Open research questions in HIV Research and Treatment

What the literature leaves open

• These results underscore coordinated functional coupling among V2, C4 (including E433), and gp41, the mechanistic basis of which remains to be fully defined.

  Natural variations at the E433 site in Env-gp120 β20-β21 cooperate with V2 and gp41 mutations to modulate HIV-1 infectivity · 2026 · DOI

• Downstream of the protein measurement in the VIP-Spot assay, the reactivated cells cannot be used in further flowcytometric analysis, which represents one of the major limitations of this assay.

  Tools to Quantify and Characterize the Persistent Reservoir in People with HIV-1: Focus on Non-B Subtypes · 2026 · DOI

• A key limitation of the RNAscope assay is that the data is semi-quantitative, since signal intensity does not always correlate linearly with viral transcripts per cell. For the FISH-Flow protocol, a major limitation is that the method is expensive, laborious, and requires high cell input (10–20 million CD4+ T cells), which limits its use in clinical settings.

  Tools to Quantify and Characterize the Persistent Reservoir in People with HIV-1: Focus on Non-B Subtypes · 2026 · DOI

• The extent to which these different aspects of TLMs are found in other PLWH, including those on ART or with uncontrolled viremia, and in HIV-negative controls remains to be determined.

  Multifaceted B cell response to transient HIV viremia in elite controllers · 2026 · DOI

• Thus, it is likely that the molecular components by which M-Sec promotes the formation of TNTs and the accumulation of HIV-1 Gag puncta are largely overlapping, although it remains unclear how those apparently unrelated phenomena are governed by these overlapping components. However, whether the enhanced Env incorporation is the sole cause of the enhanced infectivity remains unexplored.

  M-Sec promotes the production of infectious HIV-1 virus through the exocyst complex in macrophages · 2026 · DOI

• July 29, 2026 17 / 21 Finally, the extent to which CNS reservoirs contribute to systemic viral rebound following ART interruption remains uncertain.

  The brain as an HIV reservoir: Recent findings using autopsy tissues from people with HIV · 2026 · DOI

• Future studies are needed to elucidate the mechanisms underlying these associations and to explore whether targeting Th17-related pathways could potentially 389 modulate HIV disease outcomes.

  Pre-Human Immunodeficiency Virus (HIV) infection Th17 CD4+ T cells as predictors of early HIV disease progression · 2026 · DOI

• Potentially relevant factors related to cognitive function, including sleep, HIV reservoir dynamics, and sex hormones, were not available in this analysis and warrant further investigation.

  BrainBaseline Assessment of Cognition and Everyday Functioning (“BRACE”-ing for the Future): Establishing iPad-Based Norms for Cognitive Function in the Multicenter AIDS Cohort Study and Women’s Interagency HIV Study Combined Cohort Study · 2026 · DOI

• Future developments in our knowledge of reservoir biology, technical advancements, and practical therapeutic goals will determine the course of HIV cure research. Clarifying the mechanisms controlling the latent reservoir’s formation, maintenance, and heterogeneity is a top objective.

  Beyond Antiretroviral Therapy: Molecular and Immunological Innovations in HIV Treatment · 2026 · DOI

• Several technical limitations of this study should also be noted. The dataset remains imbalanced with respect to tropism, genetic variants, and sequencing completeness: it is dominated by R5-tropic isolates, HIV-1 subtype B sequences, and nucleotide sequences limited to the env gene.

  A Curated Phenotype-Linked HIV-1 Sequence Dataset for Machine Learning Approaches to Tropism Prediction, Disease Progression and Proviral Reservoir Studies · 2026 · DOI

• Moreover, its antiviral significance remains debated since SERINC5 fails to inhibit viral strains carrying certain envelope glycoproteins, including those from various primary HIV-1 isolates28,29 and other retroviruses17,18.

  SERINC5 is the primary target of retroviral antagonists among human SERINC paralogs and requires a tri-cysteine motif for its counteraction by HIV-1 Nef · 2026 · DOI

• The possibility that accelerated ageing in PLWH may be one possible mechanism through which HIV-specific associations between gait and neurocognitive function manifest should be investigated in future studies. Further exploration into the neural underpinnings of gait-cognition interactions in this patient population is warranted.

  Evidence that intrinsic brain connectivity moderates the association between gait and neurocognitive function in people living with HIV · 2026 · DOI

• Although IL-27-polarized macrophages induce multiple antiviral genes and resist replication-competent HIV infection, their impact on VSV-GHIVLuc infection has not been studied.

  IL-27 Reduces Cell-Surface LDLR in Human Macrophages and Restricts VSV-G-Pseudotyped HIV infection · 2026 · DOI

• Beyond these, a more comprehensive multi-omics strategy that aims to combine various methods such as transcriptomics, proteomics, epigenomics, and metabolomics should be used in the future. These can be used on distinct cellular subsets from various tissue reservoirs, such as latently infected, productively infected, and bystander cells.

  HIV-Induced Apoptosis: Host Defense and Viral Strategy · 2025 · DOI

• Future research should focus on developing personalized treatment protocols that effectively balance the therapeutic benefits and potential risks of IFN modulation.

  Finetuning Type I Interferon Signaling to Enhance T Cell Immunity in HIV Infection · 2025 · DOI

• Future research should address these uncertainties and investigate whether targeting AP-dependent pathways can yield novel antiviral strategies, with special attention to their potential role in a cure.

  Adaptor Protein Complexes in HIV-1 Pathogenesis: Mechanisms and Therapeutic Potential · 2025 · DOI

• While clinical trials of prophylactic vaccines have demonstrated that cytotoxic T-cell responses can reduce viral load, these responses alone are insufficient to prevent HIV infection.

  Decade-Long Sustained Cellular Immunity Induced by Sequential and Repeated Vaccination with Four Heterologous HIV Vaccines in Rhesus Macaques · 2025 · DOI

• However, when designing and optimizing boost immunogens, it remains unclear to what extent shared off-target epitopes should be eliminated to maximize the on-target antibody response10–14,35,36.

  Novel HIV-1 fusion peptide immunogens using glycan-engineered alphavirus-like particles · 2025 · DOI

• To date, only one HIV-1 vaccine regimen has been shown to modestly protect humans from HIV-1 infection, an effect that has not been replicated elsewhere.

  Non-human primate LIBRA-Seq accelerates neutralizing antibody discovery in RM vaccinated against HIV-1 · 2026 · DOI

• This is an important result because, although intrinsic noise is often considered as the main source of noise affecting transcription initiation, only a few studies have directly tested this hypothesis by assessing extrinsic versus intrinsic contributions using two-copy RNA imaging systems.

  Cell heterogeneity contributes to the variable response of HIV-1 to latency-reversing agents · 2026 · DOI

• In conclusion, the overall immunogenicity of HIV-1 Env is unusually weak compared with that of other viral glycoproteins, yet HIV-1 bNAbs are unusually highly mutated compared with other antiviral nAbs. The combined viral and host barriers render the development of HIV-1 Env vaccines exceptionally challenging.

  Advances in HIV-1 Envelope-Based Vaccine Development · 2026 · DOI

• Several key areas of interest in computational research on HIV PR (specifically subtype C) are yet to be thoroughly explored. These areas include understanding the unique structural characteristics of HIV-1 PR subtype C, developing better inhibitors, and exploring the resistance of the enzyme to existing drugs.

  Integrative Computational Approaches for Understanding Drug Resistance in HIV-1 Protease Subtype C · 2025 · DOI

• In summary, advancements in HIV-1 vaccine and treatment strategies have shown significant promise in the fight against the virus.

  Progress and Challenges in HIV-1 Vaccine Research: A Comprehensive Overview · 2025 · DOI

• Although the underlying molecular mechanisms remain to be elucidated, previous studies have proposed that 63_02A6 may possess higher replication capacity and enhanced viral fitness, potentially…

  The Molecular Epidemiology of HIV-1 in Russia, 1987–2023: Subtypes, Transmission Networks and Phylogenetic Story · 2025 · DOI

• By demonstrating that RBM39 recruits YTHDC1 and DDX5 to accelerate Tat RNA decay, we bridge a critical gap in understanding how post-transcriptional RNA modifications regulate viral persistence.

  The RNA-binding protein RBM39 scaffolds an m⁶A-dependent RNA decay complex that destabilizes Tat transcripts and restricts HIV-1 reactivation · 2025 · DOI

Most-cited papers in HIV Research and Treatment

• In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector · Science · 1996 · 4,134 citations
• Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection · Nature · 1995 · 3,330 citations
• Identification of a major co-receptor for primary isolates of HIV-1 · Nature · 1996 · 2,924 citations
• HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time · Science · 1996 · 2,756 citations
• Identification of a Reservoir for HIV-1 in Patients on Highly Active Antiretroviral Therapy · Science · 1997 · 2,687 citations
• The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus · Nature · 1984 · 2,631 citations
• Frequent Detection and Isolation of Cytopathic Retroviruses (HTLV-III) from Patients with AIDS and at Risk for AIDS · Science · 1984 · 2,593 citations
• Viral dynamics in human immunodeficiency virus type 1 infection · Nature · 1995 · 2,587 citations
• HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5 · Nature · 1996 · 2,573 citations
• Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody · Nature · 1998 · 2,513 citations

Most recent work

• Recommendations from the 2nd Consensus Workshop on Analytical Treatment Interruption in HIV Research Trials · The Lancet HIV · 2026
• Autologous neutralizing antibodies and polyfunctional T cells contribute to long-term HIV-1 post-intervention control · Nature Immunology · 2026
• Enhanced HIV-1 Control After Antibody Therapy is Associated with Autologous Antibodies and Reservoir Clearance in the RIO trial · medRxiv · 2026
• Innate antiviral and immune functions associated with the HIV reservoir decay after anti-PD-1 therapy · Nature Medicine · 2026
• Rapid elicitation of neutralizing Asn332-glycan-independent antibodies to the V3-glycan epitope of HIV-1 Env in nonhuman primates · Nature Immunology · 2026
• Initial sites of SIV rebound after antiretroviral treatment cessation in rhesus macaques · Nature Microbiology · 2026
• Identification of a potent V3 glycan site broadly neutralizing antibody targeting an N332gp120 glycan-independent epitope · Nature Immunology · 2026
• Neuroinflammation and NeuroHIV: understanding the role of HIV-1 related factors in microglial activation · Translational Psychiatry · 2026
• Germline-targeting HIV immunogen induces cross-neutralizing antibodies in outbred macaques · Immunity · 2026
• Time to HIV rebound after infusion of long-acting broadly neutralising antibodies 3BNC117-LS and 10-1074-LS and analytical treatment interruption (the RIO trial): a double-blind, randomised, placebo-controlled trial · The Lancet HIV · 2026

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