HIV infection and immunosenescence: challenges and intervention strategies

Abstract

Background

Antiretroviral therapy has extended the life expectancy of people with HIV (PWH), leading to a rapidly expanding ageing population of PWH worldwide, including in low- and middle-income countries. The interaction between ageing and chronic HIV infection is closely associated with immunosenescence, and PWH are widely regarded as a model of accelerated immune ageing. Immunosenescence, characterized by a progressive decline in immune function and increased susceptibility to infections, contributes to a higher burden of age-related comorbidities and cancers, posing a major long-term health challenge for this population.

Main body.

The main focus of this review is on immunosenescence-related phenotypic and functional alterations in innate immune cells in PWH, including natural killer cells, monocytes, macrophages, and dendritic cells. It also outlines immunosenescence-related changes in T and B cells in the context of ageing and chronic HIV infection, such as thymic atrophy, loss of naïve T cell diversity, expansion of terminally differentiated and exhausted T-cell subsets, the impact of cytomegalovirus co-infection, and the emergence of age-associated B cells that impair humoral immunity and vaccine responsiveness. Furthermore, it discusses how persistent low-grade inflammation, mitochondrial damage induced by viral proteins and certain antiretroviral regimens, together with lifestyle factors such as cigarette smoking, accelerate systemic immune ageing, and summarizes emerging therapeutic and lifestyle strategies aimed at mitigating immunosenescence and improving long-term immune health, while noting that robust evidence remains limited.

Conclusion

Despite growing insights into HIV-associated immune ageing, there is still no universally applicable biomarker of immunosenescence. This gap underscores the need to develop robust, population-tailored biomarker panels and targeted interventions for PWH, to support integrated strategies that combine antiretroviral therapy with immune restoration and anti-ageing approaches, ultimately improving immune health and quality of life.

Background

Antiretroviral therapy (ART) has substantially extended the life expectancy of people with HIV (PWH). According to UNAIDS 2024 data, the proportion of new HIV infections among individuals aged 50 and older is projected to increase sharply—from 28% of all new HIV infections in 2010 to 73% by 2030 [1]. This trend varies significantly across regions. In high-income countries, more than half of the approximately 7 million PWH are aged 50 or older. In countries such as the USA and the UK, individuals in this age group are expected to account for more than 70% of new infections by 2030 [2]. Moreover, as access to ART expands, the proportion of older adults with HIV is steadily increasing across low- and middle-income countries [3]. The number of people aged 50 and over living with HIV in sub-Saharan Africa is expected to triple in the coming decades [4]. Immunosenescence is a critical hallmark of ageing, and evidence of their reciprocal interaction has been systematically established. Immunosenescence is not only an inevitable consequence of ageing but also a catalyst for accelerated functional decline [5, 6], leading to increased susceptibility to infectious diseases, age-related diseases, and cancers [7]. Older adults, particularly those of advanced age, face an elevated risk of both developing and succumbing to viral infections such as SARS-CoV-2 [8].

HIV infection is recognized as a model for accelerated immunosenescence and systemic ageing [9]. Unlike in healthy individuals, in individuals with chronic HIV infection, immunosenescence may occur prematurely, primarily because of persistent immune activation, increased cellular replication and apoptosis linked to antiviral responses, and a heightened risk of age-related comorbidities. Moreover, prolonged viral infection can induce a shift in effector T cells towards a terminally differentiated phenotype (TEMRA) in ART-treated PWH, ultimately facilitating chronic inflammation and immune depletion [10–12]. HIV infection can accelerate immunosenescence by inducing mitochondrial dysfunction, even among ART-treated PWH [13]. Immunosenescence, a biological process typically linked to advanced age, can substantially contribute to the progressive deterioration of immune function in PWH [14]. Although immune senescence has been predominantly observed in older individuals across related studies, it is not confined exclusively to middle-aged and older adults. HIV infection can potentially induce immunosenescence even in young individuals and children, regardless of treatment status [15, 16]. The accumulation of senescent cells creates an immunosuppressive environment, promoting viral replication and transmission and thereby accelerating the progression of HIV disease. Consequently, immunosenescence in PWH may impair immune system functionality through these pathways and significantly influence chronic immune activation [14, 17, 18].

This review primarily focuses on immune senescence in PWH, integrating phenotypic and functional alterations across innate immunity and adaptive immunity during ageing and outlines the molecular mechanisms across immune cell types in HIV and the potential clinical strategies and applications for PWH. In addition, we summarize the drivers of accelerated immunosenescence in PWH, including amplification of the senescence-associated secretory phenotype (SASP) arising from persistent low-grade inflammation and immune activation, as well as mitochondrial dysfunction jointly induced by HIV proteins (e.g., Vpr) and specific antiretroviral regimens (Fig. 1). We also examine the synergistic amplifying effects of CMV co-infection and lifestyle factors such as smoking in accelerating ageing and, on this basis, briefly outline priorities for future research. Finally, we summarize current potential anti-ageing interventions, including senolytics, metabolic modulators, immunomodulation, gene/cell therapies, and lifestyle interventions, and we assess their feasibility and safety in PWH. Taken together, the review moves from phenotypic and functional changes to the underlying mechanisms, then to clinical relevance and potential interventions, providing a clear path for subsequent research and clinical evaluation.

Fig. 1.

Changes in the immune system during ageing and immunosenescence. Immune alterations across various immune cell types, including myeloid and lymphoid progenitors, macrophages, monocytes, dendritic cells [DCs], B cells, NK cells, T cells, and the thymus, occur during ageing in healthy individuals. Ageing leads to various changes, such as imbalances in macrophage polarization, alterations in antigen presentation, a reduction in antibody responses, and a decrease in cytokine production in NK cells. Additionally, age-related changes in immune cell differentiation, function, and proliferation are shown, with implications for immunosenescence and overall immune system efficacy. HSCs, haematopoietic stem cells; ABCs, age-associated B cells; SASP, senescence-associated secretory phenotype; TLR, Toll-like receptor; DCs, dendritic cells; TCR, T-cell receptor; NK, natural killer; KIR, killer-cell immunoglobulin-like receptor; TNF-α: tumour necrosis factor alpha. TEMRA: Terminally Differentiated Effector; KLRG-1, Killer Cell Lectin-Like Receptor G1; NKp46, Natural Cytotoxicity Triggering Receptor 1; NKp30, Natural Cytotoxicity Triggering Receptor 3; NKG2A, Natural Killer Group 2, member A; NKG2D, Natural Killer Group 2, member D; RTEs, recent thymic emigrants

Innate immunosenescence and HIV infection

The innate immune system serves as the primary defence front line of the host against pathogens. Although the quantity of most circulating innate immune cells remains relatively stable with age, their function is impaired in older individuals [19]; the primary manifestation is immune cell dysfunction, which impairs the ability to process and present antigens, conduct immune surveillance, and kill and phagocytize pathogens [20]. This study reviews the phenotypic and functional alterations of NK cells, dendritic cells, monocytes and macrophages during immune senescence, with a particular emphasis on the changes in innate immune cells that undergo senescence as a result of HIV infection.

The phenotypic and functional alterations in NK cells with ageing and after HIV infection

NK cells, key effectors of the innate immune system, are responsible for the early clearance of viral infections, intracellular pathogens, tumour cells and the surveillance of senescent cells [21, 22]. Functionally, NK cells are divided into two major subsets: The CD56^brightCD16⁻ subset, which secretes cytokines, and the CD56^dimCD16⁺ subset, which has greater cytotoxicity [23]. During physiological ageing, NK cells progressively transition from CD56^bright to CD56^dimCD57⁺ subsets, the latter representing terminally differentiated cells characterized by enhanced cytotoxic potential but diminished proliferative capacity and cytokine secretion [24, 25].

Similar phenotypic remodelling has been observed in PWH, even under virologically suppressive ART, and is associated with NK cell immunosenescence and mitochondrial dysfunction driven by persistent immune activation and inflammation [26–28]. During ageing, NK cells show dysfunction similar to that seen in chronic HIV infection: The CD56^dimCD16⁺ subset displays reduced proliferative potential and decreased cytotoxic capacity, which is associated with decreased perforin levels, impaired migration, and reduced activation receptors [24, 29]. Yang et al. employed single-cell RNA sequencing to expand a classical natural killer cell model (CD56^bright → CD56^dimCD57⁻ → CD56^dimCD57⁺), and reported that terminally mature natural killer cells highly expressed CX3CR1, TIM-3, and ZEB2 [30]. Although not yet directly validated in PWH, the phenotypic shift towards terminal differentiation and adaptive-like NK cell expansion strongly suggests that NK cells converge towards age-related senescence, driven by chronic immune activation and viral antigen exposure.

Ageing may further disrupt the precise regulatory balance between NK cell activation and inhibitory receptor signalling [31]. Senescent NK cells typically upregulate the expression of NK cell activation receptors such as NKG2D together with late-differentiation  inhibitory receptors KIRand KLRG1) and downregulate the expression of inhibitory receptor NKG2A and other activation receptors (NKp30 and NKp46), thereby diminishing their ability to recognize and eliminate target cells [32–34]. Concurrently, increased expression of CD57 and NKG2C indicates the expansion of adaptive-like NK cells, which exhibit reduced plasticity and responsiveness. Together, these changes indicate ageing, a proinflammatory immune landscape and compromised immune surveillance [35, 36].

The altered homing patterns of NK cells further reflect the immunological remodelling associated with ageing and chronic HIV infection. In older PWH, NK cells exhibit a shift in migratory behaviour characterized by upregulation of CCR7 expression and downregulation of α4β7 integrin expression, indicating preferential trafficking from mucosal sites to secondary lymphoid tissues [29]. This redistribution may compromise mucosal immune surveillance, which is a critical first line of defence against viral entry and replication. α4β7 is a gut-homing integrin that facilitates lymphocyte migration to gut-associated lymphoid tissue and contributes to HIV-1 transmission and reservoir formation, especially in untreated individuals, by promoting viral retention in mucosal compartments [37, 38]. In HIV-exposed individuals, reduced α4β7 expression on NK cells is correlated with impaired mucosal recruitment and suboptimal early viral control [39]. Preclinical models further demonstrate that α4β7 blockade attenuates mucosal SIV acquisition and limits the seeding of viral reservoirs [40]. Clinically, monoclonal antibodies targeting α4β7, such as vedolizumab, have achieved partial suppression of integrin expression in intestinal tissues and are associated with decreased levels of HIV DNA in gut-resident CD4⁺ T cells in individuals who received 24 weeks of ART followed by treatment interruption, underscoring the therapeutic potential of α4β7-targeted interventions in reducing viral persistence and preserving mucosal immune homeostasis in ageing PWH [41].

In summary, growing evidence indicates that chronic HIV infection and ageing synergistically accelerate NK cell immunosenescence. The resulting persistent proinflammatory immune landscape is increasingly recognized as a key contributor to the development of non-AIDS comorbidities, including cardiovascular disease, frailty, and malignancies, among PWH. A more comprehensive understanding of how NK cell dysfunction impairs activation and tissue homing may offer critical insights into the immunopathogenesis of HIV during ageing.

Phenotypic and functional changes in monocytes with ageing and after HIV infection

Monocytes play a central role in innate immunity and are classified into three subpopulations: Classical (CD14⁺CD16⁻), intermediate (CD14⁺CD16⁺), and nonclassical (CD14^lowCD16⁺), each with distinct functions in antigen presentation, cytokine secretion, and tissue surveillance [42, 43]. In both older adults and ART-treated PWH, although the absolute monocyte count remains relatively stable, their distribution significantly changes. Specifically, the classical monocyte subset is notably reduced, while the intermediate and nonclassical subsets increase, with intermediate monocytes showing increased maturation and activation [44, 45]. Additionally, the plasma levels of sCD163 and CXCL10, which serve as markers of monocyte activation, are elevated in both ageing and ART-treated PWH [46].

Importantly, intermediate and nonclassical CD16⁺ monocytes display an ageing phenotype characterized by elevated ROS levels, telomere damage, reduced Ki-67 levels, increased SA-β-Gal activity, and decreased mitochondrial membrane potential. By frequently exhibiting SASP-like characteristics and secreting elevated levels of IL-6, IL-8, and TNF-α, these cells exacerbate chronic inflammation in PWH [43, 47]. In parallel, dysfunction of cytoplasmic Pattern Recognition Receptors (PRRs) (e.g., retinoic acid-inducible gene I) impairs downstream type I interferon (IFN-I) signalling, resulting in diminished phagocytic capacity and blunted IFN-I responses [48]. Collectively, these features point to broader dysfunction of the mitochondrial–PRR axis and are closely linked to immunosenescence.

Mechanistically, regardless of ART treatment status, the dysregulation of monocyte subsets and proinflammatory programmes is partially driven by age- and HIV-associated impairments in haematopoietic stem cell differentiation [49, 50]. Epigenetic remodelling, such as elevated SET domain-containing 7 expression and increased H3 lysine 4 monomethylation at proinflammatory gene promoters (e.g., NF-κB p65), sustains monocyte proinflammatory programming [51]. Concurrently, metabolic stress characterized by mitochondrial dysfunction and a shift towards glycolysis along with transcription factor dysregulation synergistically contributes to monocyte dysfunction and systemic inflammation [52, 53]. Moreover, in ART-treated PWH, monocyte activation through the Toll like receptors (TLR) 2/4/7 pathway further amplifies cytokine production, resulting in a feedforward inflammatory cycle [46, 54]. These findings emphasize that chronic immune activation and metabolic stress drive the accumulation of dysfunctional, senescent monocytes with persistent SASP phenotypes, even under ART, potentially exacerbating inflammatory ageing in PWH. In response to the dysfunction of monocytes in immunosenescence, current research is gradually exploring how to achieve phenotypic remodelling through metabolic and inflammatory regulation.

Emerging interventions aim to restore immune function through metabolic and inflammatory regulation. One study suggested that drugs such as metformin can rebalance myeloid metabolism and suppress chronic inflammation, showing potential in ART-treated PWH and associated immune ageing, although the long-term effects remain uncertain [55]. Therefore, these findings are still preliminary, and their relevance to HIV-associated monocyte senescence, particularly the long-term effects of monocyte dynamics and inflammatory senescence, warrants further evaluation in larger, well-characterized cohorts.

Phenotypic and functional changes in macrophages with ageing and after HIV infection

Macrophages are found in various tissues and body cavities and near mucosal surfaces, where they perform three essential functions: immunomodulation, phagocytosis, and antigen presentation [56]. The deterioration of macrophage function is a crucial element of immune ageing, as the ability of macrophages to eliminate senescent cells and combat viral infections decreases with age. Senescent macrophages also exhibit decreased autophagic activity [57, 58].

Ageing macrophages exhibit reduced expression of TLRs, which impair the recognition of pathogen-associated molecular patterns (PAMPs) and contribute to dysregulated M1/M2 polarization [59]. Microbial products and proinflammatory cytokines drive M1 polarization, with IFN-γ from Th1 cells serving as a key mediator that promotes the M1 phenotype [60]. M1 macrophages produce high levels of proinflammatory cytokines and upregulate the expression of the surface markers CD80 and CD86 [61], whereas M2 macrophages express anti-inflammatory markers and mediators, including the mannose receptors CD206 and CD163 [62].

An imbalance in M1/M2 macrophage polarization contributes significantly to the pathogenesis of various age-related diseases, with tissue-specific polarization profiles observed across different organs [63]. In ageing individuals, increased CD86 expression in macrophages reflects a shift towards the M1 phenotype, characterized by heightened proinflammatory activity [64]. In animal models of liver injury, ageing amplifies M1-polarized responses and increases the expression of SASP factors such as IL-6 and TNF-α [65]. Paradoxically, ageing can also promote M2 polarization in certain contexts, leading to impaired resolution of chronic inflammation and diminished immune surveillance. For example, age-related increases in macrophage infiltration within tumour microenvironments are frequently associated with M2-like, protumourigenic phenotypes [66].

Markers such as Lymphatic Vessel Endothelial Hyaluronan Receptor 1 (LYVE1), Grancalcin (GCA), and Glucose Transporter 1 (GLUT1) have been proposed to identify senescent macrophage subtypes [63]. For instance, an increase in LYVE1⁺CD11b⁺ macrophages has been observed in the retinas of aged Kimba mice [67], whereas LYVE1⁻ macrophages predominate in the skeletal muscle of aged mice [68]. These findings further suggest that the expression patterns of these genes are tissue specific and dynamically regulated at different stages of cellular senescence. Similarly, senescent macrophages in aged bone marrow secrete GCA, which signals through the FAK-SRC-YAP pathway—a mechanism closely associated with skeletal muscle degeneration during ageing [69]. Under hyperglycaemic conditions, GLUT1-mediated glycolysis is upregulated and promotes macrophage senescence. Paradoxically, in aged muscle tissue, macrophages exhibit impaired glycolytic activity [70]. Notably, inhibition of GLUT1 has been shown to reduce mTOR signalling and attenuate SASP responses, indicating a potential therapeutic strategy for restoring metabolic homeostasis in senescent macrophages [71].

Collectively, these findings suggest that chronic infection exacerbates age-related immune dysregulation. Dectin-1 signalling in aged HIV-infected dendritic cells promotes an inflammatory cascade with M1-like characteristics [72] Although direct evidence linking HIV to macrophage senescence is limited, chronic immune activation and tissue-specific dysfunction likely contribute to systemic inflammation and impaired tissue repair, helping to explain how HIV accelerates ageing despite effective ART.

Functional changes in DC cells during senescence and HIV infection

DC cells are critical antigen-presenting cells that orchestrate communication between the innate and adaptive immune systems. They are broadly categorized into two subpopulations. Myeloid-derived dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs). pDCs play a pivotal role in antiviral defence through the robust production of IFN-I [73, 74].

With advancing age, DCs experience a marked decline in functional capacity, despite relatively stable absolute numbers and surface phenotypes. Their ability to recognize, capture, and present antigens is compromised, leading to impaired T cell activation. Additionally, age-related changes include diminished expression of costimulatory molecules, weakened IFN production, reduced endocytic activity, and increased secretion of proinflammatory cytokines such as IL-6 and TNF-α [75, 76]. These functional deficits in DCs contribute to a persistent, low-grade inflammatory state, often referred to as “inflammaging,” which is a defining feature of immune senescence. Moreover, ageing is associated with a decrease in TLR signalling in DCs, further dampening cytokine responses (e.g., TNF-α, IL-6, and IL-12) and diminishing vaccine-induced immunity in older individuals [77]. Importantly, adjuvants that mimic PAMPs have shown promise in partially restoring DC activation in aged individuals. These findings underscore the potential of targeting DC function as a therapeutic strategy to counteract age-related immune decline and improve vaccine responsiveness in older populations [78].

DCs are among the initial target cells for HIV-1 transmission, and during chronic infection, the virus induces sustained type I interferon signalling, promoting a tolerogenic DC phenotype that dampens effective immune responses [79, 80]. A central pathway implicated in this dysfunction is Dectin-1 signalling, which is significantly upregulated in the DCs of older PWH. This activation drives increased production of proinflammatory cytokines such as TNF-α, IL-12, and IFN-α. While Dectin-1 enhances innate immunity, its chronic stimulation fosters persistent inflammation and immune dysregulation—hallmarks of accelerated ageing in PWH [64]. As a double-edged sword, Dectin-1 signalling underscores the delicate balance between protective and pathological immune activation. Therapeutically, ex vivo DC-based immunotherapies have shown promise in restoring HIV-specific CD8⁺ T cell responses in ART-treated PWH, suggesting the potential to mitigate immune senescence [81]. Nonetheless, further mechanistic studies are essential to fully elucidate the role of DCs in HIV-associated immune ageing and translate these insights into effective clinical interventions.

Adaptive immunosenescence and HIV infection

T and B cells are vital components of the adaptive immune system, which is central to immune ageing. Thymic atrophy, driven by immunosenescence as well as endogenous factors (such as elevated levels of glucocorticoids and sex steroids) and exogenous insults (including chemotherapy, irradiation, malnutrition, chronic inflammation, and infections), ultimately reduces the thymic output of newly generated T cells [82, 83]. Therefore, understanding the changes in the adaptive immune system due to HIV and ageing is essential for developing effective immune interventions for older individuals.

Thymic ageing and functional changes in the thymus after HIV infection

The thymus plays a crucial role in T-cell development, resulting in self-restriction and self-tolerance. In the thymus, precursor T cells differentiate and mature into cytotoxic T cells and helper T cells [84]. Mature T cells leave the thymus and migrate to secondary lymphoid organs, where they monitor peptide fragments presented by MHC molecules on APC surfaces [85]. The T-cell system involves a distinct replenishment mechanism, wherein the production of new T cells is entirely reliant on a functional thymus. However, the thymus begins to degenerate during puberty and early adulthood [86]. As individuals reach middle age, the thymic production of T cells is gradually replaced by the sustained proliferation of peripheral T cells [87]. This homeostatic proliferation leads to a rapid decline in telomere length, and the shortening of telomeres further exacerbates the ongoing DNA damage response associated with ageing [88]. By assessing the output function of the thymus, the extent of immune senescence in an organism can be determined. Currently, the T-cell receptor excision loop and the K-deficiency recombination excision loop, which are excision products formed during the genomic rearrangement of the TCR and immunoglobulin genes, are considered reliable indicators of thymic and myeloid output [89, 90].

HIV infection induces thymic injury, resulting in impaired thymopoiesis and CD4⁺ T cell apoptosis, along with several alterations in the T-cell compartment, most notably a shift from naïve to terminally differentiated cells [91]. In ART-treated individuals, thymic degeneration is associated with clinical ageing outcomes, including metabolic syndrome, multimorbidity, and frailty. Studies have shown a negative correlation between thymus size and the presence of these ageing indicators [92]. In the context of extensive T-cell depletion and severe HIV-1 infection, the thymus is reactivated to release recently emigrated thymocytes (RTEs) to replenish and sustain the peripheral lymphocyte population [93]. Thymic production is critical for immune reconstitution during ART, particularly in PWH who have low CD4⁺ T-cell counts. If HIV replication is effectively suppressed for an extended period, adequate levels of thymic activity can help compensate for the damage caused by prior periods without combination antiretroviral therapy [94, 95]. A recent study in PWH reported good tolerability of thymosin alpha 1 (Tα1), with no serious adverse events or stable viral loads. Tα1 was further associated with a nonsignificant increase in thymic output (sjTREC), remodelling of T-cell subsets, and reduced T-cell exhaustion (lower PD-1), whereas TIM-3 remained unchanged [96].

T-cell immunosenescence

Roles of CD27, CD28, and CD57 in immunosenescence

T cells act as “fighters” against pathogens, enabling the host to mount specific immune responses and develop immune memory [97]. As thymic tissue degenerates with age, T cells become vulnerable to ageing-induced changes because of the extreme proliferative stress required to meet the demands of clonal expansion and homeostatic repopulation. This leads to a significant decline in the production of naïve T cells and the increased generation of TEMRA phenotypes, which are characterized by high ROS levels, low proliferation, DNA damage, and mitochondrial dysfunction [82, 98].

A key feature of T cell immunosenescence is the phenotypic remodelling of T cell subsets, notably marked by the loss of the costimulatory molecules CD27 and CD28, increased expression of CD57 and KLRG1, and decreased expression of CCR7. CD57⁺ T cells exhibit limited proliferative capacity, whereas KLRG1, which is predominantly expressed on TEMRA cells, is associated with senescent or apoptosis-resistant phenotypes [99, 100].

T cell ageing is further characterized by decreased telomerase activity and progressive telomere shortening. CD28 downregulation is correlated with reduced expression of human telomerase reverse transcriptase, compromising telomere maintenance and promoting genomic instability [101, 102]. The accumulation of CD27⁻CD28⁻CD8⁺ T cells is a recognized hallmark of immunosenescence. Among these, CD27⁻CD28⁺ TEMRA cells have been identified as strong predictors of all-cause mortality in older individuals, with the CD27⁻CD28⁻ subset exhibiting the shortest telomere lengths [103, 104]. Immunosenescence, marked by CD28⁻CD57⁺ T-cell accumulation, affects treatment outcomes in PWH. The degree of immune ageing partly predicts the effectiveness of immune reconstitution, with low CD4 counts linked to increased CD28⁻CD4⁺ and CD28⁻CD8⁺ ratios [105]. Moreover, CD8⁺CD28⁻ T cells exhibit a canonical immunosenescent phenotype and have prognostic value in AIDS-related non-Hodgkin lymphoma [106].

Naïve CD4⁺ and CD8⁺ T cells in immunosenescence

Among the defining features of T-cell immunosenescence is a reduction in the size of the naïve T-cell compartment, particularly among CD8⁺ T cells. While naïve CD4⁺ T cells can be partially maintained through homeostatic proliferation, naïve CD8⁺ T cells are more susceptible to age-related decline [82, 107]. A recent study using CyTOF data confirmed these trends and revealed that compared with naïve CD4⁺ T cells, naïve CD8⁺ T cells exhibit greater decreases in TCR diversity with age, indicating distinct senescence patterns in these two populations [108]. The frequency of naïve T cells, an indicator of biological age, gradually decreases with disease progression after HIV infection [42]. Wang et al. reported that PWH have lower naïve T-cell counts than healthy individuals do, with such levels not recovering to normal even after treatment, indicating immunosenescence [109]. Recent research indicates that the percentage of senescent naive T cells is significantly correlated with clinical immunity based on CD4 and CD8 T cell counts [110].

Multiple molecular markers and regulatory pathways have been implicated in the differential ageing of naïve T cells. Coexpression of the immune checkpoint receptor TIGIT and the transcription factor Helios has been shown to reliably identify senescent CD8⁺ T cells [111]. In contrast, the relative preservation of naïve CD4⁺ T cells has been associated with high expression of Tribbles pseudokinase 2, which functions by inhibiting mTORC2- and PDK1-dependent AKT phosphorylation, a process regulated by transcriptional interplay between ThPOK and RUNX3 [112]. Moreover, transcriptional regulation plays a central role in T cell fate decisions during ageing. The BATF/IRF4 axis has been identified as a key driver of CD8⁺ T cell differentiation, promoting both the transition of naïve CD8⁺ T cells into effector cells and the conversion of exhausted cells into an immunosenescent state through the modulation of downstream gene expression programmes [113, 114].

In summary, these findings highlight the subset-specific susceptibility of naïve T cells to ageing and underscore the importance of distinct molecular pathways that govern their maintenance, exhaustion, and progression towards senescence. Such insights deepen our understanding of the complex mechanisms underlying T cell immunosenescence and offer new perspectives and potential targets for interventions aimed at mitigating age-associated immune decline.

T-cell immunosenescence and HIV infection

HIV infection drives T cells to exhibit an ageing phenotype through persistent antigenic stimulation, characterized by the upregulation of markers such as PD-1 and CX3CR1, along with chronic activation and systemic inflammation [115, 116]. Furthermore, CD8⁺CD57⁺ T cells tend to migrate more strongly, with elevated expression of CX3CR1 and CCR5, while the central homing ability, as indicated by the downregulation of CCR7 and CD62L expression, is reduced, suggesting a greater propensity of these cells to migrate to inflammatory microenvironments [117]. Notably, one study indicated that in elite controllers, the proportion of CD57⁺ cells among CD8⁺ T cells was lower, and CD57⁻ cells exhibited greater cytotoxic activity, suggesting that the T cell ageing phenotype is driven more by the viral replication state than by chronological age [118]. These functional changes in immune cells not only reflect long-term immune activation but also indicate the loss of immune tolerance, leading to the degradation and senescence of immune cell function, thereby exacerbating systemic inflammation.

Persistent antigenic stimulation leads to T cell activation and terminal differentiation, ultimately resulting in functional exhaustion and loss of immune tolerance. In ART-treated individuals with HIV infection, TEMRA cells, as a terminally differentiated subset of effector memory T cells, proliferate markedly within the infectious milieu and exhibit high levels of exhaustion and activation markers [119]. These cells are frequently detected in children with vertically transmitted HIV [120] and remain persistently activated in low viral load populations, indicating that immunosenescence persists even when viral replication is controlled [121]. Furthermore, the increased proportion of CD4⁺ TEMRA and CD4⁺CD28⁻ T cells in PWH is associated with metabolic comorbidities such as diabetes, suggesting that T cell senescence affects not only immune function but also multisystem health outcomes [122].

The CD4/CD8 ratio has been recognized as a surrogate marker of immunosenescence in people with chronic HIV infection, even in the context of effective antiretroviral therapy and CD4⁺ T-cell recovery [123]. An inverted CD4/CD8 ratio less than 1 is widely recognized as a clinical indicator of immune dysregulation and is closely linked to increased T cell activation, exhaustion, and senescence [124]. Large prospective studies have demonstrated that a CD4/CD8 ratio less than 0.3 or a CD8⁺ T cell count reaching 1500 cells/μL or higher independently predicts the risk of serious non-AIDS events, even in ART-treated individuals with normalized CD4 counts [125, 126]. Moreover, sustained CD8⁺ T cell expansion has been implicated in ongoing immune activation and immunosenescence and may have greater long-term prognostic relevance than the CD4/CD8 ratio does [125]. Therefore, monitoring the CD4/CD8 ratio and TEMRA cell dynamics may provide valuable insights into the assessment of immunosenescence and residual immune function in PWH.

Role of CMV on T cell immunosenescence in HIV

As immune function declines, persistent high levels of antigenemia from pathogens such as HIV and cytomegalovirus (CMV) drive chronic inflammation, thereby accelerating immune ageing, with CMV playing a particularly critical role [127]. In ART-treated PWH, CMV infection is nearly universal, amplifying HIV-induced immune activation and contributing to non-AIDS-related comorbidities [128]. Among older individuals, CMV seropositivity is strongly associated with T-cell senescence and is a significant predictor of cardiovascular mortality [129]. In the context of CMVand HIV coinfection, activated cytotoxic CD4⁺ T cells may further exacerbate vascular pathology [130]. Studies have shown that CMV-specific CD4⁺ and CD8⁺ T cells exhibit features of immune senescence. Notably, TEMRA cells, which are key players in HIV pathogenesis, expand further in this context, promoting immune ageing through heightened cytotoxic activity and proinflammatory responses [131]. Moreover, the number of senescent T cells is positively correlated with anti-CMV antibody titres [132], underscoring the potential clinical value of targeted CMV therapy in mitigating immune senescence.

B cell immunosenescence and HIV infection

B cell immunosenescence is a critical component of immune ageing in PWH and contributes to impaired humoral immunity even under ART. With ageing, the B cell compartment undergoes architectural remodelling characterized by decreased generation of new B cells, reduced receptor diversity, diminished antibody responses, and impaired differentiation and export of mature B cells from the bone marrow [133–135]. Mechanistically, upon activation aged B cells display defective induction of the transcription factor E47, resulting in reduced expression of activation-induced cytidine deaminase (AID). AID is essential for class-switch recombination and somatic hypermutation, and its downregulation diminishes antibody affinity and compromises humoral immune protection [136, 137]. Collectively, these alterations limit the generation of high-quality antibodies, increase susceptibility to infections, and lead to suboptimal vaccine responses.

Ageing not only diminishes the differentiation and production of mature B cells in the bone marrow but also reshapes the distribution of peripheral B-cell subsets. Late or exhausted memory B cells in older individuals express elevated levels of inflammatory markers and exhibit spontaneous AMPK activation and altered metabolic signalling [138]. In parallel, a distinct proinflammatory subset of age‑associated B cells (ABCs, typically CD11b⁺CD11c⁺T‑bet⁺ with low CD21 expression) expands with advancing age and autoimmunity. These cells, also referred to as double-negative (DN), “late,” or “tissue-like” memory B cells, are enriched in both infectious and autoimmune diseases [139, 140]. ABCs and related atypical memory states represent a shift towards inflammatory, functionally impaired humoral immunity that may amplify systemic SASP-like signalling.

Despite virological suppression with ART, PWH continue to exhibit persistent low-level immune activation and antigen‑specific B‑cell dysfunction [141]. Among HIV-positive adolescents receiving ART, B-cell immunosenescence appears earlier and more pronounced than in age-matched healthy controls, indicating that HIV acts as a driver of premature B-cell ageing [142]. Phenotypically, in HIV-negative older individuals, the number of circulating DN B cells increases, whereas the number of plasma cells decreases, reflecting impaired effector output [143, 144].

T-bet⁺ ABC-like subsets are observed across chronic infections such as HIV, hepatitis C, and tuberculosis, with particularly strong enrichment in HIV [145, 146]. Nearly all B cells targeting the HIV envelope glycoprotein gp140 exhibit an ABC-like phenotype, suggesting that chronic antigen/cytokine exposure and type I inflammatory signalling select for this fate [146]. Prolonged exposure to inflammatory cytokines can also reprogram B-cell transcriptional networks, promoting ABC differentiation [147]. Concurrently, heightened metabolic activity, including spontaneous AMPK activation, is a hallmark of these senescent states and aligns with mitochondrial stress during chronic infection [138]. Taken together, these B‑cell alterations do not occur in isolation but act synergistically with senescent T cells and innate immune dysfunction to sustain a SASP‑rich microenvironment that exacerbates tissue damage and systemic inflammation. Targeted strategies to attenuate immune senescence and restore B‑cell function, such as enhancing metabolic fitness or rejuvenating AID-dependent affinity maturation, may improve vaccine immunogenicity and reduce comorbidity risk in PWH.

Immunosenescence, inflammation (SASP), and HIV infection

Inflammation is recognized as a key hallmark of immune ageing, primarily manifesting as a chronic, low-grade, systemic inflammatory state driven by SASP. The SASP consists of a complex mixture of secreted factors, including proinflammatory cytokines, chemokines, growth factors, and proteases. Persistent low-grade inflammation can affect multiple organ systems, disrupt immune homeostasis, and ultimately contribute to progressive physiological decline [7]. The accumulation of inflammatory burden over time not only disrupts tissue repair mechanisms but also intensifies oxidative stress, thereby accelerating the ageing process and increasing the risk of various chronic diseases. Key signalling pathways that regulate the SASP, such as the NF-κB, mTOR, p38 MAPK, and JAK/STAT pathways, have been recognized as potential drug intervention targets [148].

In the context of chronic inflammation driven by the SASP, immune cells across various populations exhibit significant age-related functional changes, further exacerbating immune system decline. Ageing haematopoietic stem cells (HSCs) exhibit impaired self-renewal capacity, leading them to differentiate into dysfunctional immune cells, thereby disrupting immune homeostasis [149]. As key components of the innate immune system, macrophages exhibit typical SASP characteristics during ageing, with upregulation of proinflammatory cytokines (such as TNF-α, IL-6, and IL-1β) and downregulation of the anti-inflammatory cytokine IL-10 [150]. Moreover, the effector functions of NK cells are weakened, with a reduction in the secretion of interferons accompanied by an increase in the levels of several proinflammatory cytokines, including IL-1, IL-6, and TNF-α [149]. Additionally, T cell ageing is characterized by functional impairment, which is correlated with the overexpression of inflammatory cytokines such as IL-6 and TNF-α [7]. Furthermore, senescent ABCs tend to produce IL-6 and IFN-γ, potentially contributing to the age-related exacerbation of the underlying inflammatory state [151].

In PWH, residual low-grade chronic inflammation can persist despite long-term suppression of ART and is associated with accelerated ageing [152, 153]. In addition, some ART agents may further exacerbate inflammation through mitochondrial toxicity [154]. In older PWH, elevated markers of inflammation and oxidative stress are strongly correlated with frailty and immunosenescence, regardless of ART treatment status [155]. Additionally, HIV infection is linked to a greater proportion of activated CX3CR1⁺CD8⁺ memory T cells, which display senescence markers but retain survival and proliferative capacity; however, the generation and maintenance mechanisms of these cells remain unclear [156]. Furthermore, elevated levels of inflammatory and coagulation markers, such as IL-6, D-dimer, and sCD14, are associated with increased mortality risk in both HIV-positive and HIV-negative individuals [157]. Recent studies have also shown that in HIV-positive men on ART, the levels of certain ageing-related cytokines, such as MMP-9, are correlated with persistent HIV-1 infection, suggesting that targeting the ageing pathway may help reduce the viral reservoir [158]. Thus, therapeutic strategies targeting SASP factors offer the potential to alleviate age-related diseases. While current senolytic drugs primarily exert their effects by clearing senescent cells, another promising strategy is to directly eliminate SASP factors from the circulatory system, thereby reducing their harmful systemic effects. Acoustofluidic-based interventions, as emerging antiaging strategies, show great potential for clinical application because they target and remove inflammation-driving factors [159].

Immunosenescence and mitochondrial dysfunction during HIV infection

Mitochondrial dysfunction is a primary hallmark of T cell ageing [82]. Age-related mitochondrial dysfunction impairs mitochondrial respiration and autophagy, leading to elevated levels of ROS and increased oxidative stress (Fig. 2). This oxidative stress inhibits proteasomal activity and is recognized as a key driver of the detrimental effects of ageing, contributing to chronic inflammation and cellular senescence [160]. Decreases in NAD⁺ levels and the activity of CD38 enzymes accelerate mitochondrial dysfunction, further promoting the ageing process [161, 162]. Different T cell subsets exhibit variations in mitochondrial content and sensitivity to ageing, with TFAM deficiency accelerating T cell ageing and inflammation [17, 163]. Mitochondrial dysfunction promotes a proinflammatory phenotype through the accumulation of inflammatory metabolites, epigenetic changes, and activation of the cGAS-STING pathway [164, 165]. Overactivation of the PI3K/Akt/mTOR, MAPK, and AMPK pathways is closely associated with T cell ageing and represents potential therapeutic targets [166].

Fig. 2.

Mechanisms of ageing in PWH: Exogenous, Cellular, and Systemic Factors. HIV infection, ART treatment, and various factors contribute to accelerated ageing in PWH. These factors increase oxidative stress (ROS), causing DNA damage, telomere shortening, and mitochondrial dysfunction. This activates NF-κB, leading to cell cycle arrest and the formation of senescent cells. Senescent cells secrete inflammatory factors (SASPs), which promote chronic inflammation (inflammaging) and immune exhaustion. In PWH, these processes are further exacerbated by HIV-induced immune activation and CD4⁺ T-cell depletion, accelerating ageing and increasing susceptibility to comorbidities and infections. BCL-2: B-cell lymphoma 2; SA-β-gal: senescence-associated β-galactosidase; ER stress: endoplasmic reticulum stress; ROS, reactive oxygen species; mtDNA, mitochondrial DNA; SASP, senescence-associated secretory phenotype; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PWH, people with HIV

The HIV-1 viral protein R (Vpr) induces host cell death by increasing the permeability of the mitochondrial outer membrane [167]. Various classes of ARTS have been implicated in mitochondrial dysfunction and the acceleration of cellular senescence through distinct mechanisms. Nucleoside Reverse Transcriptase Inhibitor (NRTIs) may cause mitochondrial dysfunction through disruption of mitochondrial networks, oxidative stress, and mtDNA damage [168]. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) primarily impair mitochondrial function by increasing ROS levels, disrupting the mitochondrial membrane potential (ΔΨm), and inducing apoptosis [169, 170]. Protease inhibitors (PIs) are associated with oxidative and endoplasmic reticulum stress, ΔΨm dysregulation, and metabolic disturbances, all of which may promote inflammation [171, 172]. Moreover, INSTIs are associated with increased mtDNA copy number and elevated ROS levels, suggesting their potential role in mitochondrial dysregulation via metabolic reprogramming in immune cells [173]. Although multiple ART classes can affect mitochondrial function, NRTIs remain the backbone of modern regimens, and their central role in combination therapy, broad guideline endorsement, and extensive long-term use underscore their indispensable clinical importance [174].

However, a lower mitochondrial DNA (mtDNA) copy number is associated with poorer ageing outcomes, particularly in individuals over 50 years of age, where mtDNA declines more rapidly than in HIV-negative counterparts—even among those with well-controlled HIV on ART [175]. Interestingly, despite these associations, the ageing phenotype induced by PI treatment was reversible upon drug removal in a mouse model. Furthermore, studies in C. elegans have shown that zidovudine can significantly extend lifespan without adversely affecting the electron transport chain or increasing ROS accumulation [176]. Nonetheless, because of its adverse effects in humans, zidovudine has largely been replaced by better-tolerated regimens [177, 178]. Borchard’s review suggested that NRTIs have potential repurposing effects, as they can inhibit the P2X7-mediated activation of inflammasomes at the cellular level, reducing inflammation and reversing alterations in intercellular communication [179]. Oxidative stress is a key factor in HIV-related mortality. In CD8⁺ T cells from PWH, lower levels of SHMT2 impair mitochondrial function and reduce glutathione (GSH) levels, leading to higher ROS levels and triggering ageing processes. However, glycine supplementation can help slow these effects [180]. In conclusion, targeting mitochondrial function and oxidative stress using effective regimens and dosages may provide new therapeutic strategies to alleviate ageing-related issues in PWH.

Cigarettes, HIV, and senescence

Smoking markedly increases the risk of numerous diseases and is recognized as a major external accelerator of ageing [181]. Cigarette smoke contains hundreds of toxic species, including notably high levels of volatile organic compounds (VOCs), aldehydes, and free radicals [182]. Cigarette smoke, whether through active or passive exposure, induces apoptosis, oxidative stress, and inflammation, ultimately accelerating cellular senescence and increasing the risk of premature mortality [183, 184]. Recent epigenetic studies have demonstrated that smoking-induced DNA methylation changes substantially overlap with ageing-associated CpG sites, suggesting that these alterations may mediate the accelerated ageing observed in smokers [185].

HIV infection and smoking may interact synergistically, amplifying their detrimental effects on the ageing process, which include diminished lung function, reduced bone density, and a loss of muscle mass [186]. As an exogenous stressor, cigarette smoke activates TGF-β signalling, leading to upregulated expression of HIV entry receptors such as CCR5 and CXCR4. Consequently, bronchial epithelial cells become more susceptible to infection, resulting in a higher airway viral load [187, 188]. Both HIV infection and cigarette smoke exposure are associated with elevated oxidative stress and impaired mitophagy, which in turn promote cellular senescence. Persistent activation of the SASP further amplifies local and systemic inflammation, thereby increasing the risk of inflammation-related complications. This may help explain the worsened prognosis and increased mortality among PWH who smoke [188–190].

Notably, a recent study revealed that phytosphingosine (PHS) markedly suppressed cigarette smoke-induced cellular senescence and SASP activity by upregulating and activating free fatty acid receptor 4 (FFAR4) in both in vitro and in vivo models, thereby ameliorating chronic airway inflammation and tissue degeneration [191]. These findings provide a biological rationale for delaying smoking-related accelerated lung ageing; however, their clinical applicability and long-term safety remain to be fully evaluated.

Approaches to alleviate immunosenescence

Ageing and immunosenescence are recognized as dynamic, modifiable processes that can be altered by enhancing the activation of both the innate and adaptive immune systems, along with various intervention strategies [75]. Significant progress in understanding immunosenescence has been made through the use of animal models and studies of patients with age-related diseases, leading to targeted intervention strategies (Table 1).

Table 1.

Therapeutic strategies for delaying immune ageing

Antiaging strategies		Molecular target/mechanisms	Evidence in HIV models/patients	References
Antiaging drugs	ABT263 ABT737 D + Q	Targeting the anti-apoptotic proteins BCL-2 and BCL-xL induces apoptosis and upregulates; Targeting different types of senescent cells to alleviate chronic inflammation and tissue damage	No	[192–196]
Metabolic modulators	NAD +	Supplementing NR and NMN to promote cell repair; Improve mitochondrial function, anti-inflammatory Enhancing cGPDH activity, improving mitochondrial function, and regulating oxidative-reductive balance	Yes	[197, 198]
	Ergothioneine		No	[199]
	Metformin	Inhibition of mitochondrial complex I and thus activation of AMPK; Reducing chronic inflammation	Yes	[200, 201]
Immunomodulators	α-KG	Inhibiting the mTOR pathway and activating AMPK improves the inflammatory microenvironment	No	[202]
	Rapamycin	Inhibit the mTOR pathway, induce autophagy, suppress inflammation	Yes	[203–205]
Gene and cell therapy strategies	HSCs	Restoration of Haematopoietic Stem Cells via Bone Marrow Transplantation	No	[206]
	CAR-T	Effectively alleviates tissue inflammation and functional decline	No	[207]
Lifestyle changes	Exercise	Increase the output of RTE; SIRT5 promotes the desuccinylation modification of protein kinase TBK1 and inhibits the pro-inflammatory signalling pathway	Yes	[208–211]
	Controlled diets	Modulates immune cells and influences gut microflora; increased telomere length; enhancing energy metabolism
	Calorie restrictions	Reduction in SPARC protein production

Antiaging drugs (Senolytics)

Senolytic drugs selectively induce apoptosis in senescent cells by disrupting their reliance on antiapoptotic pathways, such as BCL-2 and BCL-xL, and have emerged as prominent intervention strategies for delaying tissue ageing in recent years. Animal studies have shown that the BCL-2 family inhibitors ABT263 (Navitoclax) and ABT737 effectively eliminate SA-β-Gal-positive senescent cells, significantly enhancing the function of multiple systems and tissues, such as the haematopoietic and pulmonary systems, as well as skeletal muscle tissue [192, 212]. Nevertheless, their dose-dependent toxicity, particularly thrombocytopenia and neutropenia, represents a significant barrier to their widespread use [193]. Given the current lack of relevant clinical studies, the clinical application of these drugs should proceed cautiously, with a clear understanding of their mechanisms and a controllable safety profile. Moreover, certain naturally occurring polyphenolic compounds, such as quercetin, nifedipine, and procyanidin C1, have also demonstrated potent anti-senescence activity [194, 213]. Notably, the combination of quercetin and dasatinib (D + Q) has synergistic effects, further amplifying the therapeutic benefits against senescence [195]. In clinical practice, remaining mindful of potential side effects, including sleep disturbances and anxiety, is important [196]. Further investigation into the long-term safety and tolerability of these therapies is essential to optimize ageing interventions and maximize their clinical benefits.

PWH often experience immune exhaustion, bone marrow suppression, and chronic inflammation [214]. It remains uncertain whether senolytic drugs can exacerbate multilineage haematopoietic cell depletion or induce transient inflammation during the clearance of senescent cells. Such effects may disrupt immune homeostasis and increase the risk of infections. Given the current lack of relevant clinical studies, the clinical application of these drugs should proceed cautiously, with a clear understanding of their mechanisms and a controllable safety profile.

Nonetheless, there are significant global disparities in anti-ageing research on AIDS. While progress has been made in developed countries in this area, research remains limited in low- and middle-income countries, particularly in sub-Saharan Africa [4, 215]. These nations face numerous challenges in accessing antiaging medications, including high drug costs, inadequate regulatory systems, and limited public awareness of modern antiaging therapies [216]. Longitudinal and qualitative studies on HIV-positive older individuals should be prioritized in future research to evaluate the efficacy and relevance of anti-ageing treatments for different regional populations.

Metabolic modulators

Metabolic drugs hold significant potential for ageing intervention by reshaping energy metabolism and inflammatory pathways. Elevating NAD⁺ levels is widely recognized as an effective strategy for delaying ageing. Although direct absorption of NAD⁺ molecules is difficult for cells, their precursors—such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN)—have been shown to increase NAD⁺ levels across multiple organ systems, improving mitochondrial function and exerting anti-inflammatory effects [197, 217]. Natural sulphur-containing antioxidants, such as ergothioneine, have been demonstrated to effectively extend healthy lifespan in mice by increasing cGPDH activity, improving mitochondrial function, and regulating redox balance. These benefits include preserved muscle strength, reduced inflammation, and improved metabolism [199]. Additionally, NMN has been shown to suppress excessive activation of CD4⁺ T cells and viral replication during HIV-1 infection, indicating the potential for addressing the imbalance in the “immune activation–ageing” axis [198]. This warrants further investigation in clinical studies.

As a metabolic modulator, metformin alleviates chronic inflammation by activating AMPK and inhibiting mitochondrial complex I, demonstrating potential antiaging effects and advancing into large-scale clinical trials such as the Targeting Aging with Metformin [200, 218, 219]. As a widely used metabolic regulator, metformin has favourable safety profiles and anti-inflammatory potential in PWH. Studies suggest that metformin suppresses mTOR signalling, improves immune activation status, and reduces the expression of markers associated with the latent HIV reservoir [201]. Recent research has also indicated that metformin significantly reverses the epigenetic age of monocytes, although its effects on CD8⁺ T cells are less pronounced, suggesting that its antiaging effects may be cell specific [55].

However, clinical data on other metabolic modulators, such as NAD⁺ precursors, remain limited in humans, particularly in PWH. Additionally, whether these interventions interact with ART drugs or exhibit metabolic cross-effects requires more systematic safety and efficacy assessments in specific groups.

Immunomodulators

Multiple immunomodulatory molecules play crucial roles in regulating T cell function, inflammatory pathways, and thymic homeostasis and are emerging as promising candidate targets for interventions in immune ageing. Among them, α-ketoglutarate (α-KG) functions as a metabolic immunomodulator by inhibiting the mTOR pathway and activating AMPK, thereby improving the inflammatory microenvironment and delaying tissue dysfunction [202]. Rapamycin has demonstrated significant efficacy in animal models by inhibiting the mTOR pathway, reducing the expression of senescence markers in immune cells, and enhancing immune function [203]. Moreover, in humanized mouse models of HIV infection, rapamycin effectively suppressed type I interferon-mediated chronic inflammation through autophagy induction, restoring T cell function and suggesting its potential as an intervention to delay immune ageing [204]. In PWH receiving antiviral therapy, sirolimus significantly reduced HIV DNA levels in CD4⁺ T cells by inhibiting the mTOR pathway, decreasing T cell proliferation and the expression of immune exhaustion markers, further supporting its potential to reduce the HIV latent reservoir (HIV DNA) and improve T cell status [205].

During the reconstruction and regulation of the immune system, multiple factors have potential antiaging effects through the improvement of thymic homeostasis. For example, METTL3 helps maintain the survival of thymic double-positive (DP) cells, delaying thymic atrophy [220]. RANKL and FGF21 enhance T cell immune function and extend thymic lifespan by improving thymic architecture and regulating the mTORC1/2 pathway, respectively [221, 222].

While these strategies have demonstrated significant efficacy in animal models, their applicability to PWH remains challenging. Rapamycin may exacerbate immunosuppression risk and interact metabolically with ART [205, 223]. Thymus-related pathway interventions are still largely confined to early-stage animal studies and lack systematic evaluation in PWH. Therefore, a careful assessment is necessary, considering each individual’s viral suppression status, immune recovery level, and safety profile of ART combination therapy.

Gene and cell therapy strategies

Interventions at the cellular and genetic levels are increasingly recognized as key research avenues for delaying immune ageing. Approaches such as inducing pluripotent stem cells (iPSCs) to differentiate into autologous haematopoietic stem/progenitor cells (HSPCs) [206] or using FOXN1-reprogrammed embryonic fibroblasts to promote thymic regeneration have shown potential for immune reconstitution and tissue repair in animal models [224]. Moreover, chimeric antigen receptor T-cell (CAR-T) technology has been expanded to target and eliminate senescent cells expressing urokinase-type plasminogen activator receptor (uPAR). In mouse studies, this strategy effectively alleviated tissue inflammation and functional decline, highlighting its promising potential in antiaging immunotherapy [207].

Chronic inflammation, immune exhaustion, and the presence of latent viral reservoirs in PWH make them less tolerant to cellular or genetic engineering interventions, increasing the risk of immune-related adverse events. Additionally, heterochronic bone marrow transplantation is not practical in most clinical settings because of conditioning toxicity and prolonged immunosuppression, risks of graft-versus-host disease (GVHD) and infection, constraints in donor availability and HLA matching, and the frailty/comorbidity burden in older recipients [225]. As a result, this strategy is better suited for use as a mechanism probe rather than as a directly translatable therapy. Future efforts should focus on exploring alternative approaches that do not require transplantation and offer greater accessibility, such as targeting inflammatory pathways [226].

Lifestyle interventions

Lifestyle interventions, including regular exercise, dietary adjustments, calorie restriction, and the avoidance of tobacco exposure, have been shown to delay immune system ageing through nonpharmaceutical means. Regular physical activity significantly reduces multiple age-related comorbidities, improves immune function and inflammation levels, delays immune ageing, and promotes overall health [208]. Time-restricted eating (TRE) and intermittent fasting improve immune cell composition; reduce the number of senescent T cells; increase Treg, B cell, and Tfh cell responses; and delay the immune ageing process [209]. Calorie restriction is a key intervention for reducing age-related inflammation; moderate calorie restriction decreases the production of the ageing-associated SPARC protein, thereby extending a healthy lifespan in older adults [210].

Similarly, lifestyle interventions are highly feasible and safe for PWH, with positive effects also observed in older HIV-positive individuals. Particularly in the context of stable viral suppression with ART, these interventions may have beneficial effects on improving chronic inflammation and promoting immune recovery [211]. However, PWH often experience metabolic disorders, muscle wasting, and fatigue, which may affect their adherence to exercise and dietary interventions. Therefore, when promoting lifestyle interventions among HIV-positive individuals, it is crucial to develop progressive, long-term, and sustainable strategies tailored to individual physical fitness levels, basal metabolic conditions, and drug responses.

Conclusions and future directions

Despite substantial progress, most evidence still derives from animal models, limiting clinical generalizability. This review synthesizes the innate and adaptive features of immunosenescence and the potential of biomarkers, yet no single universal marker exists and population-specific panels (e.g., for PWH) are needed. Translational barriers are amplified in HIV, where chronic inflammation and mitochondrial dysfunction drive accelerated immune ageing across compartments. Although ART suppresses viremia, it does not reverse immunosenescence, underscoring the need for adjunct strategies. Precise clearance of senescent cells is an emerging avenue; for example, targeted senolytic delivery systems demonstrated in murine ageing models [227], whereas combining immune reconstitution and antiaging approaches with ART may strengthen host defence and quality of life; future work should tailor senescence-targeting strategies to the specific pathobiology of HIV.

In summary, five unresolved questions at the interface of HIV and immunosenescence warrant priority attention. First, to what extent is immunosenescence in PWH reversible, and what constitutes the optimal intervention strategy? Second, through which specific molecular and cellular pathways does HIV accelerate the ageing and functional reprogramming of innate immune cells, particularly macrophages and dendritic cells? Third, how do ABCs and other aberrant B cell subsets shape defects in humoral immunity, suboptimal vaccine responses, and comorbidity risk, and which of these programmes are druggable? Fourth, what is the relative contribution of CMV coinfection to accelerated immunosenescence in PWH, and should anti-CMV strategies be incorporated into the routine management of the ageing HIV population? Fifth, what are the long-term consequences of early-life (paediatric/adolescent) HIV infection for lifelong trajectories of immune ageing and therapeutic windows, and do paediatric versus adult populations require differentiated anti-senescence and immune-reconstitution approaches?

Abbreviations

ABCs

Age-associated B cells

AID

Activation-induced cytidine deaminase

ART

Antiretroviral therapy

CAR-T

Chimeric antigen receptor T-cell

cGPDH

Glycerol-3-phosphate dehydrogenase

CMV

Cytomegalovirus

CpG

Cytosine-phosphate-Guanine

D + Q

Quercetin and dasatinib

DCs

Dendritic cells

DN

Double-negative

DP

Double-positive

E47

Transcription factor E47

FFAR4

Free fatty acid receptor 4

GCA

Grancalcin

GLUT1

Glucose transporter 1

GSH

Glutathione

GVHD

Graft-versus-host disease

HSCs

Haematopoietic stem cells

HSPCs

Haematopoietic stem/progenitor cells

INSTIs

Integrase strand transfer inhibitors

iPSCs

Inducing pluripotent stem cells

KIR

Killer-cell immunoglobulin-like receptors

KLRG1

G1-Killer cell lectin-like receptor subfamily G member 1

LYVE1

Lymphatic Vessel Endothelial Hyaluronan Receptor 1

mDCs

Myeloid dendritic cells

METTL3

Methyltransferase-like 3

mtDNA

Mitochondrial DNA

mTOR

Mechanistic target of rapamycin

NAD

Nicotinamide adenine dinucleotide

NK

Natural killer cell

NMN

Nicotinamide mononucleotide

NNRTIs

Non-nucleoside Reverse Transcriptase Inhibitors

NR

Nicotinamide riboside

NRTIs

Nucleoside Reverse Transcriptase Inhibitors

P2X7

P2X purinoceptor 7

PAMPs

Pathogen-associated molecular patterns

pDCs

Plasmacytoid dendritic cells

PHS

Phytosphingosine

PIs

Protease Inhibitors

PRRs

Pattern recognition receptors

PWH

People with HIV

ROS

Reactive oxygen species

RTEs

Recently emigrated thymocytes

RUNX3

Runt-related transcription factor 3

SASP

Senescence-associated secretory phenotype

SA-β-Gal

Senescence-associated beta-galactosidase

SHMT2

Serine hydroxymethyltransferase 2

SIV

Simian immunodeficiency virus

TCR

T-cell receptor

TEMRA

Terminally Differentiated Effector Memory T Cells

ThPOK

T helper-inducing POZ/Krueppel-like factor

TLR

Toll-like receptors

TRE

Time-restricted eating

TRIB2

Tribbles pseudokinase 2

Tα1

Thymosin alpha 1

uPAR

Urokinase-type plasminogen activator receptor

VOCs

Volatile organic compounds

Vpr

HIV-1 viral protein R

ZEB2

Zinc finger E-box-binding homeobox 2

α-KG

Alpha-ketoglutarate

ΔΨm

Mitochondrial membrane potential

Authors’ contributions

JYJ, QQX, XZ and BS conceived the study, JYJ, QQX, AWZ, WX, CM, ASWC, TZ, and BS wrote and revised the review, BS supervised the whole study. All authors collaboratively discussed key decisions throughout the course of the review, provided critical feedback on preliminary manuscript, and approved the final version. All authors read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC, 82472266), the National Key R&D Program of China (2023YFE0116000, 2023YFC2308300, 2023YFC2308302), the Beijing Natural Science Foundation (Z220018, L222068), the Scientific Research Project of Beijing Youan Hospital-CCMU 2022 (BJYAYY-YN2022-18), and the Beijing Key Laboratory for HIV/AIDS Research (BZ0089). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.