Following HIV-1 entry, the innate immune system rapidly detects viral nucleic acids and mounts a robust IFN-I response. In the early phase of infection, plasmacytoid dendritic cells (pDCs) serve as the predominant IFN-I producers, sensing viral RNA through Toll-like receptor 7/8 (TLR7/8) and activating interferon regulatory factor (IRF)–mediated pathways to secrete large amounts of IFN-α and IFN-β (31, 32). This early IFN-I burst induces restriction factors such as APOBEC3G, TRIM5α, and SAMHD1, which limit replication and dissemination (33, 34). The magnitude of this early response represents one of the host’s most critical nonspecific antiviral defenses, transiently suppressing viral spread and reducing the peak viremia in acute infection (35).

However, as infection progresses, HIV-1 evolves mechanisms that blunt IFN efficacy—by selecting IFN-resistant variants, expressing viral proteins (Vif, Vpu, Nef) that antagonize restriction factors, and suppressing innate signaling (33, 36). Clinical and animal studies demonstrate that although the acute-phase IFN-I peak correlates with reduced peak viremia, this protective effect is rarely sustained over time (37, 38).

In the chronic phase of HIV-1 infection, IFN-I levels decline substantially from their acute-phase peak but typically persist at a low-grade activation state (38, 39). This low-grade, persistent IFN-I tone is typically insufficient to control viral replication but contributes to chronic immune activation and inflammation. It is associated with sustained expression of T-cell activation markers (HLA-DR, CD38), upregulation of inhibitory receptors such as PD-1 and TIM-3, and increased susceptibility to apoptosis of bystander CD4⁺ T cells (38–41). Abortive infection of CD4⁺ T cells in lymphoid tissue further amplifies inflammatory death pathways, linking persistent innate sensing and IFN-I exposure to progressive immune depletion (40, 41).

Collectively, IFN-I signaling during HIV infection exhibits a double-edged sword profile: a beneficial antiviral surge in the acute phase, contrasted with maladaptive chronic activation that perpetuates inflammation and T-cell depletion (42). Figure 1 illustrates the temporal dynamics of IFN-I levels, plasma viral load, and CD4⁺ T-cell counts across the course of infection, highlighting the distinct biological impacts of IFN-I in different disease stages.

While pDCs are the primary source of the acute IFN-I burst in HIV-1 infection, evidence indicates that during the chronic phase IFN-I production is maintained at low but persistent levels by other cell types. Emerging data show that tissue-resident macrophages, particularly in gut-associated lymphoid tissue and lymph-node stromal compartments, can harbor latent HIV-1 infection while expressing IFN-stimulated gene signatures and low-grade IFN production (48). Residual pDCs also contribute, though their frequency declines in chronic infection (49). The sustained IFN-I tone appears not merely a passive remnant of acute activation, but may reflect qualitative changes in innate cell programming: chronic inflammatory cues may rewire macrophage and dendritic-cell responsiveness, driving a self-amplifying feedback loop of tonic ISG induction and immune activation rather than effective viral clearance.

Building upon the dynamic features and dual-phase effects of IFN-I signaling described above, the following section delineates the molecular pathways by which HIV-1 induces IFN-I production and the subsequent immunological consequences. This mechanistic insight provides the foundation for understanding both the antiviral and immunomodulatory roles of IFN-I in HIV-1 infection.

Upon HIV-1 infection, the viral genomic RNA undergoes reverse transcription to generate cDNA, which integrates into the host genome and contributes to the establishment of a latent viral reservoir. During this process, innate immune cells detect viral nucleic acids through multiple pattern-recognition receptors (PRRs) and cytosolic nucleic-acid sensors. In pDCs, HIV-1 RNA and immune complexes are sensed primarily via endosomal TLR7/9, leading to MyD88-dependent activation of IRF7 and robust production of IFN-α subtype (32). In parallel, in myeloid dendritic cells, macrophages, and resting CD4⁺ T cells, HIV-1-derived cDNA is recognized by the interferon-inducible DNA sensors IFI16 and cyclic GMP–AMP synthase (cGAS), which catalyzes the synthesis of cGAMP to activate the stimulator of interferon genes (STING) pathway. Activated STING recruits and activates TANK-binding kinase 1 (TBK1), leading to phosphorylation and dimerization of IRF3, which then translocates to the nucleus to drive transcription of IFN-β and early IFN-α subtypes (50–52).

In the acute phase, IFN-α is the dominant circulating IFN-I subtype and exerts both direct antiviral and immunomodulatory effects. It can inhibit HIV-1 replication at multiple stages of the viral life cycle, particularly before and immediately after integration, by inducing a spectrum of ISGs in primary CD4⁺ T cells and macrophages (1, 23, 53, 54) As an immunotherapeutic cytokine, IFN-α enhances innate cell function and transitions to adaptive responses by promoting CD8⁺ cytotoxicity and maintaining Th1 balance. Administration of IFN-α increases CD8⁺ T-cell activation and reduces plasma HIV RNA (55) and augments NK-cell degranulation and suppressive capacity against HIV-infected targets (56). Short-course IFN-α exposure in vivo reduces plasma HIV-1 RNA and upregulates ISG expression in peripheral blood, consistent with its role as a potent early-phase antiviral mediator (54–56).

Beyond direct antiviral effects, IFN-I signaling plays a critical role in linking innate detection to adaptive immunity. Type I IFNs promote maturation of conventional dendritic cells (cDCs) (up-regulation of CD80/86, MHC I/II) and enhance their ability to cross-present cell-associated viral antigens to CD8⁺ T cells. In viral infections including HIV-1, this IFN-driven DC activation supports the priming of virus-specific CD8⁺ T-cell responses and contributes to reservoir limitation (57, 58). Incorporating this role strengthens the mechanistic link between early IFN-I responses and durable adaptive immunity.

Type I IFNs, particularly IFN-α, restrict HIV-1 replication through coordinated induction of ISGs that act at distinct stages of the viral life cycle. In primary macrophages and CD4⁺ T cells, IFN-α reduces the accumulation of HIV-1 cDNA and suppresses early replication through proteasome-dependent mechanisms (53), In resting CD4⁺ T cells, IFN-α potently enhances the antiviral activity of APOBEC3G, promoting G→A hypermutation in nascent viral DNA and thereby limiting residual replication within cells that contribute to the latent reservoir (59). In vivo studies further demonstrate that IFN-α treatment can lower HIV-1 viral load while upregulating the expression of restriction factors such as APOBEC3G/3F and BST-2/tetherin (54).

IFN-α-induced ISGs restrict HIV-1 replication at multiple checkpoints throughout the viral life cycle. (1) During viral entry and fusion, IFITM3 is strongly up-regulated and localizes to plasma and endosomal membranes, altering membrane fluidity and blocking fusion between viral and host membranes, thereby reducing entry efficiency (60). (2) During reverse transcription, SAMHD1 depletes intracellular dNTP pools in resting CD4⁺ T cells and macrophages, while CMPK2 maintains nucleotide balance under interferon signaling; together, these effects limit viral cDNA synthesis and halt reverse transcription (61, 62). (3) In the nuclear import or pre-integration stage, MX2 (MxB) acts post-reverse transcription but prior to integration by localizing to the nuclear envelope and interacting with nucleoporins (NUP214, TNPO1) to block nuclear entry of the pre-integration complex (63). In contrast, TRIM5α acts at an earlier post-entry step by recognizing the HIV-1 capsid, promoting its proteasomal degradation and preventing reverse transcription (64). (4) Following integration, APOBEC3G and APOBEC3F are packaged into virions, where they introduce G→A hypermutations that corrupt proviral genomes and reduce replication competence (59). (5) During virion assembly, ISG15 conjugates to viral and host budding factors such as Gag, hindering membrane fission and virion release, thereby reducing HIV-1 infectivity (65). (6) At the budding and release stage, BST-2/tetherin, highly expressed on activated CD4⁺ T cells and in lymphoid/mucosal tissues, anchors nascent virions at the cell surface, physically preventing virus release and cell-to-cell dissemination (66). Recent multi-omics analyses continue to expand the catalogue of cell-intrinsic effectors that contribute to IFN-I–mediated restriction of HIV-1 in primary CD4⁺ T cells (67). Table 1 summarizes the major ISGs and their anti-HIV-1 mechanisms.

Collectively, these IFN-α-induced antiviral mechanisms act in a temporally ordered cascade—from viral entry to release—to minimize productive infection and constrain the establishment of the latent reservoir. Despite the robust IFN-induced blockade observed in vitro, clinical efficacy in vivo remains limited, reflecting coordinated viral countermeasures (e.g., Vpu, Nef, capsid shielding), tissue-level constraints, and immune exhaustion driven by chronic interferon exposure. Together, these processes uncouple ISG induction from durable viral control in patients.

HIV-1 employs temporally ordered immune-evasion strategies that align with distinct stages of its replication cycle, enabling the virus to circumvent IFN-I sensing, restrictor induction, and downstream effector pathways.

Although all 13 IFN-α subtypes signal through the shared IFNAR1/2-JAK-STAT/ISGF3 axis, they exhibit distinct biological profiles in antiviral potency and immune modulation. Comparative analyses consistently identify IFN-α6, IFN-α8, and IFN-α14 as the most potent subtypes against HIV-1, markedly suppressing viral replication in humanized mice and ex vivo primary-cell systems, whereas IFN-α1 and IFN-α4 show weak activity. These differences are not absolute: their rank order varies across models, and dose–response dynamics strongly influence outcomes—at high concentrations, subtype disparities diminish, indicating that both intrinsic affinity and ligand exposure jointly shape ISG induction and antiviral efficacy (82–84).

Subtype-specific immune regulation further distinguishes their functional profiles. IFN-α14 and IFN-α8 promote NK- and CD8⁺ T-cell degranulation but induce less inflammatory cytokine release, whereas others preferentially trigger broader ISG and cytokine cascades (84). However, direct evidence that these subtypes cause greater systemic toxicity in patients is currently limited. Most safety data are derived from Peg-IFN-α2–based trials, and whether highly potent subtypes intrinsically confer a poorer tolerability profile remains an open clinical question rather than an established fact.

Despite its moderate antiviral potency, IFN-α2b remains the clinical standard due to its well-established pharmacokinetics, manufacturing stability, and tolerability. Pegylation extends its plasma half-life, smooths exposure peaks, and enables once-weekly administration, providing a controlled immunostimulatory window validated in HBV/HCV and subsequently adapted to HIV clinical research. While next-generation formulations may explore potent subtypes such as IFN-α14, Peg-IFN-α2b currently offers the most reliable balance of antiviral efficacy, safety, and translational feasibility.

Over four decades, multiple clinical and translational studies have evaluated IFN-α as both a stand-alone antiviral and an adjunct to ART in HIV-1 infection. Table 2 summarizes representative trials spanning the pre-ART, early-ART, and modern-ART eras. These investigations reveal a consistent pattern: short-term IFN-α exposure transiently reduces plasma viremia and integrated HIV-1 DNA, whereas prolonged administration yields diminishing returns accompanied by immune activation and tolerability issues.

During acute or early infection stages, initial clinical trials have shown that parenteral administration of IFN-α2b can effectively inhibit viral replication before the establishment of viral reservoirs, leading to temporary reductions in viral load and a delayed viral rebound after treatment cessation. However, in chronically infected individuals who have achieved virologic suppression under ART, pegylated IFN-α2a/α2b used as add-on therapy produces only modest reservoir perturbation, including limited reductions in integrated HIV-1 DNA and increased innate and cytotoxic effector activity (26, 54, 89). Importantly, available analytical treatment interruption studies indicate that these changes do not translate into consistent delays in viral rebound or durable post-treatment control, and rebound kinetics correlate more strongly with the size and integrity of the latent reservoir than with prior interferon exposure (89–91). Together, these data indicate that the therapeutic window of IFN-α is phase-dependent: benefits, when present, are most apparent before reservoir consolidation rather than during established chronic infection.

These findings demonstrate that IFN-α can transiently suppress plasma viremia and reduce integrated HIV-1 DNA, especially when used early in infection or as a pegylated adjunct to ART. However, the limited durability of viral control and the frequent occurrence of inflammatory side effects underscore the narrow therapeutic window of IFN-α. The following section examines the immunological consequences of sustained IFN-α signaling, including chronic immune activation, T-cell exhaustion, and their implications for long-term HIV management.

The efficacy of IFN-α in individuals with chronic HIV-1 infection remains controversial. In untreated chronic infection, plasma IFN-α concentrations strongly correlate with plasma HIV-1 RNA levels and markers of immune activation, while inversely correlating with CD4⁺ T-cell counts, suggesting that persistent IFN-α signaling contributes directly to systemic immune activation (39). Mechanistically, IFN-α downregulates IL-7 receptor α (CD127) expression on CD4⁺ and CD8⁺ T cells, in part through sustained JAK–STAT signaling and SOCS induction, thereby impairing IL-7-driven homeostatic proliferation and T-cell recovery (92, 93).

Clinical observations reveal highly variable CD4⁺ T-cell dynamics under IFN-α treatment. In some cohorts, individuals with higher baseline CD4⁺ counts or early-stage disease maintained or exhibited modest, transient increases in CD4⁺ T cells; however, these gains were short-lived (55). The magnitude of CD4⁺ response appears to depend on baseline immune status—patients initiating therapy at higher CD4⁺ levels respond more favorably, whereas those with advanced disease or immune exhaustion show minimal recovery (94, 95). Conversely, individuals with advanced HIV or HIV/HCV co-infection often experience negligible or even declining CD4⁺ counts (96).

The ability of IFN-α to reduce viral load also varies. While some studies have demonstrated reductions in HIV viral load with IFN-α therapy, not all patients respond similarly. Its impact on the viral reservoir appears limited; one study reported poor efficacy in reducing HIV DNA and no significant restriction of the viral reservoir (97). Multiple factors influence treatment outcomes, with a dose-dependent effect observed—higher IFN-α doses are associated with greater reductions in viral load and virological markers but also with increased adverse events and treatment discontinuations (98, 99). Furthermore, the virological and immunological effects of IFN-α are generally transient, with rebound occurring after treatment cessation, and tolerability issues limit long-term use (55, 100).

In summary, the use of IFN-α during chronic HIV-1 infection has not demonstrated sustained clinical benefits and may instead induce or exacerbate chronic immune activation, potentially hindering long-term immune reconstitution. Its application in this setting should therefore be carefully evaluated, taking into account the patient’s immune status, disease stage, and treatment tolerability.

Interferon-based therapy faces a central dilemma: preserving antiviral sensing without provoking systemic inflammation. STING agonists address this by activating cell-intrinsic innate immunity at tissue sites rather than raising circulating interferon. In acute infection, STING activation enhances viral sensing and type I interferon production, limiting early replication. HIV-1 is detected through the cGAS–STING axis, which initiates interferon signaling and antiviral programs (51, 52). In chronic HIV infection, however, plasma viremia is largely controlled by ART, and therapy shifts from suppressing replication to disrupting viral persistence. Accordingly, STING agonists are not intended as direct antivirals. Instead, they are used to perturb the latent reservoir by (i) promoting proviral transcription and chromatin changes that increase “visibility” of infected cells, and (ii) enhancing innate sensing and antigen presentation in lymphoid tissues to facilitate immune clearance. Sustained systemic STING activation is neither necessary nor desirable, as excessive interferon can reproduce immune dysfunction. Current strategies therefore emphasize transient or localized activation to achieve reservoir-directed effects while limiting inflammation. Intercellular transfer of cGAMP can further amplify STING signaling within tissue microenvironments, supporting this localized approach (101).

The regulatory role of ncRNAs in IFN signaling offers novel therapeutic opportunities. Type I IFN-induced lncRNA ISR2 can enhance antiviral responses when delivered via nanoparticle systems (102), miR-146a—an immunosuppressive miRNA upregulated during HIV infection—can be inhibited by anti-miR-146a, thereby augmenting IFN-mediated T-cell activation (103). Importantly, in this context, “T-cell activation” refers to restoration of antiviral competence (e.g., cytotoxic activity and responsiveness to antigenic stimulation) rather than nonspecific inflammatory activation, which is already excessive in chronic HIV-1 infection. In chronic disease, persistent miR-146a expression may blunt antiviral signaling as part of a negative-feedback program restraining IFN and NF-κB pathways; although anti-inflammatory in principle, this may also contribute to immune dysfunction and incomplete viral control when sustained. ncRNA-based therapy remains conceptual rather than clinical: efficient and cell-specific delivery to CD4⁺ T cells or macrophages is still a major obstacle. Technical barriers include vector safety, off-target effects, and metabolic stability (104, 105).Incorporating ncRNA regulation into IFN-pathway modulation could eventually complement latency-reversing or immune-boosting strategies, but requires significant preclinical validation.

TLR7 agonists, represented by vesatolimod (GS-9620), selectively activate innate immune signaling pathways and induce type I IFN responses. In HIV-infected individuals receiving suppressive ART, vesatolimod has demonstrated a favorable safety profile, eliciting transient increases in ISGs, plasma cytokines, and activation markers on peripheral immune cells without causing sustained inflammation or viral rebound (106). Notably, this contrasts with pegylated IFN-α therapy, in which continuous systemic exposure results in prolonged interferon signaling and cumulative toxicity. In comparison, TLR7 agonists induce short, intermittent interferon “pulses” that more closely resemble physiological innate immune activation rather than sustained pharmacologic exposure.In preclinical nonhuman primate models, TLR7-driven immune stimulation in combination with broadly neutralizing antibodies (bNAbs) significantly delayed viral rebound following ART interruption (107). Parallel studies have shown that combining therapeutic vaccination (Ad26/MVA ± gp140) with intermittent TLR7 administration enhances virologic control and strengthens antiviral T-cell responses, particularly when ART is initiated during acute infection (108). Current translational research focuses on optimizing the timing and sequence of TLR7 agonist administration relative to ART and immunotherapeutic interventions—for instance, priming with bNAbs or therapeutic vaccines before innate immune activation—to maximize efficacy while minimizing immune hyperactivation. In summary, TLR7 agonists targeting the IFN signaling pathway hold considerable promise in HIV cure research and warrant further mechanistic refinement and preclinical evaluation.