Abstract Persistent high-risk HPV infections drive most anal cancers, disproportionately affecting people with HIV (PLH), for whom cytology-based screening remains essential. However, the biological context of abnormal anal cytology, particular regarding local immune cells, is incompletely understood. In this pilot study, 57 PLH underwent longitudinal non-invasive anal sampling over one year, including cytology, HPV genotyping, and phenotypic characterization of ano-mucosal immune cells. Anal HPV infection and persistence were highly prevalent. Abnormal cytology was associated with more concurrent (high-risk) HPV infections, lower viral loads, and anal immune-microenvironment characterized by increased CD4 and CD8 T cells with upregulated tissue residency, activation, and effector markers. In summary, non-invasive anal sampling revealed that abnormal anal cytology in PLH is characterized by a distinct microenvironmental signature marked by multiple (HR) HPV infections and increased levels of tissue resident, activated and effector ano-mucosal T cells, potentially highlighting the important role of local immune cells.

Background People living with HIV are at increased risk for developing cancer, a leading cause of death in this population. The management of cancer in people living with HIV is particularly challenging, necessitating specialized, interdisciplinary care. However, insights into cancer care provision for people living with HIV in Germany remain scarce. Objective This study analyzed inpatient cancer care for people living with HIV, comparing treatment patterns and complications with those of an HIV-negative control group. Using claims data from 3 German university hospitals related to admissions between 2005 and 2022, we aimed to identify care disparities and provide evidence to support improved cancer management. Methods A customized federated approach was used to analyze inpatient claims data of patients across the 3 data-holding institutions. The data included demographics, diagnoses, procedures, and treatment codes as well as discharge information. Using nearest-neighbor matching, we analyzed demographic features, cancer diagnoses, anticancer therapies, and outcomes in people living with HIV and cancer and for a control group of HIV-negative patients with cancer. Results Among 162,380 patients, 907 (0.6%) were people living with HIV and cancer. The count of cancer diagnoses declined over time, particularly for AIDS-defining cancers (total cancer diagnoses: P=.001; AIDS-defining cancers: P=.002), with a shift toward older age at diagnosis. Compared with matched controls, people living with HIV and cancer had longer hospital stays, experienced more postchemotherapy complications (cancer with HIV: 64/907, 15.6%; cancer without HIV: 20/907, 5.5%; P<.001), and showed higher rates of metastasis after initial diagnosis (cancer with HIV: 128/267, 47.9%; cancer without HIV: 97/287, 33.8%; P<.001). People living with HIV and cancer also showed increased in-hospital mortality, although mortality declined over time (P=.02). Our data suggested differences in documented therapy modalities between the compared groups, with people living with HIV and cancer receiving more chemo- and immunotherapy and less surgery. Conclusions Using federated analysis techniques, we were able to show that cancer diagnoses and mortality among people living with HIV in Germany have decreased over time; however, disparities in treatment and outcomes persisted as compared with HIV-negative patients with cancer. Our findings underscore the need for tailored, multidisciplinary care strategies to improve cancer management for this population.

IntroductionHuman papillomavirus (HPV) prevalence is high among men who have sex with men (MSM), increasing the risk of anal cancer. Key risk factors include HIV co-infection and persistent HPV infection, although the underlying mechanisms remain unclear.MethodsWe characterized HPV burden in 75 men (median age 53 years [IQR 41–60]) presenting to LMU University Hospital or the medical practice prinzmed between 2022 and 2024. 64/75 defined themselves as MSM, 49 MSM were living HIV and 15 without HIV. 11/75 non-MSM were living with HIV. To identify systemic immunological correlates of HPV clearance or persistence, we performed IFN-γ ELISpot and peripheral blood T cells were analyzed by flow cytometry. Further, in a subgroup ano-mucosal CD8+ T cells were profiled via low-input RNA sequencing to determine immune signatures associated with persistent HPV infection.ResultsAnal HPV infection was highly prevalent at baseline (67/75) in this largely unvaccinated cohort (73/75), particularly among MSM (59/64), and was independent of HIV status. At baseline, simultaneous infection with multiple HPV types was detected in 50/64 MSM versus 4/11 non-MSM, and most infections persisted over 1 year. Type-specific systemic T-cell responses were detected in 3/4 individuals who cleared a given HR HPV type, compared with 0/14 with persistent HR HPV (p = 0.049). Among men living with HIV, HR HPV clearance was lower compared to men without HIV. Peripheral T cells in men living with HIV and infected with at least one HR HPV strain exhibited markers of exhaustion (TIM-3+ CD4+ and CD8+ T cells [p-value = 0.01 for CD4+ and p-value = 0.04 for CD8+]; Tcf1–PD-1+TIM-3+ CD4+ T cells [p-value = 0.02]), and senescence (CD57+ CD4+ T cells, p-value = 0.02). Ano-mucosal CD8+ T cells of HR HPV infected men living with HIV showed upregulation of genes associated with exhaustion (CTLA4, CD101), activation and effector function (GZMK, CTSW) compared to non-HR HPV infected men.DiscussionOur findings show a high anal HPV burden and low clearance among MSM, regardless of HIV status. Clearance was associated with type-specific systemic T-cell responses, while T-cell exhaustion and senescence may contribute to reduced clearance in men living with HIV.

Background:Data on the impact of completing 2 doses of the modified vaccinia Ankara vaccine and/or smallpox vaccination in childhood on Mpox disease severity remain limited. During the last months of 2024, Germany faced a second Mpox wave, providing the opportunity to study the impact of different vaccine regimens including smallpox vaccination. Methods:Retrospective analysis of all cases diagnosed at 17 participating German centers 2022-2024. Cases were grouped according to smallpox vaccine history: "unvaccinated," "incomplete" (vaccinations only during childhood and/or only one MVA BN), "complete" (2 MVA BN > 1 month prior to Mpox diagnosis). Disease severity was assessed by a 7-item Mpox Severity Scoring System (MPOX-SSS). Results:Of 273 Mpox infections, 42% occurred in men who have sex with men (MSM) living with HIV (median CD4 724 cells/µl, 91% <50 HIV-RNA copies/ml), 58% occurred in MSM without HIV, most of them using HIV PrEP. Median age was 38 years (IQR 30-44). Vaccinated individuals demonstrated lower MPOX-SSS scores compared to unvaccinated individuals (mean score 5.46 vs 7.15, P < .001). Vaccinated individuals also had less fever (23% vs 59%, P < .001), headaches/chills (29% vs 54%, P < .001), and swollen lymph nodes (38% vs 56%, P = .02). Conclusions:Both incomplete and complete vaccine courses including smallpox vaccination during childhood appear to reduce Mpox disease severity and symptoms. In settings of limited vaccine resources, unvaccinated risk groups should be prioritized.

KIR3DS1 is an activating natural killer (NK) cell receptor gene– present in 10-40% of humans– and is associated with extended AIDS-free survival. Although its ligand HLA-F has been identified, the underlying protective mechanism in HIV-1 is not yet understood. We sought to uncover the role of the KIR3DS1/HLA-F axis through investigating HLA-F surface and transcriptional changes during acute and chronic HIV-1 infection. HLA-F+ CD4 T cells were detected in people living with HIV (PLHIV) without antiretroviral treatment (N=102) and frequencies correlated with viremia but not with CD4 T cell count. Single-cell transcriptome analyses of PLHIV following acute HIV-1 acquisition revealed increased HLA-F mRNA levels in CD4 T cells associated with innate signaling signatures. In vitro, HLA-F mRNA was upregulated in both HIV-1–infected and bystander CD4 T cells. Functional studies demonstrated that bystander-activated CD4 T cells were reduced in the presence of NK cells during HIV-1 infection, and depleting NK cells increased the frequency of HLA-F+ CD4 T cells. Genotyping of our cohort revealed that KIR3DS1+ PLHIV exhibited significantly lower frequencies of HLA-F+ CD4 T cells. Taken together, these results establish HLA-F as a novel marker of innate T cell activation that is linked to HIV-1 viremia and suggest an immunoregulatory role of NK cells in controlling HIV-1-mediated inflammation by killing activated bystander CD4 T cells.

BACKGROUND:Post-coronavirus disease 2019 syndrome (PCS) is characterized by persistent symptoms lasting >12 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The underlying pathological mechanisms remain poorly understood. METHODS:We conducted detailed immunological analyses in 47 individuals with PCS, assessed >12 weeks after acute SARS-CoV-2 infection, and we compared them with 25 convalescent controls without symptoms. We performed immune phenotyping of T- and B-cell subsets, assessed SARS-CoV-2-specific responses using activation-induced marker (AIM) flow cytometry for T cells, and tetramer staining of spike-specific B cells. Cytokine levels in peptide-stimulated cell supernatants and plasma were quantified using a Luminex platform. RESULTS:Individuals with PCS exhibited reduced frequencies of AIM-positive SARS-CoV-2-specific T cells (OX40+PDL1+) and CD8 T cells (CD137+CD69+) following peptide stimulation with spike or nucleocapsid antigen, accompanied by diminished interferon γ and interleukin 2, as measured in the cell culture supernatants. In contrast, non-virus-specific T-cell populations, including memory differentiation, activation and helper cell differentiation status, did not differ between the groups. Individuals with PCS showed a significant increase in total (CD19+) and activated (CD86+HLA-DR+) B cells but not in SARS-CoV-2 spike-specific B cells (approximately 0.2% of total B cells). Plasma cytokine analysis revealed elevated markers associated with vascular damage and inflammation in those with PCS. CONCLUSIONS:Persistent immune disturbances in individuals with PCS are characterized by reduced SARS-CoV-2-specific T-cell responses, increased B-cell activation, and altered inflammatory and vascular biomarkers. These findings provide insights into the underlying mechanisms of PCS and may contribute to biomarker discovery and therapeutic development. TRIAL NO:DRKS00030974 (registry: https://www.bfarm.de/EN/BfArM/Tasks/German-Clinical-Trials-Register/_node.html).

After sporadic reports of post-treatment control of HIV in children who initiated combination anti-retroviral therapy (cART) early, we prospectively studied 284 very-early-cART-treated children from KwaZulu-Natal, South Africa, after vertical HIV transmission to assess control of viremia. Eighty-four percent of the children achieved aviremia on cART, but aviremia persisting to 36 or more months was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (P = 0.01). Unexpectedly, a subset (n = 5) of males maintained aviremia despite unscheduled complete discontinuation of cART lasting 3-10 months (n = 4) or intermittent cART adherence during 17-month loss to follow-up (n = 1). We further observed, in vertically transmitted viruses, a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (P < 0.0001) that was markedly stronger for males than for females (r = -0.51 versus r = -0.07 for IFN-alpha). Although viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (P < 0.0001 and P = 0.0003, respectively), the viruses transmitted to the five males maintaining cART-free aviremia had significantly lower replication capacity (P < 0.0001). These data suggest that viremic control can occur in some infants with in utero-acquired HIV infection after early cART initiation and may be associated with innate immune sex differences.

OBJECTIVES:With the near normalization of life expectancy in people living with HIV through antiretroviral therapy, the management of age-related comorbidities has become increasingly important. Non-AIDS-defining cancers now contribute significantly to both morbidity and mortality in this population, with non-small cell lung cancer (NSCLC) being one of the leading causes of cancer-related deaths among people living with HIV. METHODS:Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of NSCLC in the general population. However, people living with HIV have been largely excluded from pivotal clinical trials, resulting in limited evidence regarding safety and efficacy in this population. This review summarizes the main available literature on ICI therapy in people living with HIV with NSCLC. RESULTS:The presented data from retrospective analyses and cohort studies suggest that people living with HIV benefit from ICI therapy, with similar response rates and survival outcomes as people living without HIV. The risk of immune-related adverse events in people living with HIV was reported to be comparable to people living without HIV. Importantly, no significant effects of ICI on HIV viral load or CD4+ T cell count were reported. CONCLUSIONS:ICI therapy appears to be both safe and effective in people living with HIV with NSCLC. Optimal management of this patient population requires close interdisciplinary collaboration between oncologists and HIV care specialists. To enhance our understanding, broader inclusion of people living with HIV in clinical trials and the conduct of dedicated HIV-specific studies would be essential.

Background Post–coronavirus disease 2019 syndrome (PCS) is characterized by persistent symptoms lasting >12 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The underlying pathological mechanisms remain poorly understood. Methods We conducted detailed immunological analyses in 47 individuals with PCS, assessed >12 weeks after acute SARS-CoV-2 infection, and we compared them with 25 convalescent controls without symptoms. We performed immune phenotyping of T- and B-cell subsets, assessed SARS-CoV-2–specific responses using activation-induced marker (AIM) flow cytometry for T cells, and tetramer staining of spike-specific B cells. Cytokine levels in peptide-stimulated cell supernatants and plasma were quantified using a Luminex platform. Results Individuals with PCS exhibited reduced frequencies of AIM-positive SARS-CoV-2–specific T cells (OX40+PDL1+) and CD8 T cells (CD137+CD69+) following peptide stimulation with spike or nucleocapsid antigen, accompanied by diminished interferon γ and interleukin 2, as measured in the cell culture supernatants. In contrast, non–virus-specific T-cell populations, including memory differentiation, activation and helper cell differentiation status, did not differ between the groups. Individuals with PCS showed a significant increase in total (CD19+) and activated (CD86+HLA-DR+) B cells but not in SARS-CoV-2 spike–specific B cells (approximately 0.2% of total B cells). Plasma cytokine analysis revealed elevated markers associated with vascular damage and inflammation in those with PCS. Conclusions Persistent immune disturbances in individuals with PCS are characterized by reduced SARS-CoV-2–specific T-cell responses, increased B-cell activation, and altered inflammatory and vascular biomarkers. These findings provide insights into the underlying mechanisms of PCS and may contribute to biomarker discovery and therapeutic development. Trial no DRKS00030974 (registry: https://www.bfarm.de/EN/BfArM/Tasks/German-Clinical-Trials-Register/_node.html).

People living with HIV treated during acute infection are the group for whom achieving functional cure appears most viable. Follicular CD8+ T cells could contribute to HIV reservoir clearance by accessing B cell follicles through CXCR5 expression. This study examines peripheral follicular CD8+ T cells using flow cytometry, transcriptome analyses, and functional assays in people treated during acute (n = 37) and chronic (n = 18) infection, as well as in individuals naturally controlling HIV (n = 20) and living without HIV (n = 10). Our results reveal that early, as opposed to late, treatment initiation preserves antiviral effector functions of follicular CD8+ T cells, which are further enhanced by PD1 inhibition. We also identify a correlation between follicular CD8+ T cells and intact proviral HIV DNA levels in acute, but not chronic, infection. Longitudinal transcriptomic analysis of peripheral effector cells after 48 weeks of suppressive therapy indicated traits of recent antigen exposure, suggesting potential recirculation into lymphoid tissue. These findings underscore the pivotal role of follicular CD8+ T cells in anti-HIV responses and support investigating targeted cure strategies, such as antiPD1 therapy, especially in individuals initiating treatment during acute infection.

The Post COVID-19 condition (PCC) is a complex disease affecting health and everyday functioning. This is well reflected by a patient's inability to work (ITW). In this study, we aimed to investigate factors associated with ITW (1) and to design a machine learning-based model for predicting ITW (2) twelve months after baseline. We selected patients from the post COVID care study (PCC-study) with data on their ability to work. To identify factors associated with ITW, we compared PCC patients with and without ITW. For constructing a predictive model, we selected nine clinical parameters: hospitalization during the acute SARS-CoV-2 infection, WHO severity of acute infection, presence of somatic comorbidities, presence of psychiatric comorbidities, age, height, weight, Karnofsky index, and symptoms. The model was trained to predict ITW twelve months after baseline using TensorFlow Decision Forests. Its performance was investigated using cross-validation and an independent testing dataset. In total, 259 PCC patients were included in this analysis. We observed that ITW was associated with dyslipidemia, worse patient reported outcomes (FSS, WHOQOL-BREF, PHQ-9), a higher rate of preexisting psychiatric conditions, and a more extensive medical work-up. The predictive model exhibited a mean AUC of 0.83 (95% CI: 0.78; 0.88) in the 10-fold cross-validation. In the testing dataset, the AUC was 0.76 (95% CI: 0.58; 0.93). In conclusion, we identified several factors associated with ITW. The predictive model performed very well. It could guide management decisions and help setting mid- to long-term treatment goals by aiding the identification of patients at risk of extended ITW.

Memory T cells play an important role in mediating long-lasting adaptive immune responses to viral infections, such as SARS-CoV-2. In the context of the latter, much of our current knowledge stems from studies in vaccinated individuals or repeatedly infected individuals. However, limited knowledge is available on these responses in fully naive individuals in German communities. We performed immunophenotyping of a previously naive SARS-CoV-2 cohort in convalescent individuals after asymptomatic to moderate COVID-19. The samples were collected median 250 days post infection during the first wave of the COVID pandemic in Germany (March – May 2020). In this cohort of 174 individuals, we phenotyped different leukocyte cell populations in peripheral blood (B, T and Natural Killer cells). We then assessed the serostatus against the SARS-CoV-2 antigens Nucleocapsid (N) and Spike subunit (S1) with its receptor binding domain (RBD), as these are important correlates of protection, by testing for presence of immunoglobulin G (IgG) antibodies. We also measured IgG antibody responses against the N antigen of the common cold coronaviruses HCoV-OC43, HCoV-HKU1, HCoV-NL63 and HCoV-229E, to determine possible cross-reactivity. In a subset of the cohort (n = 76), we performed intracellular staining assays (ICS) after stimulation with SARS-CoV-2 and HCoV antigens. Key findings are significant differences in frequency of CD4+ memory T cell populations, notably CD4+ T EM and CD4+ T EMRA cells, between the group of SARS-CoV-2 positive individuals and the control group. These differences correlated with cytokine production (TNFα, IFNγ) after stimulation with SARS-CoV-2 peptides, indicating a specific T cell immune response. In conclusion, a clear memory T cell and humoral response can be detected up to 250 days post mild to moderate COVID-19 disease. Our results underline findings reported by others indicating a lasting cellular immune response even in a population which previously had not been exposed to SARS-CoV-2.

Die Herpes-simplex-Virus-2(HSV-2)-Primärinfektion verläuft in der Regel asymptomatisch, kann aber mit stark schmerzhaften, zumeist genitalen Läsionen und Allgemeinsymptomen einhergehen. Die Diagnostik erfolgt mittels PCR und/oder Serologie. Für die Akuttherapie stehen Aciclovir, Valaciclovir und Famciclovir zur Verfügung. Nach Primärinfektion bleibt das Virus in neuronalen Ganglien lebenslang latent. Rezidive können selbst bei immungesunden Personen mehrere Male im Jahr auftreten und die Betroffenen auch psychisch schwer belasten. Eine medikamentöse Prophylaxe kann dann indiziert sei. Hierbei wird zwischen einer kontinuierlichen suppressiven Therapie und einer Standby-Medikation unterschieden. Eine Impfung steht bisher nicht zur Verfügung. Insbesondere bei Risikogruppen sollte der Kontakt zu infektiösen Trägerinnen und Trägern vermieden werden. Hierzu zählen seronegative Schwangere kurz vor dem Geburtstermin, die das Virus perinatal auf das Neugeborene übertragen können, sowie Menschen mit einer schweren Immundefizienz (z.B. in den ersten 100 Tagen nach allogener Stammzelltransplantation). Ein Herpes neonatorum (= Primärinfektion des Neugeborenen während des Geburtsvorgangs) kann mit einer Enzephalitis einhergehen, deren Letalität hoch ist.

Immune cell phenotyping frequently detects lineage-unrelated receptors. Here, we report that surface receptors can be transferred from primary macrophages to CD4 T cells and identify the Fcγ receptor CD32 as driver and cargo of this trogocytotic transfer. Filamentous CD32+ nanoprotrusions deposit distinct plasma membrane patches onto target T cells. Transferred receptors confer cell migration and adhesion properties, and macrophage-derived membrane patches render resting CD4 T cells susceptible to infection by serving as hotspots for HIV-1 binding. Antibodies that recognize T cell epitopes enhance CD32-mediated trogocytosis. Such autoreactive anti-HIV-1 envelope antibodies can be found in the blood of HIV-1 patients and, consistently, the percentage of CD32+ CD4 T cells is increased in their blood. This CD32-mediated, antigen-independent cell communication mode transiently expands the receptor repertoire and functionality of immune cells. HIV-1 hijacks this mechanism by triggering the generation of trogocytosis-promoting autoantibodies to gain access to immune cells critical to its persistence.

Background Innate lymphoid cells (ILCs) are key organizers of tissue immune responses and regulate tissue development, repair, and pathology. Persistent clinical sequelae beyond 12 weeks following acute COVID-19 disease, named post-COVID syndrome (PCS), are increasingly recognized in convalescent individuals. ILCs have been associated with the severity of COVID-19 symptoms but their role in the development of PCS remains poorly defined. Methods and results Here, we used multiparametric immune phenotyping, finding expanded circulating ILC precursors (ILCPs) and concurrent decreased group 2 innate lymphoid cells (ILC2s) in PCS patients compared to well-matched convalescent control groups at > 3 months after infection or healthy controls. Patients with PCS showed elevated expression of chemokines and cytokines associated with trafficking of immune cells (CCL19/MIP-3b, FLT3-ligand), endothelial inflammation and repair (CXCL1, EGF, RANTES, IL-1RA, PDGF-AA). Conclusion These results define immunological parameters associated with PCS and might help find biomarkers and disease-relevant therapeutic strategies.