Although rollout of combined antiretroviral treatment (cART) has blunted human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) onset, there is increased development of cardiovascular diseases (CVDs) in HIV-infected individuals. While most HIV-infected individuals on cART achieve viral suppression, this may not necessarily result in complete immunological recovery. This study therefore evaluated T-cell-mediated changes and coagulation markers in HIV-positive individuals to ascertain their potential to increase CVD risk. Eighty participants were recruited (Worcester, South Africa), and fasted blood was collected to evaluate: 1) immune activation (CD38 expression on CD4⁺and CD8⁺T cells) and thrombus formation [tissue factor (CD142)] on CD4⁺and CD8⁺T cells; 2) monocyte subpopulations (nonclassical, intermediate, and classical); and 3) classical regulatory T (Treg) cells with activation markers [glycoprotein A repetitions predominant (GARP) and special AT-rich sequence-binding protein 1 (SATB-1)]. High- and low-density lipoprotein subclasses (Lipoprint) were also determined. This study revealed four key findings for HIV-positive patients: 1) coexpression of the CD142 coagulation marker together with immune activation on both CD4⁺and CD8⁺T cells during chronic infection stages; 2) Treg cell activation and upregulated GARP and SATB-1 contributing to Treg dysfunction in chronic HIV; 3) proatherogenic monocyte subset expansion with significant correlation between T-cell activation and macrophage activation (marker: CD163); and 4) significant correlation between immune activation and lipid subclasses, revealing crucial changes that can be missed by traditional lipid marker assessments (LDL and HDL). These data also implicate lipopolysaccharide-binding protein as a crucial link between immune activation, lipid alterations, and increased CVD risk.NEW & NOTEWORTHY With combined antiretroviral treatment rollout, HIV-AIDS patients are increasingly associated with cardiovascular diseases onset. This study demonstrated the significant interplay between adaptive immune cell activation and monocyte/macrophage markers in especially HIV-positive individuals with virological failure and on second line treatment. Our data also show a unique link between immune activation and lipid subclass alterations, revealing important changes that can be missed by traditional lipid marker assessments (e.g., LDL and HDL).

Co-infection with HIV negatively impacts the progression of chronic hepatitis B virus (HBV) infection, including causing rapid progression to liver fibrosis. Sub-Saharan Africa represents arguably the most important intersection of high endemicity of both chronic hepatitis B virus (HBV) infection and HIV infection. We recruited 46 HBV/HIV-co-infected; 47 HBV-monoinfected; 39 HIV-monoinfected; and 37 HBV/HIV-uninfected patients from Tygerberg Hospital, Cape Town, South Africa. All HIV-infected patients were on antiretroviral therapy for ≥3 months. Liver stiffness measurements were assessed using the Fibroscan (Fibroscan 402, Echosens). Cell-based immunomarkers were measured by flow cytometry. Soluble serum/plasma immunomarkers were measured by Luminex technology and enzyme immunoassays. HIV (COBAS/Ampliprep TaqMan HIV-1) and HBV viral loads (in-house assay) were also performed. HBV/HIV co-infected patients showed significantly higher levels of immune activation %CD8+/HLA-DR+/CD38+ (median 30%, interquartile range: 17–53) and %CD8+/PD-1 (median 22%, interquartile range: 15–33), p ≤ 0.01 compared to all other study groups. Despite this, the HBV-mono-infected group had the highest proportion of patients with advanced liver fibrosis (≥13 kPa) as measured by Fibroscan (18%). HBV mono-infected patients showed highest expression of most cytokines including IL-17 and basic fibroblastic growth factor. There was significant positive correlation between detectable HIV and HBV viral replication and liver fibrosis but not immune activation or gut translocation. Highly-active antiretroviral therapy, including tenofovir, is effective against both HIV and HBV. Earlier therapy in the co-infected patients may therefore have controlled viral replication leading to better fibrosis scores when compared to HBV mono-infection in this study. On-going HBV and HIV viraemia, rather than microbial translocation or immune activation, appear to be the drivers of liver fibrosis. Moderate to advanced liver fibrosis in HBV-mono-infection may well indicate poor access to screening and treatment of HBV infection.

Immune activation, which is accompanied by the production of proinflammatory cytokines, is a strong predictor of disease progression in HIV infection. Inflammation is critical in neuronal damage linked to HIV-associated neurocognitive disorders. We examined the relationship between plasma cytokine levels and deficits in neurocognitive function. Multiplex profiling by Luminex^® technology was used to quantify 27 cytokines/chemokines from 139 plasma samples of people living with HIV (PLWH). The relationship of plasma cytokine markers, clinical parameters, and cognitive impairment, was assessed using Spearman correlations. Partial least squares regression and variable importance in projection scores were used for further evaluation of the association. Forty-nine (35.3%) participants exhibited neurocognitive impairment based on a global deficit score (GDS) of at least 0.5 and 90 (64.7%) were classified as nonimpaired. Twenty-three (16.5%) initiated on combination antiretroviral therapy for 4 weeks before cognitive assessment and 116 (83.5%) were not on treatment. We identified five proinflammatory cytokines that were significant predictors of GDS namely, IP-10 (β = 0.058; p = .007), RANTES (β = 0.049; p = .005), IL-2 (β = 0.047, p = .006), Eotaxin (β = 0.042, p = .003), and IL-7 (β = 0.039, p = .003). IP-10 and RANTES were the strongest predictors of GDS. Both cytokines correlated with plasma viral load and lymphocyte proviral load and were inversely correlated with CD4⁺ T cell counts. IP-10 and RANTES formed a separate cluster with highest proximity. Study findings describe novel associations among IP-10, RANTES, cognitive status, plasma viral load, and cell-associated viral load.

The pathogenesis of HIV-associated neurocognitive disorders is complex and multifactorial. It is hypothesized that the critical events initiating this condition occur outside the brain, particularly in the peripheral blood. Diagnoses of HIV-induced neurocognitive disorders largely rely on neuropsychometric assessments, which are not precise. Total HIV DNA in the peripheral blood mononuclear cells (PBMCs), quantified by PCR, correlate with disease progression, which is a promising biomarker to predict HAND. Numerous PCR assays for HIV DNA in cell compartments are prone to variation due to the lack of standardization and, therefore, their utility in predicting HAND produced different outcomes. This review evaluates the clinical relevance of total HIV DNA in circulating mononuclear cells using different published quantitative PCR (qPCR) protocols. The rationale is to shed light on the most appropriate assays and sample types used to accurately quantify HIV DNA load, which predicts severity of neurocognitive impairment. The role of monocytes as a vehicle for trafficking HIV into the CNS makes it the most suitable sample for determining a HAND associated reservoir. Studies have also shown significant associations between monocyte HIV DNA levels with markers of neurodamage. However, qPCR assays using PBMCs are cheaper and available commercially, thus could be beneficial in clinical settings. There is need, however, to standardise DNA extraction, normalisation and limit of detection.

Summary: Inborn errors of immunity (IEI) are inherited monogenic disorders resulting in defective immune response. Non‐infectious presentations are increasingly more apparent. Widely available, cost‐effective early indicators are needed. Peripheral‐blood cytopenia may be a presenting laboratory feature or an observed secondary phenomenon. This retrospective review of the South African Primary Immunodeficiency Registry (SAPIDR) aimed to assess the haematological indices at presentation and their association with the International Union of Immunological Societies (IUIS) 2019 IEI classification and mortality. Of 396 patients on the SAPIDR, 66% (n = 257) had available haematological results. Sixty percent were males and 85% under 18 years. A majority (53%) had predominantly antibody deficiency. At presentation, infection was prominent (86%) followed by cytopenia (62%). Neutropenia was associated with IUIS III [odds ratio (OR) 3.65, confidence interval (CI) 1.44–9.25], thrombocytopenia with IUIS II (OR 14.39, CI 2.89–71.57), lymphopenia with IUIS I (OR 12.16, CI 2.75–53.73) and pancytopenia with IUSI I (OR 12.24, CI 3.82–39.05) and IUIS II (OR 5.99, CI 2.80–12.76). Cytopenia showed shorter overall survival (OR 2.81, CI 1.288–4.16). Cytopenias that are severe, persistent, unusual and/or recurrent should prompt further investigation for IEI. The full blood count and leucocyte differential may facilitate earlier identification and serve as an adjunct to definitive molecular classification.

Background: Antiretroviral therapy (ART) started between 7 and 12 weeks of age improves neurodevelopmental outcomes in HIV-infected (HIV+) infants, but the impact of even earlier initiation is not yet described.Objective: We assessed the early neurodevelopment of HIV+ infants who started ART within 21 days of life. Methods: Participants were enrolled from the public sector birth HIV-diagnosis program. Inclusion criteria included: birth weight 2000g, infant commencing ART 6 weeks and no infant Cytomegalovirus disease. ART included Zidovudine/Lamivudine/Nevirapine for the first 2 weeks, the latter then replaced by Lopinavir/Ritonavir. Once body weight 3kg and gestational age 44 weeks, Abacavir replaced Zidovudine. The Griffiths Mental Development Scales (GMDS) were administered at 10-12 months.Results: Of 29 infants assessed, 23 (79%) were girls. Mean birth weight was 3002 ± 501g. Twenty-four mothers (83%) received ART during pregnancy. Seven (24%) infants were diagnosed HIV+ within 48 hours of birth. Median [IQR] viral load (VL) at diagnosis was 3904 [259;16922] copies/ml, age starting ART was 6.0 [3;10] days and age at VL suppression was 19.1 [15; 36] weeks. At the GMDS assessment nine (31%) participants had detectable VL and 26 (90%) had WHO clinical stage I disease. GMDS was performed at a mean age of 11.5±0.8 months. Mean quotients were within the average range: Global Griffiths score was 103.6±10.9 and mean quotients on the subscales ranged from lowest 95.9±13.4 for Locomotor to highest 112.8±11.3 for Hearing-and-language.Conclusion: Preliminary findings in this small group suggest that early neurodevelopmental scores are within the normal range in infants with perinatal HIV-infection who started ART at a median of 6 days.