What's Hot in HIV in 2025—A Basic and Translational Science Review From IDWeek 2025

Abstract

Advances in basic and translational human immunodeficiency virus (HIV-1) research have refined our understanding of viral persistence while informing new strategies aimed at prevention and durable virologic control. Here, we present an overview of selected advances in HIV vaccine development, cure-directed strategies, and new insights into the mechanisms of HIV persistence, highlighting key basic and translational studies published over the past year and featured in What's Hot in HIV Basic Science 2025. Notable progress includes promising results in germline-targeting and sequential immunization for the induction of broadly neutralizing antibody precursors, a better understanding of the mechanisms of reservoir persistence, and encouraging signals that immune-based strategies can lead to postintervention control. Collectively, these insights emphasize the value of experimental medicine trials and underscore a shift toward more precise, mechanism-informed strategies for HIV prevention and cure, pointing to a future in which durable virologic control may be achievable through rationally designed combination approaches.

The present review highlights select advances of HIV research into vaccine development, cure-directed strategies, and reservoir persistence published within the past year and which were featured in the presentation “What's Hot in HIV Basic Sciences” at IDWeek 2025.

The development of antiretroviral therapy (ART) for the prevention and treatment of HIV infection represents one of the greatest achievements of modern medicine. Individuals with sustained access to antiretrovirals can achieve durable viral suppression, dramatically reducing morbidity, mortality, and onward transmission. Despite these successes, HIV continues to pose a substantial global health burden, with ongoing transmission and the requirement for lifelong therapy underscoring the limitations of ART as a sole strategy to end the epidemic [1, 2]. These realities underscore the need for complementary approaches.

An effective and scalable preventive vaccine that provides durable, population-level immunity without imposing resistance pressure remains a critical unmet need. In parallel, curative or remission-inducing interventions that enable durable ART-free virologic control could transform long-term management for people with HIV (PWH). Recent advances have begun to address these challenges, driven by deeper mechanistic insight into the evolution and maturation of immune responses, viral persistence, and host–virus interactions. In particular, progress in rational vaccine design, an evolving understanding of the heterogeneity and immune sensitivity of the HIV reservoir, and early clinical signals from immune-based interventions have collectively reframed expectations for what may be achievable in HIV prevention and cure research.

In this review, targeted for clinicians and researchers, we provide an overview of selected studies in HIV basic and translational science presented or published between 2024 and 2025, with a focus on HIV vaccine development, mechanisms of viral persistence, and cure-directed strategies, as summarized in Figure 1. The content is adapted from a presentation delivered at IDWeek 2025: “What's Hot in HIV Basic Science Research.” The discussed studies were selected by the authors based on their assessment of clinical relevance.

Figure 1.

A graphical summary of the basic and translational HIV research selected for review in the present article, encompassing breakthroughs in vaccine development (A), HIV persistence (B) and postintervention immune-mediated virological control (C). Abbreviations: ART, antiretroviral therapy; bNAbs, broadly neutralizing antibodies; LRA, latency-reversing agent; TCR, T-cell receptor; TLR, toll-like receptor; LNP, lipid nanoparticle. Created in BioRender. Teixeira, R. (2026) https://BioRender.com/dbxi6m6.

ADVANCES IN HIV VACCINES: GERMLINE-TARGETING STRATEGIES

An effective HIV vaccine remains a critical unmet need. Traditional vaccine strategies have largely failed to achieve this goal, reflecting the extraordinary genetic diversity and immune evasion strategies of HIV. Proof of principle that antibodies can prevent HIV acquisition in humans was established by the antibody-mediated prevention (AMP) trials, which demonstrated that passively administered broadly neutralizing antibodies (bNAbs) can reduce the risk of infection with antibody-sensitive viruses when maintained at sufficiently high serum concentrations [3]. In recent years, vaccine development has entered a new phase driven by structure-based immunogen design, germline targeting, and sequential immunization strategies aimed at inducing bNAbs [4].

A central challenge in inducing broadly neutralizing responses is the rarity and stringent maturation requirements of bNAb precursors. These precursors are naïve B cells with germline-encoded B-cell receptors that can mature into bNAbs. Germline-targeting strategies seek to overcome this barrier by designing immunogens that specifically engage naive B cells expressing germline versions of bNAb lineages, followed by sequential boosts to guide affinity maturation toward increased breadth. Recent studies provide compelling evidence that this approach is feasible in humans [5, 6].

Caniels et al reported first-in-human immunogenicity data following immunization with a native-like HIV Env trimer, GT1.1, which was designed to engage bNAb precursors against the trimer apex and the CD4 binding site (CD4bs) regions of Env. GT1.1 immunizations induced CD4bs- and apex-memory B cells in all participants, with high-frequency of VRC01-class precursor responses that underwent affinity maturation resembling natural infection. Structural and functional analyses demonstrated that selected vaccine-elicited VRC01-class antibodies acquired features enabling binding to more native-like HIV envelope trimers [7]. Importantly, some of these antibodies exhibited angles of approach and contact sites increasingly similar to those of naturally occurring bNAbs, indicating maturation along the intended pathway. Although these antibodies do not yet achieve the breadth or potency required for protection, these findings establish that vaccination can induce antibodies with bNAb-like characteristics.

Building on this concept, Willis et al showed that heterologous boosting strategies using mRNA-encoded immunogens can further drive maturation of VRC01-class precursors [8]. Germline-targeting priming with eOD-GT8 delivered as mRNA lipid nanoparticles followed by mRNA delivery of the heterologous booster core-g28v2 60mer resulted in antibodies with increased somatic hypermutation and improved neutralization profiles. These results highlight the flexibility of mRNA platforms for iterative vaccine design. Importantly, the findings establish proof of concept in humans that heterologous boosting can advance bNAb precursor maturation. At the same time, tolerability concerns, including the occurrence of urticarial reactions in some participants, underscore the importance of continued optimization of dose, formulation, and delivery as these strategies move forward.

An important extension of germline-targeting vaccine research has been the exploration of pediatric and early-life immunization. Nelson et al demonstrated that infant nonhuman primates (NHPs) can mount robust bNAb precursor responses comparable to, or exceeding, those observed in adult animals and human vaccine recipients [9]. These findings support the concept of a developmental “window of opportunity” during which the naive B-cell repertoire may be particularly amenable to bNAb lineage induction. Early-life vaccination strategies may therefore offer a unique avenue to guide antibody maturation over extended periods, potentially before sexual debut and HIV exposure.

Together, these studies mark a conceptual inflection point in HIV vaccine research. While fully mature bNAbs have not yet been elicited by vaccination, these studies demonstrate the ability to initiate and shape desired antibody lineages in humans. Nonetheless, major hurdles remain to boost the breadth and potency of these responses to sufficient levels. Ongoing work aimed at refining immunogen design and targeting multiple bNAb epitopes simultaneously will be essential to translate these advances into a protective vaccine.

An increasingly important driver of progress in this area has been the use of streamlined experimental medicine trial designs that prioritize rapid, high-resolution immunologic readouts over traditional efficacy endpoints, enabling iterative testing and down-selection of immunogens, platforms, and prime-boost sequences. Extending such studies to PWH on suppressive ART may further accelerate vaccine development. As recently articulated by Moore and Trkola, PWH represent a uniquely informative population for immunogen evaluation, as prior and prolonged exposure to diverse HIV Env variants provides a biologically relevant context in which to assess the capacity of candidate vaccines to re-stimulate existing antibody specificities or engage new bNAb lineages [10]. Immunization studies in PWH could therefore provide rapid insights into off-target immunodominance, redirection of antibody responses, and the boosting potential and maturation of vaccine-elicited responses, while simultaneously informing the development of both preventive and therapeutic vaccine strategies.

NEW INSIGHTS INTO HIV PERSISTENCE

The extreme rarity of HIV-infected cells in PWH on suppressive ART has long limited detailed study of the reservoir. Two recent studies by Ferreira et al and Bittar et al address this challenge by enriching and expanding infected cells from peripheral blood to generate in vitro populations containing a single authentic reservoir clone (ARC) [11, 12]. Using complementary enrichment strategies, both groups showed that in vitro-expanded ARCs remain closely related to their ex vivo counterparts at the transcriptional level, as assessed by single-cell RNA sequencing, even after prolonged culture. These ARCs provide an experimentally tractable system to study HIV expression, latency, clonal persistence, and immune targeting in cells derived from bona fide reservoirs.

After several years of suppressive ART, the intact HIV reservoir size remains roughly constant, but its clonal composition continues to evolve [13]. Over time, reservoir diversity decreases, with enrichment of clones harboring proviruses integrated into genomic regions traditionally considered transcriptionally repressive, including zinc finger genes and heterochromatin (a condensed chromatin state that is typically transcriptionally inactive) [14–16]. This pattern has been interpreted as evidence that clones with higher reactivation potential are preferentially eliminated. Notably, however, proviruses integrated within actively transcribed genes can persist for decades, indicating that integration site alone does not fully determine clonal fate.

The recent analyses of ARCs by Bittar et al and Ferreira et al revealed substantial heterogeneity in proviral expression within individual clones. Across studies, only a small fraction of cells within a given clone expressed HIV RNA or Gag at any time, with marked cell-to-cell variability, even among clones integrated into transcriptionally permissive regions [11, 12]. Consistent with this, reporter-based studies of authentic integration sites demonstrated heterogeneous transcriptional activity within single clones [17]. Interestingly, Bittar et al also showed that some ARCs with integrations in pericentromeric human satellite DNA, a heterochromatin region, exhibited high levels of proviral transcription [11]. These findings demonstrate that integration into repressive chromatin does not uniformly result in proviral silencing. In parallel, Ferreira et al showed that some ARCs are relatively resistant to cytotoxic CD8⁺ T-cell–mediated killing, indicating that immune evasion, in addition to transcriptional silencing, contributes to clonal persistence.

Extending these observations beyond peripheral blood, Wei et al applied multiomic approaches and found that, in gut tissue, HIV–infected CD4⁺ T cells are enriched within BACH2–expressing tissue-resident memory populations, a cellular context that favors long-term survival and may constrain immune-mediated clearance. The authors also show that BACH2+ HIV-specific CD8⁺ T cells carry epigenetic marks of immune exhaustion and of restrained interferon response [18].

Taken together, heterogeneity in proviral expression, the ability of infected cells to proliferate without inducing viral replication, and to partially evade immune clearance, provide a mechanistic basis for clonal persistence that is not fully determined by the site of integration.

Sex-based differences in HIV control have been observed across multiple settings, with females overrepresented among elite and posttreatment controllers and exhibiting lower levels of cell-associated RNA, residual viremia, and replication-competent viruses during ART [19–21]. In a comparative analysis of long-term ART-treated individuals, Tan et al found that while intact reservoir size did not differ by sex, reservoirs in females were more clonal and enriched for proviruses integrated into heterochromatic genomic regions. Notably, the frequency of heterochromatic integrations correlated with the presence of activated natural killer (NK) cells, which were more abundant in females [22]. These data suggest that NK cell-mediated immune pressure contributes to shaping reservoir composition during long-term ART, with a more prominent imprint in females.

Latency-reversal agents (LRAs) are compounds that can induce HIV transcription in latently infected cells to facilitate their elimination, an approach known as “shock and kill.” While multiple LRAs have demonstrated activity in vitro, ex vivo, and in animal models, none have consistently reduced reservoir size in clinical trials [23, 24], highlighting fundamental biological and translational challenges.

Mechanistic insight into these failures has emerged from the analyses of ARCs. Bittar et al found that no single LRA uniformly activated proviral transcription in all cells of a clone, and that LRA effects were not universal, varying greatly between different clones [12]. This data illustrates that latency reversal is intrinsically heterogeneous and clone specific, providing a compelling explanation for the limited effects of LRAs observed in clinical trials.

In parallel, proof-of-concept studies established the feasibility of HIV-specific nucleic acid–based latency reversal strategies. Lipid nanoparticles delivering mRNA encoding the HIV transactivator of transcription (Tat) enhanced transcriptional processivity but required combination with nonspecific LRAs, consistent with inefficient delivery to resting CD4⁺ T cells [25, 26]. Similarly, HIV LTR–targeted CRISPR activation (CRISPRa) enabled highly specific induction of HIV transcription with minimal host gene perturbation [27–29]. However, neither approach progressed beyond in vitro or limited ex vivo systems due to the absence of an efficient delivery platform for resting CD4⁺ T cells.

An important advance was reported by Cevaal et al, who developed a lipid nanoparticle formulation (LNP X) capable of efficiently delivering mRNA cargo to resting CD4⁺ T cells without inducing cellular activation. Delivery of HIV Tat mRNA resulted in potent ex vivo reactivation of HIV transcription in primary CD4⁺ T cells from PWH on ART, overcoming multiple blocks in HIV transcription and RNA processing and exceeding mitogenic stimulation while avoiding global T-cell activation or toxicity. Despite this robust induction, no reduction in intact proviral DNA was observed over short-term culture, highlighting persistent barriers to infected-cell elimination. Importantly, LNP X also enabled delivery of CRISPR-based transcriptional activators targeting the HIV LTR, establishing a versatile platform for highly HIV-specific latency reversal [30]. Together, these findings support further development of clinically viable next-generation latency reversal strategies.

IMMUNOLOGIC INTERVENTIONS TO ACHIEVE ART-FREE VIRAL CONTROL

A growing body of work indicates that immune-based interventions can, in some individuals, delay or prevent viral rebound following analytical treatment interruption (ATI), supporting the feasibility of achieving durable ART-free virologic control [31, 32]. These approaches aim to enhance HIV-specific immune responses, reduce the intact reservoir, or both, and are increasingly being evaluated in combination regimens through experimental medicine trials.

Bailon et al reported results from AELIX-003, a trial of a T-cell–based therapeutic vaccine administered with the toll-like receptor 7 (TLR7) agonist vesatolimod in early-treated PWH on suppressive ART. Although no significant difference in overall virologic control during ATI was observed between vaccine and placebo groups, a subset of vaccine recipients demonstrated delayed viral rebound, and longer time off ART correlated with higher levels of vaccine-induced T-cell responses [33]. These findings support the notion that therapeutic vaccination can contribute to postintervention control (PIC) in selected individuals.

Broadly neutralizing antibodies have emerged as one of the most advanced immune-based strategies for achieving HIV remission [31, 34–37]. In the randomized, placebo-controlled RIO trial, long-acting Fc-engineered bNAbs targeting distinct Env epitopes were administered to individuals who initiated ART during early HIV infection, followed by ATI [38]. Compared with placebo, bNAb-treated participants experienced markedly delayed viral rebound, with a substantial subset maintaining virologic control for extended periods off ART.

Additional combination strategies are also being explored. In a single-arm proof-of-concept study (UCSF-amfAR trial), Peluso et al treated 10 PWH on suppressive ART with a multimodal immunotherapy regimen combining therapeutic vaccination, 2 bNAbs, and a TLR9 agonist, with repeat bNAb dosing at the time of ART interruption [39]. Following ART discontinuation, 7 participants exhibited PIC, ranging from sustained suppression to slow or oscillating low-level viremia, despite declining bNAb plasma concentrations. Similarly, in the FRESH cohort, early-treated women received long-acting bNAbs in combination with the TLR7 agonist vesatolimod prior to ATI [40]. Notably, viral rebound dynamics in this cohort mirrored those observed in the RIO and UCSF-amfAR studies. Across these studies, suppression or low-level viremia persisted in some individuals even after modeled bNAb concentrations declined below levels expected to mediate direct antiviral activity, suggesting that mechanisms beyond neutralization contribute to sustained virologic control.

Finally, novel cellular immunotherapies further expand the immunologic toolkit. Early clinical evaluation of a soluble T-cell receptor (TCR) bispecific engineered to simultaneously bind a defined peptide–HLA complex (eg, an HIV Gag–derived peptide presented by HLA-A*02:01) and CD3 on T cells to redirect cytotoxic activity has demonstrated feasibility and biologic activity in PWH on suppressive ART. In an ongoing phase 1/2 study, administration of HIV Gag × CD3 bispecific (IMC-M113 V) [41] was associated with reductions in cell-associated HIV RNA and partial virologic control following initial rebound during ATI in a subset of participants, supporting continued evaluation of T-cell–engaging strategies as potential remission-oriented approaches.

CORRELATES OF POSTINTERVENTION CONTROL

Substantial efforts have focused on identifying immune and virologic correlates that distinguish individuals who achieve PIC from those who rapidly rebound following ATI. Emerging data indicate that durable ART-free virologic control is not attributable to a single factor but instead reflects coordinated features of the viral reservoir and host immune response.

Insights from the RIO and UCSF-amfAR trials underscore this complexity. Although administration of long-acting bNAbs robustly delayed viral rebound, extended ART-free remission was not fully explained by circulating antibody concentrations alone, pointing to host- and reservoir-dependent mechanisms. In this context, Fumagalli et al reported that qualitative features of autologous antibody responses were associated with time to viral rebound and that bNAb administration was linked to preferential decay of the intact proviral reservoir relative to defective proviruses [42]. Together, these observations suggest that endogenous humoral immunity and reservoir susceptibility contribute to sustained viral control following antibody-based interventions.

A role for cytotoxic T-cell responses in PIC has also been supported by earlier bNAb studies [43, 44] and was observed in the therapeutic vaccine trial by Bailon et al [33], as well as in emerging data from RIO [45]. Detailed analyses from bNAb-based ATI trials demonstrated that PIC was associated with preintervention HIV-specific CD8⁺ T-cell proliferative capacity, stem-like features, and robust recall cytotoxic potential [46]. Following bNAb administration, these CD8⁺ T-cell populations exhibited further functional enhancement. That PIC correlated with preintervention features indicates that baseline immune state strongly conditions the likelihood of successful remission. Extending these findings, Peluso et al reported that in viremic PICs, viral rebound was accompanied by a robust expansion of activated CD8⁺ T cells and that the magnitude of this response and the expression of the stem-like marker TCF-1 correlated with establishment of a lower viral load set point [39]. These observations demonstrate that, following combination immunotherapy, a strong in vivo CD8⁺ T-cell response to emerging virus is associated with improved virologic control after ART interruption, consistent with a model in which antibody-mediated modulation of antigen exposure promotes effective T-cell re-engagement.

Although these are small mechanistic studies, the findings suggest that bNAbs function not only as direct antiviral agents but also as immune modulators that shape the balance between viral antigen availability and immune responsiveness. By delaying early viral rebound while permitting controlled antigenic stimulation, antibody-based interventions may create conditions that sustain effective humoral and cellular immunity. This balance helps explain why PIC can persist even after antibody concentrations decline below levels expected to mediate direct neutralization.

Collectively, these studies suggest that achieving durable ART-free viral control will likely require rationally designed combination strategies guided by multidimensional immune and virologic correlates. Prospectively validating such signatures will be essential for optimizing trial design, identifying individuals most likely to benefit from immune-based interventions, and advancing the field toward scalable remission and cure strategies.

CONCLUSIONS

Recent advances in HIV basic and translational research have sharpened our understanding of viral persistence and highlighted emerging strategies aimed at durable ART-free virologic control. Progress in rational vaccine design has demonstrated the feasibility of initiating bNAb lineages in humans, while high-resolution studies of the reservoir have revealed heterogeneity in transcriptional activity, immune susceptibility, and impact of tissue context. In parallel, early clinical studies of immune-based interventions have begun to define the immune and virologic features associated with PIC. Together, these findings underscore the value of experimental medicine trials and support a shift toward mechanism-informed combination approaches to HIV prevention and cure.