BACKGROUND: Identifying a quantitative biomarker of neuropsychiatric dysfunction in people with HIV (PWH) remains a significant challenge in the neuroHIV field. The strongest evidence to date implicates the role of monocytes in central nervous system (CNS) dysfunction in HIV, yet no study has examined monocyte subsets in blood as a correlate and/or predictor of neuropsychiatric function in virally suppressed PWH. METHODS: In 2 independent cohorts of virologically suppressed women with HIV (vsWWH; n = 25 and n = 18), whole blood samples were obtained either in conjunction with neuropsychiatric assessments (neuropsychological [NP] test battery, self-report depression and stress-related symptom questionnaires) or 1 year prior to assessments. Immune cell subsets were assessed by flow cytometry. RESULTS: A higher proportion of intermediate monocytes (CD14 ⁺ CD16 ⁺ ) was associated with lower global NP function when assessing monocytes concurrently and approximately 1 year before (predictive) NP testing. The same pattern was seen for executive function (mental flexibility) and processing speed. Conversely, there were no associations with monocyte subsets and depression or stress-related symptoms. Additionally, we found that a higher proportion of classical monocytes was associated with better cognition. CONCLUSION: Although it is widely accepted that lentiviral infection of the CNS targets cells of monocyte-macrophage-microglial lineage and is associated with an increase in intermediate monocytes in the blood and monocyte migration into the brain, the percentage of intermediate monocytes in blood of vsWWH has not been associated with neuropsychiatric outcomes. Our findings provide evidence for a new, easily measured, blood-based cognitive biomarker in vsWWH. FUNDING: R01-MH113512, R01-MH113512-S, P30-AI094189, R01-MH112391, R01-AI127142, R00-DA044838, U01-AI35004, and P30-MH075673

BACKGROUND. HIV-1–infected CD4⁺ T cells contribute to latent reservoir persistence by proliferating while avoiding immune recognition. Integration features of intact proviruses in elite controllers (ECs) and people on long-term therapy suggest that proviruses in specific chromosomal locations can evade immune surveillance. However, direct evidence of this mechanism is missing. METHODS. In this case report, we characterized integration sites and full genome sequences of expanded T cell clones in an EC before and after chemoradiation. We identified the cognate peptide of infected clones to investigate cell proliferation and virus production induced by T cell activation, and susceptibility to autologous CD8⁺ T cells. RESULTS. The proviral landscape was dominated by 2 large clones with replication-competent proviruses integrated into zinc finger (ZNF) genes (ZNF470 and ZNF721) in locations previously associated with deeper latency. A third nearly intact provirus, with a stop codon in Pol, was integrated into an intergenic site. Upon stimulation with cognate Gag peptides, infected clones proliferated extensively and produced virus, but the provirus in ZNF721 was 200-fold less inducible. While autologous CD8⁺ T cells decreased the proliferation of cells carrying the intergenic provirus, they had no effect on cells with the provirus in the ZNF721 gene. CONCLUSIONS. We provide direct evidence that upon activation of infected clones by cognate antigen, the lower inducibility of intact proviruses in ZNF genes can result in immune evasion and persistence. FUNDING. Office of the NIH Director and National Institute of Dental & Craniofacial Research; NIAID, NIH; Johns Hopkins University Center for AIDS Research.

Developing strong animal models is essential for furthering our understanding of how the immune system functions in response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. The alarming speed at which SARS-CoV-2 has spread, and the high mortality rate of severe Coronavirus Disease 2019 (COVID-19), has required both basic science and clinical research to move at an unprecedented pace. Models previously developed to study the immune response against SARS-CoV have been rapidly deployed to now study SARS-CoV-2. To date, both small and large animal models are remarkably consistent when infected with SARS-CoV-2; however, certain models have proven more useful when answering specific immunological questions than others. Small animal models, such as Syrian hamsters, ferrets, and mice carrying the hACE2 transgene, appear to reliably recapitulate the initial cytokine surge seen in COVID-19 as well as show significant innate and adaptive cell infiltration in to the lung early in infection. Additionally, these models develop strong antibody responses to the virus, are protected from reinfection, and genetically modified versions exist that can be used to ask specific immunological questions. Large animal models such as rhesus and cynomologus macaques and African green monkeys are critical to understanding how the immune system responds to SARS-CoV-2 infection because they are considered to be the most similar to humans. These models are considered the gold standard for assessing vaccine efficacy and protection, and recapitulate the initial cytokine surge, immune cell infiltration into the lung, certain aspects of thrombosis, and the antibody and T-cell response to the virus. In this review, we discuss both small and large animal model studies previously used in SARS-CoV-2 research that may be useful in elucidating the immunological contributions to hallmark syndromes observed with COVID-19.

Objective: Early life trauma (ELT) and HIV are associated with social processing deficits. In people with HIV (PWH), we examined whether facial emotion identification accuracy differs by ELT and whether neuroendocrine factors including cortisol, oxytocin (OT), and arginine vasopressin, and/or immune system measures play a role in the ELT-performance association. Methods: We used secondary data from the placebo condition of a pharmacologic challenge study in PWH. Presence of ELT was measured with the Childhood Trauma Questionnaire (at least moderate experiences of sexual, physical, and/or emotional abuse). Social processing was measured with the Facial Emotion Perception Test (FEPT). Salivary immune system measures and cortisol were sampled across a 5-hour study session. Blood was collected at study session start (12 pm ) to measure OT and arginine vasopressin. We examined the association of ELT with FEPT and five biological moderators (from principal components analysis of 12 biomarkers) of ELT-FEPT associations. Results: Of 58 PWH (42 men; mean [standard deviation] age = 33.7 [8.9] years), 50% endorsed ELT. ELT-exposed PWH demonstrated lower identification accuracy across all emotional expressions (unstandardized β [ B ] = 0.13; standard error [SE] = 0.05; p = .021, d = 0.63) and had higher OT levels compared with ELT-unexposed PWH ( t _(1,56) = 2.12, p = .039; d = 0.57). For total accuracy, an OT/C-reactive protein factor moderated the ELT-FEPT association ( B = 0.14; SE = 0.05; p = .014); accuracy was lower in ELT-exposed PWH versus ELT-unexposed PWH when the factor was low but not when high. Similar results were obtained for fearful, neutral, and happy faces ( p values < .05). Regardless of ELT, a myeloid migration (MCP-1/MMP-9) factor was associated with reduced accuracy ( p values < .05). Conclusions: Our pilot findings suggest that ELT may alter social processing in PWH, and OT and C-reactive protein may be a target for improving social processing in ELT-exposed PWH, and myeloid migration markers may be a target in PWH more generally.

Viral encephalitis is a growing public health threat with limited diagnostic and treatment options. Simian immunodeficiency virus (SIV)-infected macaques are an established model for human immunodeficiency virus (HIV), and approximately 60% of untreated pigtail macaques rapidly progress to characteristic SIV encephalitis (SIVE). The immune responses of SIV-infected macaques are investigated in plasma, cerebrospinal fluid (CSF), and brain tissue to determine correlates with SIVE pathology. Macaques with SIVE show myeloid-dominant brain lesions with inflammasome activation in infected and bystander cells, as assessed by interleukin (IL)-1β, IL-18, and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and elevations in monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and tumor necrosis factor alpha (TNF-α). SIV-specific immunoglobulin (Ig)G in plasma and CSF is predictive of SIVE as early as 21 days post-inoculation; animals with SIVE continue to show negligible seroconversion 3 months after infection. This dichotomy in immune responses, wherein some macaques fail to initiate robust IgG responses and subsequently develop SIVE, provides insight into the pathogenesis and heterogeneous outcomes in viral encephalitis.