Open research questions in HIV Research and Treatment

What the literature leaves open

• The interplay between viral factors, patient demographics, and clinical presentation context is not fully understood. The drivers of advanced immune depletion at HIV diagnosis are multifaceted and not fully resolved. There is a need for further research to identify the strongest independent predictors of baseline disease severity.

  Late Clinical Presentation Outweighs Viral Characteristics in Determining Immune Depletion at HIV Diagnosis: A Five-Year Retrospective Study · 2026 · DOI

• The need to identify key Env sites that modulate Env-CD4 interactions. The lack of understanding of how specific combinations of mutations affect viral infectivity. The need for a system to analyze growth-enhanced adaptive mutants and quantify infectivity.

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

• small sample size of 15 HIV-1-infected mothers, - lack of confounding coinfections or major gestational comorbidities, - study only included pregnant women living with HIV-1 with gestational ages ranging from 35 to 40 weeks

  Enrichment of the TRIM21-IgG complex in placental villi during HIV-1 infection · 2026 · DOI

• evaluation of whether maternal TRIM21 can be transferred to the newborn to participate in neonatal antiviral defense, - investigation of the role of TRIM21 in the placenta during chronic, ART-controlled HIV-1 infection, - study of the effects of HIV-1 infection on placental immunity in different gestational ages

  Enrichment of the TRIM21-IgG complex in placental villi during HIV-1 infection · 2026 · DOI

• The study faced challenges due to the COVID-19 pandemic, which limited the enrollment of people with HIV-1 with active viremia. The study had to develop a complex PK model to describe the serum concentration and CD4RO data of 10E8.4/iMab due to the interaction of the iMab arm and host CD4 receptors.

  Bispecific 10E8.4/iMab broadly neutralizing antibody in people with or without HIV-1: a partially randomized phase 1 trial · 2026 · DOI

• The study was conducted partially during the COVID-19 pandemic, with attendant challenges and successes, - Amendments to the protocol limited the ability to draw conclusions about 10E8.4/iMab antiviral properties, - The sample size was limited, with 54 participants enrolled

  Bispecific 10E8.4/iMab broadly neutralizing antibody in people with or without HIV-1: a partially randomized phase 1 trial · 2026 · DOI

• One challenge is the potential for viral rebound after treatment interruption. Another challenge is the need to remove residual bNAbs from longitudinal IgG samples to accurately assess autologous neutralization activity.

  Broadly neutralizing antibodies in adult males living with HIV undergoing analytical treatment interruption: secondary and exploratory outcomes of the phase II randomized controlled RIO trial · 2026 · DOI

• The study identifies a gap in understanding the effects of broadly neutralizing antibodies on viral rebound and reservoir dynamics. The trial aims to address this gap by assessing the effects of the antibodies in a randomized controlled setting.

  Broadly neutralizing antibodies in adult males living with HIV undergoing analytical treatment interruption: secondary and exploratory outcomes of the phase II randomized controlled RIO trial · 2026 · DOI

• The effects of lenacapavir on HIV-1 capsid defects during virion maturation are not well understood. The mechanistic impact of lenacapavir during the late phase of HIV-1 replication remains poorly understood.

  Structural basis of lenacapavir-induced HIV-1 capsid defects during virion maturation · 2026 · DOI

• A useful preclinical model to study ADLD would be to expose AD mice to HIV-positive EVs to identify candidate EV-miRs that mediate the HIV-specific effects underlying ADLD. Characterization of the candidate EV-miRs may provide novel therapeutic armamentaria for ADLD.

  HIV-Associated Neurocognitive Disorder (HAND) and Alzheimer’s Disease Pathogenesis: Future Directions for Diagnosis and Treatment · 2024 · DOI

• The lack of definitive diagnostic testing for HAND/HAD further confounds the differences between the two disease entities. The differentiation between neurocognitive disorders in people living with HIV (PLWH) is crucial for preventative management and therapeutic strategies. Current screening tools lack validation.

  HIV-Associated Neurocognitive Disorder (HAND) and Alzheimer’s Disease Pathogenesis: Future Directions for Diagnosis and Treatment · 2024 · DOI

• However, their interactions with intact trimeric fusion proteins remain elusive; direct observation of binding on virions or native-like trimers has been lacking.

  Peptide inhibitors recognize prefusion viral fusion proteins with heterogeneous stoichiometry and rapid kinetics · 2026 · DOI

• Anti-PD-1 therapies have reduced the HIV reservoir in people living with HIV (PLWH) and cancer; however, the individuals who benefit and the mechanisms driving reservoir reduction remain unclear.

  Innate antiviral and immune functions associated with the HIV reservoir decay after anti-PD-1 therapy · 2026 · DOI

• Transcription and translation have been documented from latent and defective proviruses, but their impact on inflammation associated with chronic HIV-1 infection remains poorly understood.

  Intragenic transcription from defective HIV proviruses triggers interferon responses in myeloid cells · 2026 · DOI

• Although controllers have less HIV DNA, it remains unclear how HIV transcription differs from noncontrollers, and whether ART further reduces HIV DNA or RNA in controllers.

  HIV DNA and transcription before and after ART in natural controllers compared to noncontrollers · 2026 · DOI

• Future studies are warranted to determine whether these transient transcriptional modifications of innate immune cells in early infancy are associated with increased risk of infectious disease in CHEU.

  Maternal HIV Exposure Is Associated With Transient Transcriptional Changes in Monocytes and Natural Killer Cells in Early Infancy · 2026 · DOI

• In contrast, its effects during the late phase of replication, when the capsid assembles and matures within budding virions, remain poorly understood.

  Structural basis of lenacapavir-induced HIV-1 capsid defects during virion maturation · 2026 · DOI

• However, if not well understood and handled carefully, phylogenetic results have the potential to harm individuals and groups.

  Ethical considerations and the social context of HIV phylogenetic research in uMkhanyakude district, KwaZulu-Natal, South Africa · 2026 · DOI

• LEN binds to a hydrophobic pocket between neighboring capsid (CA) proteins in hexamers and stabilizes the capsid lattice, but its effect on HIV-1 capsids is not fully understood.

  Lenacapavir disrupts HIV-1 core integrity while stabilizing the capsid lattice · 2025 · DOI

• Most studies report on neurodevelopmental outcomes in the first 2 years of life, with limited data available for school-aged CHEU.

  Intelligence and language outcomes in school-aged children who are HIV-exposed, uninfected: the role of sex, perinatal risk factors, and socioeconomic status · 2025 · DOI

• However, little is known about how the B cells and Ab responses elicited by mRNA-expressed HIV immunogens compare to those elicited by corresponding recombinant (rec) proteins.

  Self-amplifying RNA-based activation of HIV-1 broadly neutralizing antibody B cell precursors 2690 · 2025 · DOI

• chronic infection and how these responses differ from elite controllers (ECs)–who control HIV without ART, remain poorly defined.

  Total and HIV-specific T cells from elite controllers preferentially express the follicle homing receptor CXCR5 4472 · 2025 · DOI

• However, there are relatively few reports on the comprehensive systematic transmission data in Yunnan.

  Rapid circulation of HIV-1 CRF85_BC in Southwest China: its geographic origins and molecular transmission networks analysis · 2025 · DOI

• Abstract Objective Long-term management of people living with HIV (PLWHs) often relies on CD4+ T cell counts for assessing immune recovery, yet a single metric offers limited information.

  The CD4/CD8 ratio is associated with T lymphocyte functions in long-term virally suppressed patients with HIV · 2025 · DOI

• BACKGROUND: The impact of human immunodeficiency virus (HIV) low-level viremia (LLV) on CD4 + T lymphocyte (CD4) cell count recovery during antiretroviral therapy (ART) remains unknown in China.

  Association of HIV low-level viremia with CD4 count recovery among persons living with HIV during antiretroviral therapy in Dehong Prefecture, Southwest China in 2008–2021: a longitudinal study · 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

• 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
• HIV-1 infection of human microglia activates inflammatory pathways associated with HIV-associated neurocognitive disorders (HAND) · bioRxiv · 2026
• Induction of broadly neutralizing HIV antibodies by a two-step mechanism informs vaccine design · Science · 2026
• Systematic discovery of pro- and anti-HIV host factors in primary human CD4+ T cells · Cell · 2026
• Conformational Variability of HIV-1 Env Trimer and Viral Vulnerability · bioRxiv · 2026
• Lenacapavir-induced lattice hyperstabilization is central to HIV-1 capsid failure at the nuclear pore complex and in the cytoplasm · eLife · 2026
• Functional Convergence of Genetically Diverse B-Cell Receptors in Simian-HIV Infected Rhesus Macaques · bioRxiv · 2026
• CD169 expression of CD14+ monocyte as a biomarker in the early infection of HIV-1 · BMC Infectious Diseases · 2026
• HIV ‐1 viral load and reservoir size remain stable following SARS ‐ CoV ‐2 mRNA vaccination in people with HIV · HIV Medicine · 2026

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