Search Results (178)

Background and Aim: Syphilis, caused by Treponema pallidum, classically presents with genital or anal chancres; rectal involvement is rare and frequently misdiagnosed as inflammatory bowel disease or malignancy. We describe an unusually severe case of syphilitic proctitis in the setting of advanced HIV-related immunosuppression (CD4 39 cells/µL), in which targeted immunophenotyping (ERG and CD38) was a valuable adjunctive tool in the differential diagnosis. Case Presentation: A 46-year-old man with a recent history of erosive gastritis and esophageal candidiasis presented after six months of unintentional 20 kg weight loss, profound fatigue, intermittent fevers, profuse diarrhea, and two episodes of hematemesis. Workup revealed a new diagnosis of HIV infection (CD4: 39 cells/µL; viral load: 87,837 copies/mL). Contrast-enhanced CT demonstrated uniform, concentric rectal wall thickening (“target sign”). Colonoscopic biopsy showed exuberant granulation tissue and dense plasma cell infiltrates. Immunohistochemistry revealed a dense infiltrate of CD38-positive plasma cells and ERG-positive endothelial proliferation. These findings, in the context of positive serology, were highly supportive of a spirochetal etiology and helped differentiate it from potential mimics. Serology was positive for latent late syphilis (VDRL 1:64). The patient received three weekly doses of intramuscular benzathine penicillin; lumbar puncture excluded neurosyphilis. Discussion: This is among the first reported cases of syphilitic proctitis in a patient with CD4 < 50 cells/µL, where advanced immunophenotyping differentiated syphilitic inflammation from neoplastic or inflammatory mimics. Profound immunosuppression accelerates disease progression and yields atypical clinical features. Conclusion: In HIV-infected patients with chronic rectal symptoms, especially those with CD4 < 50 cells/µL, syphilitic proctitis must be considered. Integration of radiologic assessment, histopathology with ERG/CD38 staining, and serologic testing permits prompt diagnosis. Early benzathine penicillin therapy and rigorous clinical and serologic follow-up are essential to prevent complications, including neurosyphilis. Full article

HIV-1 Tat acts as a central molecular switch governing the transition between viral latency and active replication, making it a pivotal target for HIV-1 functional cure strategies. By binding to the viral long terminal repeat (LTR) and hijacking host transcriptional machinery, Tat dynamically regulates RNA polymerase II processivity to alter viral transcription states. Recent studies reveal its context-dependent variability: while Tat recruits chromatin modifiers and scaffolds non-coding RNAs to stabilize epigenetic silencing in latently infected cells, it also triggers rapid transcriptional amplification upon cellular activation. This review systematically analyzes the bistable regulatory mechanism of Tat and investigates advanced technologies for reprogramming this switch to eliminateviral reservoirs and achieve functional cures. Conventional approaches targeting Tat are limited by compensatory viral evolution and poor bioavailability. Next-generation interventions will employ precision-engineered tools, such as AI-optimized small molecules blocking Tat-P-TEFb interfaces and CRISPR-dCas9/Tat chimeric systems, for locus-specific LTR silencing or reactivation (“block and lock” or “shock and kill”). Advanced delivery platforms, including brain-penetrant lipid nanoparticles (LNPs), enable the targeted delivery of Tat-editing mRNA or base editors to microglial reservoirs. Single-cell multiomics elucidates Tat-mediated clonal heterogeneity, identifying “switchable” subpopulations for timed interventions. By integrating systems-level Tat interactomics, epigenetic engineering, and spatiotemporally controlled delivery, this review proposes a roadmap to disrupt HIV-1 persistence by hijacking the Tat switch, ultimately bridging mechanistic insights to clinical applications. Full article

Psychostimulants such as methamphetamine (Meth) induce high dopamine (DA) levels in the brain, which can modify immune cells expressing DA receptors. This is relevant in conditions of infection with the human immunodeficiency virus (HIV), overlapping with substance use. However, the effects of DA on HIV latency phenotypes are largely unknown. We used single-cell methods and gene network computational analysis to understand these relationships, using the U1 latent promonocyte model to identify signatures of latency and its reversal in the context of DA exposure. Our findings point to mechanisms by which high DA levels in the brains of substance users may impact HIV transcription and neuroinflammation. Our data indicate that latency is maintained along with the expression of histone linkers and components of chromatin organization, with increased metabolic pathways that may lead to pathways in neurodegeneration. DA exposure decreased latency signature genes, histone linkers, and protein-containing complex organization components, unleashing inflammatory pathways and HIV gene transcription. Overall, this work suggests that DA can induce latency reversal through mechanisms that can be harnessed to drive cells. The proposed methods developed here in cell lines can be used to identify latency signatures in other HIV infection systems. Full article

The CRISPR–Cas system has transformed molecular biology by providing precise tools for genome editing and pathogen detection. Originating from bacterial adaptive immunity, CRISPR technology identifies and cleaves genetic material from pathogens, thereby preventing infections. CRISPR–Cas9, the most widely utilized variant, creates double-stranded breaks in the target DNA, enabling genetic disruptions or edits. This approach has shown significant potential in antiviral therapies, addressing chronic infections, such as HIV, SARS-CoV-2, and hepatitis viruses. In HIV, CRISPR–Cas9 edits the essential viral genes and disrupts latent reservoirs, while CCR5 gene modifications render the T cells resistant to viral entry. Similarly, SARS-CoV-2 is targeted using CRISPR–Cas13d to inhibit the conserved viral genes, significantly reducing viral loads. Hepatitis B and C treatments leverage CRISPR technologies to target conserved genomic regions, limiting replication and expression. Emerging innovations, such as the PAC-MAN approach for influenza and base-editing systems to reduce off-target effects, further highlight the therapeutic versatility of CRISPR. Additionally, advances in Cas12a and Cas13 have driven the development of diagnostic platforms like DETECTR and SHERLOCK, which provide rapid and cost-effective viral detection. Innovative tools like AIOD-CRISPR enable accessible point-of-care diagnostics for early viral detection. Experimental approaches, such as targeting latent HSV-1 reservoirs, highlight the transformative potential of CRISPR in combating persistent infections. Full article

HIV-1 infection in microglia induces HIV-associated neurocognitive disorder (HAND). Recent evidence suggests that microglia can be infected with HIV-1 in the active, persistent, or latent replication stages. The molecular mechanisms governing these stages of infection are still the subject of continuous study. In this study, we analyzed the relationship between HIV-1 infection and two lncRNAs, NEAT1 and ZBTB11-AS1, on different days post-infection. We found that on days 1 and 4 post-infection, HIV-1 was actively replicating; meanwhile, by day 21, HIV-1 had entered a persistent stage. We also noted that the expression levels of NEAT1 and ZBTB11-AS1 varied during these different stages of HIV-1 infection in microglia, as did their subcellular localization. We performed an interaction network analysis and identified DDX3X and ZC3HAV1 as hypothetically related to NEAT1 and ZBTB11-AS1 in the C20 human microglial cell line. Additionally, we determined that IL-6, a cytokine regulated by DDX3X and ZC3HAV1, exhibits changes in protein expression levels during both active and persistent HIV-1 infection. Full article

Microglia are the primary target and reservoir of HIV infection in the central nervous system (CNS), which contributes to HIV-associated neurocognitive disorder (HAND). However, studying HIV infection of microglia has been challenged by the limited availability of primary human microglial cells. To overcome this issue, investigators have developed various microglial models for HIV studies, including immortalized human microglial cell lines, HIV latently infected microglial clones, peripheral blood monocyte-derived microglia (MMG), induced pluripotent stem cell (iPSC)-derived microglia (iMg), and microglia-containing cerebral organoids (MCOs) from iPSCs. Though these models have been used in many laboratories, the published data about their expression of the specific human microglia markers and the HIV entry receptors are conflicting. In addition, there is limited information about their feasibility and applicability as a suitable model for acute and/or latent HIV infection. This review provides a concise summary of the currently used human microglial models, with a focus on their suitability for NeuroHIV research. Full article

Based on observations that HIV-1 envelope (Env) proteins on the surfaces of cells have the capacity to fuse with neighboring cells or enveloped viruses that express CD4 receptors and CXCR4 co-receptors, we tested factors that affect the capacities of lentiviral vectors pseudotyped with CD4 and CXCR4 variants to infect Env-expressing cells. The process, which we refer to as fusion in reverse, involves the binding and activation of cellular Env proteins to fuse membranes with lentiviruses carrying CD4 and CXCR4 proteins. We have found that infection via fusion in reverse depends on cell surface Env levels, is inhibitable by an HIV-1-specific fusion inhibitor, and preferentially requires lentiviral pseudotyping with a glycosylphosphatidylinositol (GPI)-anchored CD4 variant and a cytoplasmic tail-truncated CXCR4 protein. We have demonstrated that latently HIV-1-infected cells can be specifically infected using this mechanism, and that activation of latently infected cells increases infection efficiency. The fusion in reverse approach allowed us to characterize how alteration of CD4 plus CXCR4 lipid membranes affected Env protein activities. In particular, we found that perturbation of membrane cholesterol levels did not affect Env activity. In contrast, viruses assembled in cells deficient for long-chain sphingolipids showed increased infectivities, while viruses that incorporated a lipid scramblase were non-infectious. Our results yield new insights into factors that influence envelope protein functions. Full article

The persistence of latent HIV-1 proviruses in CD4⁺ T cells is a major obstacle to curing HIV. The “shock and kill” strategy involves reversing latency with latency-reversing agents (LRAs) and selectively inducing cell death in infected cells. However, current LRAs have shown limited efficacy in eliminating the ex vivo HIV reservoir and thus failed in clinical study. In this study, we repurposed PZ703b, a pro-apoptotic protein degrader initially developed for anti-leukemia therapy, to target HIV eradication. PZ703b induced the degradation of Bcl-2 and Bcl-xL, activating the non-canonical NF-kB pathway and caspases cascade, resulting in latency reversal and the selective apoptosis of infected cells. The treatment of ex vivo CD4⁺ T cells from ART-suppressed HIV-1 patients led to approximately a 50% reduction in the replication-competent reservoir. While this result does not reach the threshold required for a complete cure, it demonstrates the potential of a dual degrader of Bcl-2/Bcl-xL in reversing HIV latency and inducing selective cell death. Our study provides a proof-of-concept for using dual degraders of Bcl-2/Bcl-xL as a novel category of LRAs in therapeutic strategies aimed at reducing HIV reservoirs. This approach may pave the way for the further exploration of targeted interventions to eliminate the HIV-inducible reservoir. Full article

HIV-1 infection is successfully treated by antiretroviral therapy; however, it is not curative as HIV-1 remains present in the viral reservoir. A strategy to eliminate the viral reservoir relies on the reactivation of the latent provirus to subsequently trigger immune-mediated clearance. Here, we investigated whether the activation of Toll-like receptor 8 (TLR8) or RIG-I-like receptor (RLR) together with the latency reversal agent (LRA) second mitochondrial-derived activator of caspases mimetics (SMACm) leads to HIV-1 reservoir reduction and antiviral immune activation. The TLR8 and RLR agonist elicited a robust pro-inflammatory cytokine response in PBMCs from both PWH and uninfected people. Notably, co-stimulation with SMACm specifically enhanced TLR8 induced pro-inflammatory cytokine as well as CD8 T cell responses. Ex vivo treatment of PBMCs from PWH with SMACm significantly decreased the size of the inducible HIV-1 reservoir, whereas targeting TLR8 or RLR reduced the HIV-1 reservoir in 50% of PWH ex vivo. Although co-stimulation with TLR8/RLR agonists further reduced the HIV-1 reservoir in 25% of PWH ex vivo, effectively inducing antiviral immunity may help eliminate reactivated HIV-1 cells in vivo. Our findings strongly suggest that LRAs can be used in combination with agonists for pattern recognition receptors to reactivate HIV-1 and induce antiviral immunity. Full article

The “Kick and Kill” strategy, which aims to reactivate latent HIV reservoirs and facilitate the clearance of reactivated HIV-infected cells, has yet to achieve a functional cure due to the limited efficacy of current latency reversal agents. This study evaluates the combination efficacy of histone deacetylase (HDAC) inhibitor with poly(ADP-ribose) polymerase (PARP) inhibitor in latency reversal and immune-mediated clearance. Latently infected J-Lat cells and dual-fluorescent HIV-infected primary CD4 T cells were treated with the HDAC inhibitor (vorinostat) and one of four PARP inhibitors (olaparib, rucaparib, niraparib, or talazoparib). PARP inhibitors, when administered alone, showed no latency reversal activity. However, when combined with vorinostat, their efficacy increased threefold compared to vorinostat alone. This effect was mediated by the inhibition of tankyrase, a PARP superfamily member, which modulates the Hippo signaling pathway. In HIV_GR670-infected primary cells, the combination reduced the reservoir size by 67%. In addition, talazoparib alone significantly reduced actively infected cells by 50%. Talazoparib-treated peripheral blood mononuclear cells co-cultured with K562 cells demonstrated enhanced NK-cell-mediated cytotoxicity, with a 10% reduction in K562 cell viability. These findings demonstrate that combining HDAC and PARP inhibitors augments latency reversal and reservoir reduction. With both the HDAC inhibitors and PARP inhibitors used in this study approved by the FDA for cancer treatment, this combination therapy holds strong potential for rapid clinical integration, contingent upon the confirmation of efficacy and safety in ongoing in vivo studies. Full article

HIV-1 infection cannot be cured due to the presence of HIV-1 latently infected cells. These cells do not produce the virus, but they can resume virus production at any time in the absence of antiretroviral therapy. Therefore, people living with HIV (PLWH) need to take lifelong therapy. Strategies have been coined to eradicate the viral reservoir by reactivating HIV-1 latently infected cells and subsequently killing them. Various latency reversing agents (LRAs) that can reactivate HIV-1 in vitro and ex vivo have been identified. The most potent LRAs also strongly activate T cells and therefore cannot be applied in vivo. Many LRAs that reactivate HIV in the absence of general T cell activation have been identified and have been tested in clinical trials. Although some LRAs could reduce the reservoir size in clinical trials, so far, they have failed to eradicate the reservoir. More recently, immune modulators have been applied in PLWH, and the first results seem to indicate that these may reduce the reservoir and possibly improve immunological control after therapy interruption. Potentially, combinations of LRAs and immune modulators could reduce the reservoir size, and in the future, immunological control may enable PLWH to live without developing HIV-related disease in the absence of therapy. Full article

Combination antiretroviral therapy (ART) suppresses detectible HIV-1 replication, but latent reservoirs and persistent immune activation contribute to residual viral-associated morbidities and potential viral reactivation. youth with HIV (YWH) virally suppressed on ART early in infection before CD4 T cell decline with fewer comorbidities compared to adults represent a critical population for identifying markers associated with viral control and predictors of viral breakthrough. This study employed a multi-omics approach to evaluate plasma biomarkers and cellular gene expression profiles in 52 participants, including 27 YWH on ART for 144 weeks and 25 youth with no infection (NI) (ages 18–24). Among the 27 YWH, 19 were virally suppressed (VS; <50 RNA copies/mL), while eight were non-suppressed (VNS; >50 RNA copies/mL). VS YWH displayed unique bioprofiles distinct from either VNS or NI. Early viral suppression mitigates inflammatory pathways and normalizes key biomarkers associated with HIV-related comorbidities. Genes upregulated in pathways linked to cellular homeostasis such as DNA repair, RNA processing, and transcription regulation may diminish viral breakthrough and maintain sustained HIV control on ART. Candidate markers and putative molecular mechanisms were identified, offering potential therapeutic targets to limit viral persistence, enhance HIV treatment strategies, and pave the way for improved clinical outcomes. Full article

Despite the high prevalence of latent Kaposi’s sarcoma-associated herpesvirus (KSHV) infections in patients from endemic areas with a high human immunodeficiency virus (HIV) prevalence, KSHV lytic reactivation in the context of other co-infections is not well understood. Lytic KSHV infections can contribute to severe inflammatory symptoms and KSHV-associated pathogenesis. We have previously reported on KSHV reactivation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure in a non-hospitalised cohort of people living with HIV (PLWH). From this cohort, we identified a 34-year-old male who presented for routine HIV care in May 2021 with an unusually high KSHV viral load (VL) of 189,946.3 copies/10⁶ cells, before SARS-CoV-2 infection. The patient was invited into a 2-year follow-up study where his peripheral blood was analysed for selected virological, clinical, and inflammatory parameters every 6 months. He remained highly viremic for KSHV throughout the 2-year study period, during which he was infected with SARS-CoV-2 and developed disseminated tuberculosis, with steadily increasing levels of the inflammatory markers C-reactive protein (CRP), and interleukin-6 (IL-6). His HIV VL remained controlled (<1000 copies/mL) and his CD4 count bordered immunosuppression (±200 cells/µL), suggesting some responsiveness to antiretroviral treatment (ART). However, the patient’s uncontrolled lytic KSHV infection may increase his risk for developing a KSHV-associated pathology manifesting with inflammation which should be closely monitored beyond the study period. Full article

SUMOylation, the post-translational modification of proteins by small ubiquitin-like modifiers, plays a critical role in regulating various cellular processes, including innate immunity. This modification is essential for modulating immune responses and influencing signaling pathways that govern the activation and function of immune cells. Recent studies suggest that SUMOylation also contributes to the pathophysiology of central nervous system (CNS) viral infections, where it contributes to the host response and viral replication dynamics. Here, we explore the multifaceted role of SUMOylation in innate immune signaling and its implications for viral infections within the CNS. Notably, we present novel proteomic analyses aimed at elucidating the role of the small ubiquitin-related modifier (SUMO) in human immunodeficiency virus (HIV) latency in microglial cells. Our findings indicate that SUMOylation may regulate key proteins involved in maintaining viral latency, suggesting a potential mechanism by which HIV evades immune detection in the CNS. By integrating insights from proteomics with functional studies, we anticipate these findings to be the groundwork for future studies on HIV–host interactions and the mechanisms that underlie SUMOylation during latent and productive infection. Full article

Merkel cell polyomavirus (MCV) was named for its role as the causative agent of Merkel cell carcinoma (MCC), which is MCV positive in approximately 80% of cases. MCV is classified as a Group 2A carcinogen, which promotes carcinogenesis by integrating T-antigen into the cell genome. The prevalence of anti-MCV antibodies in the general population can be as high as 90%. MCV typically promotes cancer by integrating T-antigen genes into the host cell genome, and 80% of MCC cases are attributed to MCV activation. In immunocompetent individuals, MCV usually remains latent after infection. However, the incidence of MCC increases significantly in immunocompromised or immunodeficient patients, such as those who have undergone organ transplantation, have chronic lymphocytic leukemia, or are living with human immunodeficiency virus (HIV) infection. Acquired immunodeficiency is a particular feature of people living with HIV. Currently, research on HIV/AIDS patients with MCV infection, clinical outcomes, and treatments is quite limited. This paper reviews previous research and systematically examines the relationship between HIV/AIDS and MCV-associated diseases, with the aim of providing valuable information for the prevention, diagnosis, and treatment of MCV in vulnerable populations. Full article