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Alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells in the lung to encounter bacteria. We previously showed that AMs initially respond to Mtb in vivo by mounting a cell-protective, rather than pro-inflammatory response. However, the plasticity of the initial AM response was unknown. Here, we characterize how previous exposure to Mycobacterium , either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb) that mimics aspects of concomitant immunity, impacts the initial response by AMs. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory response to Mtb in vivo by AMs. Within the lung environment, AMs from scBCG vaccinated mice mount a robust interferon-associated response, while AMs from coMtb mice produce a broader inflammatory response that is not dominated by Interferon Stimulated Genes. Using scRNAseq, we identify changes to the frequency and phenotype of airway-resident macrophages following Mycobacterium exposure, with enrichment for both interferon-associated and pro-inflammatory populations of AMs. In contrast, minimal changes were found for airway-resident T cells and dendritic cells after exposures. Ex vivo stimulation of AMs with Pam3Cys, LPS and Mtb reveal that scBCG and coMtb exposures generate stronger interferon-associated responses to LPS and Mtb that are cell-intrinsic changes. However, AM profiles that were unique to each exposure modality following Mtb infection in vivo are dependent on the lung environment and do not emerge following ex vivo stimulation. Overall, our studies reveal significant and durable remodeling of AMs following exposure to Mycobacterium , with evidence for both AM-intrinsic changes and contributions from the altered lung microenvironments. Comparisons between the scBCG and coMtb models highlight the plasticity of AMs in the airway and opportunities to target their function through vaccination or host-directed therapies.

Progress in tuberculosis vaccine development is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Although the M72/ASOE1 trial yielded encouraging results (54% efficacy in subjects with prior exposure to Mtb), a highly effective vaccine against adult tuberculosis remains elusive. We show that in a mouse model, establishment of a contained and persistent yet non-pathogenic infection with Mtb (\"contained Mtb infection\", CMTB) rapidly and durably reduces tuberculosis disease burden after re-exposure through aerosol challenge. Protection is associated with elevated activation of alveolar macrophages, the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma. Systems approaches, as well as ex vivo functional assays and in vivo infection experiments, demonstrate that CMTB reconfigures tissue resident alveolar macrophages via low grade interferon-γ exposure. These studies demonstrate that under certain circumstances, the continuous interaction of the immune system with Mtb is beneficial to the host by maintaining elevated innate immune responses.

Co-infection with Mycobacterium tuberculosis (MTB) differentially modulates untreated HIV-1 infection, with asymptomatic MTB reducing HIV-1 viremia and opportunistic infections and active tuberculosis (TB) accelerating AIDS progression. Here, we investigate antibody (Ab) responses to HIV-1 in people with HIV (PWH) without MTB, with asymptomatic MTB, and with later progression to active TB to elucidate MTB-associated effects on HIV-1 immune control. Using the Swiss HIV Cohort Study (SHCS), we conducted a retrospective study that included 2,840 PWH with data on MTB status and HIV-1-specific plasma binding-/neutralizing-responses. We evaluated associations between MTB status and binding-/neutralizing-responses while adjusting for key disease and demographic parameters. Among the included 2,840 PWH, 263 PWH had asymptomatic MTB based on either a positive TST-/IGRA-test at the baseline (time of HIV-1 Ab measurement) or on later progression to active TB. Compared to PWH without MTB infection, PWH with asymptomatic MTB infection showed reduced HIV-1 Ab levels, both for Env binding (e.g., IgG1 BG505 trimer antigen, p = 0.024) and neutralization of a diverse panel of HIV-1 viruses (p = 0.012). Conversely, PWH (n = 32) who later progressed to active TB (>180 days after baseline) demonstrated a significant shift towards IgG3 in their HIV-1 Ab repertoire (p = 0.011), detectable in median 3.8 years (IQR 2.4 - 8.7) before active TB onset. Our data indicate that asymptomatic MTB infection and active TB exert profound heterologous effects on HIV-1 specific Ab development. These findings advance our understanding of host-pathogen dynamics and may have implications for new diagnostic approaches in predicting future active TB.

We still lack reliable tools to predict who will develop tuberculosis (TB) among people with HIV. Moreover, the underlying biological events driving progression remain poorly understood. Our study reveals early immune changes that include unexpected alterations in B cell activation and antibody responses. These findings suggest that humoral immunity may play a more important role in TB pathogenesis than previously recognized and offer promising new directions for biomarker discovery and targeted prevention.

Approximately 28% of the human population have been exposed to Mycobacterium tuberculosis (MTB), with the overwhelming majority of infected individuals not developing disease (latent TB infection (LTBI)). While it is known that uncontrolled HIV infection is a major risk factor for the development of TB, the effect of underlying LTBI on HIV disease progression is less well characterized, in part because longitudinal data are lacking. We sorted all participants of the Swiss HIV Cohort Study (SHCS) with at least 1 documented MTB test into one of the 3 groups: MTB uninfected, LTBI, or active TB. To detect differences in the HIV set point viral load (SPVL), linear regression was used; the frequency of the most common opportunistic infections (OIs) in the SHCS between MTB uninfected patients, patients with LTBI, and patients with active TB were compared using logistic regression and time-to-event analyses. In adjusted models, we corrected for baseline demographic characteristics, i.e., HIV transmission risk group and gender, geographic region, year of HIV diagnosis, and CD4 nadir. A total of 13,943 SHCS patients had at least 1 MTB test documented, of whom 840 (6.0%) had LTBI and 770 (5.5%) developed active TB. Compared to MTB uninfected patients, LTBI was associated with a 0.24 decreased log HIV SPVL in the adjusted model ( p < 0.0001). Patients with LTBI had lower odds of having candida stomatitis (adjusted odds ratio (OR) = 0.68, p = 0.0035) and oral hairy leukoplakia (adjusted OR = 0.67, p = 0.033) when compared to MTB uninfected patients. The association of LTBI with a reduced HIV set point virus load and fewer unrelated infections in HIV/TB coinfected patients suggests a more complex interaction between LTBI and HIV than previously assumed.

A treatment-experienced, highly adherent person living with HIV for over 25 years developed resistance mutations against all four major ART classes, including bictegravir (BIC). This led to viral failure on a quadruple regimen including BIC and doravirine (DOR). Resistance emergence was associated with M184V, thymidine analog mutations (TAMs), NNRTI mutations (108I, 234I, 318F), and INSTI mutations (T97A, G140S, Q148H, G149A), likely driven by suboptimal BIC levels due to divalent cation interactions. During a two-month ART interruption, the resistant virus was rapidly replaced by an ancient wild-type strain. Despite resistance to all four ART classes, a genotype-adapted salvage regimen, including fostemsavir, achieved viral suppression within seven months.

Background: In individuals living with HIV infection the development of tuberculosis (TB) is associated with rapid progression from asymptomatic TB infection to active TB disease. Sputum-based diagnostic tests for TB have low sensitivity in minimal and subclinical TB precluding early diagnosis. The immune response to novel Mycobacterium tuberculosis in-vivo expressed and latency associated antigens may help to measure the early stages of infection and disease progression and thereby improve early diagnosis of active TB disease. Methods: Serial prospectively sampled cryopreserved lymphocytes from patients of the Swiss HIV Cohort Study developing TB disease (“cases”) and matched patients with no TB disease (“controls”) were stimulated with 10 novel Mycobacterium tuberculosis antigens. Cytokine concentrations were measured in cases and controls at four time points prior to diagnosis of TB: T1-T4 with T4 being the closest time point to diagnosis. Results: 50 samples from nine cases and nine controls were included. Median CD4 cell count at T4 was 289/ul for the TB-group and 456/ul for the control group. Viral loads were suppressed in both groups. At T4 Rv2431c-induced and Rv3614/15c-induced interferon gamma-induced protein (IP)-10 responses and Rv2031c-induced and Rv2346/Rv2347c-induced tumor necrosis factor (TNF)-α responses were significantly higher in cases compared to controls ( p < 0.004). At T3 - being up to 2 years prior to TB diagnosis - Rv2031c-induced TNF-α was significantly higher in cases compared to controls ( p < 0.004). Area under the receiver operating characteristics (AUROC) curves resulted in an AUC > 0.92 for all four antigen-cytokine pairs. Conclusion: The in vitro Mycobacterium tuberculosis -specific immune response in HIV-infected individuals that progress toward developing TB disease is different from those in HIV-infected individuals that do not progress to developing TB. These differences precede the clinical diagnosis of active TB up to 2 years, paving the way for the development of immune based diagnostics to predict TB disease at an early stage.

Background Among people living with HIV, there has been a shift of focus from HIV-related health issues to cardiovascular diseases and cancer. For both, tobacco smoking is a major but insufficiently addressed etiological factor. Evidence from randomized trials suggests that nicotine substitute products such as e-cigarettes and nicotine patches can reduce tobacco smoking and its associated health burden. However, most previous smoking cessation trials primarily included people who are motivated to quit smoking and focused on testing a single nicotine substitute product. The effectiveness of offering a menu of nicotine substitute products to tobacco smokers regardless of their willingness to quit smoking (“opt-out” approach) is unknown. Methods Reduce tobacco use in people living with HIV in Switzerland (RETUNE, NCT06789692) is a pragmatic, 1:1 randomized, multicenter, superiority clinical trial using the Trials within Cohorts (TwiCs) design within the Swiss HIV Cohort Study. RETUNE assesses the effectiveness of offering a menu of different nicotine substitute products, namely electronic cigarettes, nicotine pouches, and nicotine patches, versus usual care. Cohort participants are eligible if they smoke more than one tobacco cigarette per day, do not use any of the substitute products, and have signed the randomization consent following the TwiCs design. Participants randomized to the intervention may choose any of the offered substitutes to be used free of charge for 6 months or decline the offer. Overall, we plan to recruit 972 participants. The primary outcome is tobacco abstinence at 6 months measured as participant-reported past 7-day prevalence abstinence. The primary outcome will be assessed in the intention-to-treat set using a logistic regression model adjusted for region, men having sex with men, current drug users, and number of cigarettes per day at baseline. Secondary outcomes are long-term smoking cessation rates and tobacco-associated health outcomes. Discussion RETUNE started recruitment in February 2025 and is currently ongoing. RETUNE using the TwiCs design will clarify the effectiveness of a preference-based opt-out smoking cessation intervention among people living with HIV. Trial registration Clinicaltrials.gov NCT06789692. Registered on January 17th, 2025. The manuscript is aligned with the registry. https://clinicaltrials.gov/study/NCT06789692?cond=NCT06789692&rank=1

A test for diagnosis of active Tuberculosis (TB) from peripheral blood could tremendously improve clinical management of patients. Of 178 prospectively enrolled patients with possible TB, 60 patients were diagnosed with pulmonary and 27 patients with extrapulmonary TB. The frequencies of Mycobacterium tuberculosis (MTB) specific CD4(+) T cells and CD8(+) T cells producing cytokines were assessed using overnight stimulation with purified protein derivate (PPD) or early secretory antigenic target (ESAT)-6, respectively. Among patients with active TB, an increased type 1 cytokine profile consisting of mainly CD4(+) T cell derived interferon (IFN)-γ was detectable. Despite contributing to the cytokine profile as a whole, the independent diagnostic performance of one cytokine producing T cells as well as polyfunctional T cells was poor. IFN-γ/Interleukin(IL)-2 cytokine ratios discriminated best between active TB and other diseases. T cells producing one cytokine and polyfunctional T cells have a limited role in diagnosis of active TB. The significant shift from a \"memory type\" to an \"effector type\" cytokine profile may be useful for further development of a rapid immune-diagnostic tool for active TB.

Before April 2022, monkeypox virus infection in humans was seldom reported outside African regions where it is endemic. Currently, cases are occurring worldwide. Transmission, risk factors, clinical presentation, and outcomes of infection are poorly defined. We formed an international collaborative group of clinicians who contributed to an international case series to describe the presentation, clinical course, and outcomes of polymerase-chain-reaction-confirmed monkeypox virus infections. We report 528 infections diagnosed between April 27 and June 24, 2022, at 43 sites in 16 countries. Overall, 98% of the persons with infection were gay or bisexual men, 75% were White, and 41% had human immunodeficiency virus infection; the median age was 38 years. Transmission was suspected to have occurred through sexual activity in 95% of the persons with infection. In this case series, 95% of the persons presented with a rash (with 64% having ≤10 lesions), 73% had anogenital lesions, and 41% had mucosal lesions (with 54 having a single genital lesion). Common systemic features preceding the rash included fever (62%), lethargy (41%), myalgia (31%), and headache (27%); lymphadenopathy was also common (reported in 56%). Concomitant sexually transmitted infections were reported in 109 of 377 persons (29%) who were tested. Among the 23 persons with a clear exposure history, the median incubation period was 7 days (range, 3 to 20). Monkeypox virus DNA was detected in 29 of the 32 persons in whom seminal fluid was analyzed. Antiviral treatment was given to 5% of the persons overall, and 70 (13%) were hospitalized; the reasons for hospitalization were pain management, mostly for severe anorectal pain (21 persons); soft-tissue superinfection (18); pharyngitis limiting oral intake (5); eye lesions (2); acute kidney injury (2); myocarditis (2); and infection-control purposes (13). No deaths were reported. In this case series, monkeypox manifested with a variety of dermatologic and systemic clinical findings. The simultaneous identification of cases outside areas where monkeypox has traditionally been endemic highlights the need for rapid identification and diagnosis of cases to contain further community spread.