the superior ability of children to develop high-frequency, potent bnAbs. These findings suggest the possibility that the optimal timing for next generation vaccine strategies designed to induce high-frequency, potent bnAbs to prevent HIV infection in adults would be in childhood.

Four-year persistence of type-specific immunity after quadrivalent human papillomavirus vaccination in HIV-infected children: Effect of a fourth dose of vaccine.

OBJECTIVE: Although HIV-infected children are recommended to receive quadrivalent human papillomavirus vaccine (QHPV) there is limited information on their response to QHPV. This study in HIV-infected children, evaluated the magnitude and duration of immune responses to QHPV. This report describes type-specific serum antibody responses over a 4-to-5year period after either 3 or 4 doses of QHPV. DESIGN/METHODS: HIV-infected children, ages 7-to-11years, received 3 doses of QHPV (n=96) or placebo (n=30). At 72weeks QHPV recipients received a fourth dose (n=84), while placebo recipients began the 3-dose QHPV schedule (n=27). HPV serotype-specific antibody was determined, by competitive Luminex immunoassay (cLIA) and IgG Luminex immunoassay, at 2, 3.5, and 4-to-5years after the last dose of QHPV in each treatment arm. RESULTS: At 4-to-5years after the last dose of QHPV, antibody titers were significantly higher in 4-dose than in 3-dose group. However, the proportion of vaccinees with a seroresponse in the cLIA assay was not different between the two groups (86-93% for HPV types 6, 11, and 16, and 64% for HPV type 18). These results were very similar to the seroresponse rate in these HIV-infected children at 1month after completing vaccination. CONCLUSIONS: Children with well-controlled HIV infection who receive 3 doses of the QHPV vaccine maintain seropositivity and antibody levels that are generally similar to children of the same age who are not HIV-infected. Antibody titer correlated strongly with low log HIV RNA, low CD8%, and high CD4%. Additionally, a fourth dose of vaccine in HIV-infected children produces a marked rise in antibody characteristic of an anamnestic response and persistence of high antibody levels. Study identification: IMPAACT P1085 (V501-021). CLINICALTRIALS.GOV identifier: NCT01206556.