TARDBP (TDP-43), a multifunctional RNA-binding protein, has emerged as a critical host factor controlling HIV-1 replication by destabilizing the viral Pr55Gag polyprotein, precursor to capsid (CA), matrix, and nucleocapsid. TARDBP promotes HDAC6-mediated autophagic degradation of HIV-1 Pr55Gag and Vif, impairing nascent virion assembly and infectivity. Simultaneously, TARDBP disrupts viral entry by modulating HDAC6-dependent microtubule (MT) deacetylation, blocking the viral core at the pore fusion step in target cells. These dual mechanisms position TARDBP as a central antiviral defender, paralleling the CA- and viral core-targeting activity of nonhuman TRIM5α and novel therapeutic inhibitors such as lenacapavir. This review synthesizes evidence for TARDBP’s roles in HIV-1 restriction, highlighting its potential to destabilize the CA-formed viral core during both viral assembly and entry. We propose that enhancing TARDBP activity, combined with destabilizing CA-binding drugs, could offer a synergistic strategy to combat drug-resistant HIV-1 strains and target viral reservoirs, providing hope for functional cure approaches. TARDBP (TDP-43) is a protein that normally helps cells manage RNA, but recent studies have shown that TARDBP also plays a surprisingly powerful role in fighting HIV-1. This protein weakens the virus in two main ways. First, TARDBP regulates and works with another protein called HDAC6 to break down important viral components (particularly HIV-1 Pr55Gag and Vif) through the cell’s natural recycling system, known as autophagy. Since Pr55Gag is needed to construct the viral core that contains and protects the viral genome, as well as the matrix and nucleocapsid, destroying it prevents new virus particles from forming correctly or becoming infectious. Second, TARDBP hinders HIV-1´s ability to enter cells. It does this by affecting the microtubules inside the cells, which are similar to tiny tracks that the virus uses to reach the nucleus. By modulating the effect of HDAC6 on microtubules, TARDBP prevents HIV-1 from completing the fusion step needed to release its viral core (capsid) and genome into the host cell. Together, these two actions make TARDBP a strong natural defender against HIV-1 by avoiding CA (viral core) formation and/or viral core entry into the cells. Its behaviour is complementary and in phase to that of other antiviral factors, such as nonhuman TRIM5α, as well as to that of new drugs that target the CA (viral core), such as lenacapavir. Researchers propose that boosting TARDBP activity, especially alongside capsid-targeting drugs, could offer a dual strategy: combating drug-resistant HIV-1 and helping to reduce the viral reservoir.

Purpose of reviewSpontaneous control of HIV replication has been primarily associated with cellular immune responses. However, it remains multifactorial, and viral determinants, innate and humoral immune responses could be additional relevant contributors. Furthermore, posttreatment control cases reveal new roles for humoral responses. This review describes the direct, indirect and passive roles of humoral responses in HIV control.Recent findingsNew evidence supports the role of the humoral responses in the natural control of HIV. Indeed, a strong association has been reported between polyfunctional humoral responses and slow disease progression, highlighting the active role of both neutralizing and nonneutralizing antibodies in natural control. Moreover, broadly neutralizing antibodies (bNAbs) are being considered as therapeutic interventions to directly or indirectly mediate HIV control in cure strategies. Data from the latest clinical trials show that treatment with bNAbs may induce high-quality CD8 T-cell responses, pointing to bNAbs as a major indirect strategy to induce durable HIV control. Finally, humoral responses can serve as biomarkers for monitoring elite controllers and have been useful to identify stable aviremic controllers, providing new clinical monitoring tools.SummaryHumoral responses are relevant for understanding immune mechanisms of control, for defining therapeutic interventions and for the clinical follow-up of elite controllers.

The biological mechanisms underlying long COVID in the pediatric population are poorly understood. Our study aimed to characterize the immune pathophysiology of long COVID in this population. We analyzed major immune cell compartments in PBMCs and the specific SARSCoV-2 antibody response in 99 patients with long COVID and in 18 patients without long COVID at 3 months after acute infection. Our findings indicate that pediatric long COVID is associated with a dysregulated immune response characterized by altered innate immunity and overactivated T, B, and NK cell responses. Furthermore, young people with long COVID had an impaired humoral response to SARS-CoV-2 marked by a dysregulated B cell compartment and lower levels of antiRBD IgG and IgA. This correlated with reduced neutralizing capacity against SARS-CoV-2. Random forest analysis identified CCR6 expression on myeloid cells as the most relevant biomarker that distinguishes individuals with long COVID from control individuals with 79% accuracy.

The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compromised the efficacy of many authorized monoclonal antibody products. This highlights the need for alternative strategies, especially for vulnerable populations such as immunocompromised individuals. Here, we optimized angiotensin-converting enzyme 2 (ACE2)-Fc fusion proteins by combining three engineering steps: in silico mutagenesis of the S protein binding interface to increase affinity, insertion of a flexible linker to improve protein stability and S protein accessibility, and generation of a tetrameric molecule to maximize avidity. Neutralizing activity was tested against a large panel of pre-Omicron and Omicron pseudoviruses and authentic viruses, including JN.1 and KP.2 variants. Optimized ACE2-Fc molecules demonstrated potent neutralizing activity, in the picomolar range, against all SARS-CoV-2 variants. Our molecules displayed similar potency but better resilience when compared to the monoclonal antibody Sipavibart. These findings support ACE2-Fc proteins as robust candidates for next-generation interventions against infection by an evolving SARS-CoV-2.

Dual antiretroviral therapy with dolutegravir and lamivudine (DTG/3TC) is a recommended first-line regimen for people with HIV, but whether reduced-drug therapy maintains adequate antiviral pressure within lymph node (LN) reservoirs remains uncertain. In the DUALITY clinical trial, peripheral HIV-1 reservoir markers declined similarly in participants initiating DTG/3TC or dolutegravir-based triple therapy. Here we investigated viral persistence and antiretroviral drug distribution in LN using multimodal imaging. In 39 participants undergoing inguinal LN excision at baseline or during the first year of treatment, HIV-1 DNA and RNA were detected by DNAscope/RNAscope and antiretroviral spatial distribution was mapped by mass spectrometry imaging. HIV-1-infected cells declined rapidly after treatment initiation, with comparable reductions between treatment groups. Antiretrovirals were widely detected within LN tissue regions susceptible to containing HIV-positive cells. These findings provide spatial evidence that DTG/3TC achieves effective LN penetration and supports effective antiviral exposure within a key anatomical HIV reservoir.

OBJECTIVES:SARS-CoV-2 antigens have been detected in plasma months after acute infection, but their long-term dynamics and clinical relevance remain unclear. We aimed to assess the persistence and clinical specificity of plasma SARS-CoV-2 antigenemia over 2 years after acute infection. METHODS:We conducted a 2-year longitudinal study involving 425 adults who developed Long COVID (n = 167) or fully recovered from acute COVID-19 (n = 148), and uninfected controls (n = 110). Plasma samples were collected at 6-12 months and 18-24 months after infection. SARS-CoV-2 spike, S1 subunit, and nucleocapsid antigens were quantified using the ultrasensitive Simoa® platform blinded for clinical features. SARS-CoV-2 specific humoral responses, including neutralizing antibodies, were also assessed. RESULTS:At 6-12 months, SARS-CoV-2 antigenemia (any antigen) was detected in 31% of individuals with Long COVID, in 20% of those fully recovered and in 5.4% of uninfected controls. By 18-24 months, positivity declined to 3.5%, 0%, and 1.5%, respectively. Full spike was the most frequent antigen detected, whereas S1 was rarely observed and nucleocapsid was absent in recovered participants. Antigenemia was not associated with number or type of persistent symptoms, antibody titres, including neutralizing capacity, or vaccination status. CONCLUSIONS:SARS-CoV-2 antigens circulate in plasma up to 1 year after infection in a minority of individuals, regardless of whether they develop Long COVID or not, and become rarely detectable later on. Therefore, current evidence does not support its use to guide clinical monitoring or treatment decisions in Long COVID.

A subset of people living with HIV (PLHIV), known as immunological non-responders (INR), fails to achieve adequate CD4⁺ T cell recovery despite viral suppression with antiretroviral therapy (ART). These individuals face an increased risk of adverse clinical outcomes. This study aims to explore the intracellular mechanisms and molecular signatures underlying this incomplete immune recovery using a multi-omics approach. The study analysed CD4⁺ and CD8⁺ T cells from 100 ART-naïve PLHIV. Participants were classified into controls (baseline CD4⁺ > 200 cells/µL, n = 49) and cases (baseline CD4⁺ ≤ 200 cells/µL, n = 51). Cases were further categorised after 48 weeks of ART as immunological responders (IR, n = 34) or INR (n = 16) based on a recovery cut-off of 250 cells/µL. The research employed integrative proteomic and metabolomic analyses, adjusted for sex, complemented by miRNA and qRT-PCR validation in a subset of samples to identify differential molecular signatures. In CD4⁺ T cells, a baseline signature of 381 proteins and 45 metabolites significantly differentiated controls from cases; notably, 34 proteins and 16 metabolites specifically discriminated future IR from INR before starting treatment. CD8⁺ T cells showed a more limited signature with minimal stratification between IR and INR. Integrative analysis revealed coordinated dysregulation in CD4⁺ T cells of INR, characterised by altered glycolytic flux, metabolic exhaustion, and oxidative stress. Exploratory analyses via miRNA and qRT-PCR confirmed these findings and suggested post-transcriptional mechanisms contribute to the impairment. Incomplete immune recovery in PLHIV is primarily driven by pre-existing metabolic dysfunction and oxidative stress within CD4⁺ T cells, rather than CD8⁺ T cells. These findings identify specific molecular signatures present before ART initiation, highlighting early potential therapeutic targets and strategies to enhance immune reconstitution in this vulnerable population.

The identification of a new Asn332 glycan-independent anti-HIV-1 neutralizing antibody that targets the V3 epitope, together with an Asn332 glycan-deficient priming immunogen capable of inducing B cell precursors of Asn332 glycan-dependent and -independent neutralizing antibodies, redefines the V3 loop in HIV-1 vaccine development.

Telomere shortening is a hallmark of aging and immune dysfunction, offering a reliable indicator of cellular replicative history and biological age. Measuring telomere length in defined immune subsets provides critical insights into immune aging and disease-associated remodeling. However, conventional methods often require prior cell sorting or compromise surface marker detection, limiting their ability to integrate telomere length with immunophenotyping. The advent of spectral flow cytometry enables highly multiplexed single-sample analysis, overcoming many of these technical constraints. Here, we present a streamlined protocol that combines flow cytometry-based fluorescence in situ hybridization (flow-FISH) with spectral cytometry to measure relative telomere length (RTL) in peripheral blood mononuclear cells (PBMCs). This 18-color panel simultaneously captures RTL across 15 immune subsets, alongside five functional and phenotypic markers reflecting activation, differentiation, senescence, and exhaustion. Our flow-FISH method integrates telomere analysis and immune profiling into a single, reproducible workflow. Key optimizations include dual fixation to preserve membrane staining, use of the 1301 cell line as an internal telomere reference, and exclusion of dividing cells via cell cycle staining to ensure accurate RTL quantification. Validation in PBMCs from older adults demonstrated the method's ability to detect expected RTL decreases with T-cell differentiation and senescence progression, confirming its utility for studies on immune aging, chronic infection, and other age-related conditions. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Staining and flow cytometry for flow-FISH to measure telomere length and immunophenotype in peripheral blood mononuclear cells (PBMCs) Support Protocol: Preparation and cryopreservation of 1301 internal control cell line Basic Protocol 2: Data analysis and interpretation for telomere length and immunophenotype measurements in PBMCs.

BackgroundSARS-CoV-2 neutralizing antibodies may protect against symptomatic infection in immunized individuals. However, vaccine-induced antibody levels wane over time, reducing vaccine efficacy. The definition of the waning kinetics of neutralizing SARS-CoV-2 responses and the potential impact of sequential antigen encounters are still poorly defined.MethodsPlasma neutralizing activity was determined in longitudinally collected samples from SARS-CoV-2 infected, primo-vaccinated and boosted individuals. Neutralizing activity decay kinetics were modeled against time using Log-Log and biexponential models.ResultsNeutralizing antibody levels wane after an initial peak in all groups of vaccinated individuals with half-life ranging from 29 to 60 days. Exponential models showed a subsequent stabilization of neutralizing titers to a plateau. Both the peak response and the plateau values depended on vaccine type, infection status and severity of infection. Booster immunization by either vaccines or breakthrough infections did not modify peak, plateau or decay rate values.ConclusionsOur results indicate that the waning of SARS-CoV-2 neutralizing antibody responses was recurrent even after several antigen encounters. Repeated immunizations would be required to maintain high levels of neutralizing antibodies and protect vulnerable individuals from symptomatic infection.

The HIPRA-HH-2 was a multicentre, randomized, active-controlled, double-blind, non-inferiority phase IIb clinical trial comparing the immunogenicity and safety of the PHH-1V adjuvanted recombinant vaccine as a heterologous booster against homologous booster with BNT162b2. Interim results demonstrated strong humoral and cellular immune response against the SARS-CoV-2 Wuhan-Hu-1 strain and the Beta, Delta, and Omicron BA.1 variants up to day 98 post-dosing. Here we report that these responses with PHH-1V are sustained up to 6 months, including in participants over 65 years, despite their smaller sample size. The PHH-1V booster was non-inferior in eliciting neutralizing antibodies for SARS-CoV-2 Omicron XBB.1.5 variant compared to BNT162b2 after 6 months. No severe COVID-19 cases occurred in any group, and mild cases were similar (50.4 % for PHH-1V vs. 47.8 % for BNT162b2). While both groups may have reached comparable immunity levels, these findings suggest that the PHH-1V vaccine provides long-lasting immunity against various of SARS-CoV-2 variants. ClinicalTrials.gov Identifier: NCT05142553.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the coronavirus disease 19 (COVID-19) pandemic, significantly impacting global health, economies, and social stability. In February 2020, the first cases of SARS-CoV-2 infections in animals were documented, highlighting the potential risks posed by regular human-animal interactions in facilitating viral transmission. In consequence, it is essential to validate surveillance methods for SARS-CoV-2 in animals. In the present study, 101 sera from different animal species (36 cats, 41 dogs, 4 ferrets, 10 wild boar, 6 domestic goats, and 4 lions) were tested using three different ELISA kits to evaluate humoral responses against SARS-CoV-2. ELISA results were compared and correlated with a pseudovirus neutralization test (pVNT), considered as the reference assay. ELISA-1, targeting the receptor binding domain (RBD) neutralizing antibodies (nAbs) of SARS-CoV-2, exhibited the highest diagnostic performance, and proved to be a reliable tool for initial screenings in high-throughput animal studies. In contrast, ELISA-2 (also targeting RBD nAbs) and ELISA-3 (targeting nucleoprotein antibodies) demonstrated lower sensitivity for detecting seropositive animals.

The human immunodeficiency virus (HIV) is a retrovirus discovered in 1983 as the causative agent of acquired immunodeficiency syndrome (AIDS). Following several zoonotic spillover events from non-human primates, the virus spread between humans for more than 60 years under the radar. HIV infects and kills CD4 T cells, the cells that coordinate adaptive immune responses. Primoinfection is associated with a flu-like symptomatology and chronic infection is clinically silent, and mostly not diagnosed, contributing to viral spread and leading to fatal long-term outcomes. HIV genome codes for a poor reading-proof reverse transcriptase, which facilitates high sequence variability, particularly in the envelope glycoprotein complex, the sole external viral protein and main target of humoral immune responses. This antigenic variability precludes the development of an efficacious vaccine despite 40 years of research. In contrast, the development of antiretroviral drugs represents a scientific and medical success which saved the lives of millions of infected people and provides today an excellent protection against AIDS, although it does not permit viral eradication. Indeed, HIV can integrate its genome in target cells and generates a pool of latently infected cells which escape eradication by both the natural immune response and treatments. In summary, the efforts to tackle HIV have been suboptimal, and the virus has infected more than 90 million people and caused 44 million deaths worldwide. In the absence of a vaccine, a better deployment of available preventative and therapeutic tools is needed, particularly in geographical areas and communities with the highest incidence of infection.

Although rare, severe complications may follow SARS-CoV-2 infection in pediatric populations. PHH-1V, a protein-based, bivalent, adjuvanted COVID-19 vaccine, demonstrated strong immunogenicity and favorable safety as a booster in adults. This study further evaluated PHH-1V as a heterologous booster in pediatric adolescent population. HIPRA-HH-3 was a phase IIb, open-label, multicenter, non-inferiority trial assessing the immunogenicity and safety of PHH-1V in 240 healthy adolescents (≥ 12 to < 18 years) previously vaccinated with BNT162b2. Immunogenicity (N = 88) was evaluated by measuring neutralizing antibodies against SARS-CoV-2 variants, total binding antibodies, and T-cell responses at day 14 post-booster, compared to young adults (≥ 18 to ≤ 25 years) (N = 81) from the previous HIPRA-HH-2 study, who had also received the PHH-1V booster vaccine. Safety endpoints included all adverse events through day 28. Neutralizing titers against Omicron BA.1 (primary endpoint), WH1, Beta, and Delta variants and total binding antibodies were significantly higher in adolescents than in young adults (p < 0.001), demonstrating non-inferiority (margin < 1.5). T-cell responses against Omicron BA.1 and Beta variants also increased significantly (p < 0.001). Adverse events were mostly mild or moderate, primarily injection-site pain and headache. No serious adverse events were reported. PHH-1V is safe and immunogenic as a heterologous booster in adolescents, inducing both humoral and cellular responses with SARS-CoV-2 cross-variant immune recognition. These findings support the use of PHH-1V in adolescent vaccination strategies. Additional data on long-term protection in this population, including specific risk groups, remain needed. NCT06234956 ( https://clinicaltrials.gov/study/NCT06234956 ) and 2023-504639-42-00 ( https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2023-504639-42-00 ).

Immune memory is essential for the effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. In the current context of the pandemic, with a diminished vaccine efficacy against emerging variants, it remains crucial to perform long-term studies to evaluate the durability and quality of immune responses. Here, we examined the antibody and memory B-cell responses in a cohort of 113 healthcare workers with distinct exposure histories over a 3-year period. Previously infected and naive participants developed comparable humoral responses by 17 months after receiving a full three-dose mRNA vaccination. In addition, both maintained a substantial SARS-CoV-2-reactive memory B-cell pool, associated with a lower incidence of breakthrough infections in naive participants. Of note, previously infected participants developed an expanded SARS-CoV-2-reactive CD27-CD21- atypical B-cell population that remained stable throughout the follow-up period. Thus, previous SARS-CoV-2 infection differentially imprints the memory B-cell compartment without compromising the development of long-lasting humoral responses.

Plitidepsin is an antitumoral compound safe for treating COVID-19 that targets the translation elongation factor eEF1A. Here we detect that plitidepsin decreases de novo cap-dependent translation of SARS-CoV-2 and non-viral RNAs but affects less than 13% of the host proteome, thus preserving cellular viability. In response to plitidepsin, cells upregulate EIF2AK3 and proteins that reduce translation, but also proteins that support proteostasis via ribosome synthesis and cap-independent translation by eIF4G2 and IGF2BP2. While plitidepsin inhibits cap- or internal ribosome entry sites (IRES)-mediated translation, its impact on N6-methyladenosine (m6A) translation is limited. In agreement, plitidepsin blocks members of Coronaviridae, Flaviviridae, Pneumoviridae and Herpesviridae families. Yet, it fails to inhibit retroviruses that exploit m6A synthesis routes and are blocked by drugs targeting IGF2BP2 m6A reader. By deciphering the molecular fingerprint of cells treated with therapies targeting translation we identify a rational approach to select broad-spectrum antivirals with potential to counteract future pandemic viruses.

Summary The HIPRA-HH-2 was a multicentre, randomized, active-controlled, double-blind, non-inferiority phase IIb clinical trial to compare the immunogenicity and safety of a heterologous booster with PHH-1V adjuvanted recombinant vaccine versus a homologous booster with mRNA vaccine. Interim results showed a strong humoral and cellular immune response against the SARS-CoV-2 Wuhan-Hu-1 strain and the Beta, Delta, and Omicron BA.1 variants up to day 98 after dosing. Here we report that these humoral and cellular responses after PHH-1V dosing are sustained up to 6 months. These results are observed both when including or not participants who reported SARS-CoV-2 infection and in a high-risk population (≥65 years). Additional analysis revealed a non-inferiority of PHH-1V booster in eliciting neutralizing antibodies also for SARS-CoV-2 Omicron XBB.1.5 when compared to mRNA vaccine after 6 months. The PHH-1V vaccine provides long-lasting protection against a wide variety of SARS-CoV-2 emerging variants to prevent severe COVID-19. ClinicalTrials.gov Identifier NCT05142553

IntroductionThe negative efficacy results of coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) as early treatment in the COnV-ert trial have been attributed to the use of methylene blue (MB). We characterized immune responses after MB-treated CCP infusion and the impact of MB on antibodies of the infused CCP units.MethodsWe measured antibody isotypes (IgG, IgM, and IgA) and IgG subclasses (IgG1, IgG2, IgG3, and IgG4) against SARS-CoV-2 nucleocapsid and spike (S) antigens, neutralizing antibody titers, and IgG avidity in 128 participants of the COnV-ert trial 7 and 60 days after infusion and in paired CCP units before and after MB treatment.ResultsTreatment with CCP significantly increased the levels of IgG and IgG1 to receptor-binding domain (RBD) and S, IgG3 to S and S2, and IgG avidity in recipients 7 days after infusion, without an increase in IgA, IgM, IgG2, IgG4, or neutralization. At day 7 post-infusion, recipients exhibited lower IgG, all IgG subclasses, and avidity; higher IgA and IgM; and comparable neutralization relative to paired CCP units. MB was associated with a significant decrease in cytophilic subclasses IgG1 and IgG3 to S and S2, and IgA to RBD, S and S2 in CCP units IgA to RBD, S and S2 in CCP units, without a reduction in neutralization titer and with a modest increase in IgG2 to RBD and S.DiscussionOur study shows a modest impact of a single intravenous infusion of MB-treated high-titer CCP on circulating antibody levels compared to those generated by the host by day 7 and an adverse effect of MB on IgG1 and IgG3, which are essential for effector functions.Clinical trial registrationhttps://www.clinicaltrials.gov/, identifier NCT04621123.

Background: SARS-CoV-2 booster vaccination remains essential to prevent severe COVID-19, particularly in vulnerable populations such as older adults. This study evaluated the durability and dynamics of immune responses following booster vaccination(s) in >65-year-old individuals and examined their association with protection against new infections. Methods: Immune responses were evaluated at 3, 9, and 15 months post-booster, measuring SARS-CoV-2-specific IgG antibodies against spike [IgG(S)] and nucleocapsid [IgG(N)] proteins, neutralizing activity against the Omicron BA.2 variant, and cellular immunity. A subset of participants was tested before booster administration. Regression analyses examined the influence of clinical and immunological factors—including a bivalent fourth dose—on infection risk over time. Results: Booster vaccination significantly enhanced IgG(S) and neutralizing capacity, peaking at 3 months. Although a decline was observed by 9 months, responses remained above baseline. Individuals with prior SARS-CoV-2 infection exhibited higher IgG(S) levels and neutralizing titers, and significantly lower reinfection rates (15%), compared to uninfected individuals. A fourth vaccine dose further increased IgG(S) levels. While neutralizing capacity was not consistently enhanced by the fourth dose, recipients experienced a lower rate of new infections. Immune trajectory analyses revealed that breakthrough infections elicited strong humoral responses comparable to those seen in previously infected individuals, highlighting the role of hybrid immunity. Conclusions: In older adults, booster vaccination induces durable immune responses, with hybrid immunity offering enhanced protection. A fourth dose boosts antibody levels and reduces infection risk, supporting its use in this high-risk group. Continued monitoring is needed to determine the long-term effectiveness of boosters, particularly against emerging variants.

TARDBP (TDP-43), a multifunctional RNA-binding protein, has emerged as a critical host factor controlling HIV-1 replication by destabilizing the viral capsid protein (CA) 55 kDa Gag precursor (Pr55Gag). TARDBP promotes HDAC6-mediated autophagic degradation of HIV-1 Pr55Gag and Vif, impairing nascent virion assembly and infectivity. Simultaneously, TARDBP disrupts viral entry by modulating HDAC6-dependent microtubule (MT) deacetylation, blocking the viral core at the pore fusion step in target cells. These dual mechanisms position TARDBP as a central antiviral defender, paralleling the CA (viral core)-targeting activity of TRIM5α and novel therapeutic inhibitors such as lenacapavir. This review synthesizes evidence for TARDBP’s roles in HIV-1 restriction, highlighting its potential to destabilize the CA-formed viral core during both viral assembly and entry. We propose that enhancing TARDBP activity, combined with destabilizing CA-binding drugs, could offer a synergistic strategy to combat drug-resistant HIV-1 strains and target viral reservoirs, providing hope for functional cure approaches.