The availability of oral and long-acting injectable pre-exposure prophylaxis (PrEP) has transformed human immunodeficiency virus (HIV) prevention; however, some individuals may prefer behaviorally congruent, nonsystemic, on-demand rectal PrEP options that avoid chronic systemic exposure. The Q-Griffithsin (Q-GRFT) rectal douche is a novel, user-controlled PrEP candidate, containing a natural (red alga–derived), potent broad-spectrum antiviral lectin for pericoital rectal use. This first-in-human Phase 1 trial evaluated the safety, pharmacokinetics (PKs), pharmacodynamics (PDs), and acceptability of a single Q-GRFT rectal douche dose. Sixteen HIV-negative participants (eight female and eight male) with a history of recent receptive anal intercourse were enrolled in this randomized, double-blind study. Following single-dose administration, blood, rectal fluid, and rectal tissue samples were collected for safety, PK, and PD analyses using an ex vivo rectal explant HIV challenge model. Acceptability was measured using structured questionnaires. The Q-GRFT douche was safe with no Grade 3 or 4 adverse events or significant histological abnormalities. Acceptability was high at 93% of the study product. At 1 h postdose, geometric mean (range) Q-GRFT concentrations were 522.18 ng/mL (52.8–12,482.2) in rectal swab eluate and 6.85 µg (0.80–51.07) in rectal tissue, declining over 24 h. Q-GRFT was not detectable in plasma. Higher individual tissue drug levels correlated with reduced HIV infectivity in both rectal eluate ( p = 0.036) and tissue explant ( p = 0.003). In this first-in-human study, a single administration of Q-GRFT as a rectal douche demonstrated favorable safety, acceptability, and high local drug exposure without systemic absorption, supporting further evaluation as an on-demand, nonsystemic rectal PrEP strategy.
Objectives: The human papillomavirus (HPV) E7 oncoprotein drives cervical cancer progression through sustained overexpression in HPV16-positive cells, making it an ideal therapeutic target. This study developed a novel affitoxin (ZHPV16E7-GrB) to target HPV16E7 and elucidated its antitumor mechanism in HPV16-positive cervical cancer. Methods: ZHPV16E7-GrB was developed by fusing a cell-penetrating peptide (CPP) to an affibody (ZHPV16E7) specific for HPV16E7 and conjugating it with human granzyme B (GrB), a cytotoxic effector molecule. Its binding specificity, cellular uptake, and ability to induce pyroptosis were evaluated using in vitro assays. The underlying mechanisms were investigated using siRNA-mediated knockdown and pan-caspase inhibition, and its in vivo antitumor efficacy was assessed in a TC-1 syngeneic tumor model. Results: The purified ZHPV16E7-GrB exhibited specific binding to the HPV16E7 protein and rapid cellular uptake in HPV16-positive cervical cancer cells. Treatment with ZHPV16E7-GrB clearly induced pyroptosis, characterized by bubble-like protrusions of the cell membrane, GSDME cleavage, and the release of proinflammatory cytokines (IL-18, IL-1 beta, and HMGB1) and LDH. Importantly, this pyroptosis occurred independently of caspase-3 activation, as demonstrated by caspase-3 knockdown and pan-caspase inhibition, with GSDME identified as the key executor of pyroptosis. Consistently, ZHPV16E7-GrB significantly suppressed tumor growth in a TC-1 syngeneic tumor model, with pyroptosis likely contributing to its antitumor activity. Conclusions: Our findings provide mechanistic insights into a previously unrecognized antitumor pathway triggered by ZHPV16E7-GrB, which directly regulates pyroptosis mediated by GSDME cleavage by bypassing the caspase-3 activation pathway, revealing a novel approach for HPV16-specific cancer therapy. (c) 2026 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Human immunodeficiency virus (HIV) persists in diverse body tissues, including the gut, lymph nodes (LNs), and lungs, requiring direct sampling to characterize heterogeneous reservoirs. HIV cure-related trials may include tissue sampling to evaluate intervention efficacy and mechanisms to eliminate viral reservoirs. Repeated invasive sampling carries risks that must be balanced against safety, acceptability, and scientific value. We assessed the experiences of young women undergoing serial excisional LN and gut biopsies during an HIV cure-related trial in South Africa. We conducted a qualitative secondary analysis of in-depth interviews (IDIs) with women enrolled in a Phase 2A HIV cure-related trial (NCT05281510) that included an analytical treatment interruption (ATI). We conducted IDIs at enrollment and pre-ATI at the Females Rising through Education, Support and Health research site in Durban, South Africa, in isiZulu. We audio-recorded, transcribed, translated, and deidentified the interviews and analyzed them using inductive conventional content analysis. We interviewed 19 participants. Each underwent LN excision 1-3 times (mean 2.6) and gut biopsy 0-3 times (mean 2.5). Motivations included scientific curiosity and contributing to future generations. LN excision was generally painless, although some reported itching and slow healing. Gut biopsies caused abdominal pressure and transient bloating. One adverse event occurred among 48 LN excisions. Initial apprehension was common, but clear communication, supportive staff, and recognition of contributions fostered trust and willingness to undergo repeat procedures. Serial tissue sampling was acceptable among young South African women despite some discomfort. Altruism was a primary motivator, while clear communication and participant-centered care were critical to supporting informed participation and repeat sampling.
India has 2.6 million people living with human immunodeficiency virus (HIV) (PLWHIV) yet remains underrepresented in global hospitalization analyses. This study characterizes hospitalization patterns during India's transition toward universal antiretroviral therapy (ART) access (2013-2017) and quantifies the protective effect of sustained ART against acquired immunodeficiency syndrome (AIDS)-defining hospitalizations. A retrospective cohort study of HIV-positive patients aged >= 18 years admitted to a tertiary care center in Manipal, India was performed. Primary hospitalization reasons were categorized as AIDS-defining illness, HIV-associated non-AIDS (HANA), or non-HANA conditions. Multivariable logistic regression estimated associations between ART duration (>= 9 vs. <9 months) and AIDS-defining hospitalization. Among 1,280 patients (2,157 admissions), median age was 44 years, 68% were male, and 46% were newly diagnosed at admission. AIDS-defining illnesses accounted for 45% of admissions, with tuberculosis being most prevalent (18%). Patients receiving ART >= 9 months had significantly lower odds of AIDS-defining hospitalization (adjusted odds ratio 0.78, 95% confidence interval 0.61-0.99). AIDS-defining illnesses, particularly tuberculosis, remain the predominant cause of HIV-related hospitalization in India. The high proportion of new diagnoses at admission and protective effect of sustained ART underscore the need for earlier HIV testing, rapid ART initiation, and adherence support.
In 2021, a Perspective article suggested that principles of HIV neuropathogenesis could provide a conceptual framework for understanding the neurological complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection when mechanistic evidence was limited. Five years later, extensive clinical, neuropathological, and experimental studies allow reassessment of that framework. Current evidence has shifted emphasis away from direct viral infection of the central nervous system toward host-mediated mechanisms involving persistent immune activation, endothelial dysfunction, glial activation, thromboinflammation, and disruption of the neuroimmune axis. At the same time, persistent viral antigens and adaptive immune responses, including autoantibodies in subsets of patients, have expanded our understanding of the biological heterogeneity underlying post-acute sequelae of SARS-CoV-2 infection with neurological manifestations. This Perspective revisits the original framework in light of these advances and examines how concepts derived from HIV neuropathogenesis continue to inform our understanding of persistent neurological dysfunction following SARS-CoV-2 infection.
