HIV type 1

Overview

Human immunodeficiency virus type 1 (HIV-1) is a lentivirus belonging to the family Retroviridae and the primary causative agent of acquired immunodeficiency syndrome (AIDS) worldwide. HIV-1 selectively targets CD4+ T lymphocytes, macrophages, and dendritic cells by binding the CD4 receptor in concert with co-receptors CCR5 or CXCR4, leading to progressive depletion of CD4+ effector memory T cells and systemic immune dysfunction. Upon cell entry, the viral reverse transcriptase enzyme converts the single-stranded RNA genome into double-stranded DNA, which is then integrated into the host genome by the viral integrase — a step that establishes a latent proviral reservoir impervious to current antiretroviral therapy (ART). HIV-1 is genetically diverse, with multiple subtypes and circulating recombinant forms distributed unevenly across global populations, complicating vaccine development and resistance surveillance.

Despite ART rendering HIV-1 a manageable chronic condition, it is not curative. Persistent proviral DNA in long-lived CD4+ T cells — including CD4+ effector memory T cells — underpins viral rebound upon treatment interruption. Chronic HIV-1 infection drives sustained immune activation, systemic inflammation marked by elevated Tumour necrosis factor alpha and dysregulation of B-cell populations, and end-organ complications affecting the brain, liver, cardiovascular system, and metabolic health. These sequelae occur even in virologically suppressed individuals on ART, making HIV-1 a continuing focus of intense basic, translational, and clinical research.

Focus of Latest Publications

Recent literature reflects a broad and rapidly evolving HIV-1 research landscape spanning novel therapeutics, cure strategies, comorbidity management, and global implementation science.

antiretroviral therapy optimization dominates the current clinical evidence base. Several studies evaluated the switch from integrase strand transfer inhibitor (INSTI)-based triple-drug regimens to dual regimens. A 48-week real-world cohort study (PMID 42124360) examined switching from INSTI-based triple therapy to dolutegravir/lamivudine (DTG/3TC) in Chinese treatment-experienced patients, addressing a gap in population-specific real-world data. Comparisons between bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and dolutegravir plus lamivudine as first-line regimens in treatment-naive individuals (PMID 42036350) highlighted long-term metabolic and renal outcome differences in real-world cohorts. A retrospective cohort study (PMID 42175517) further affirmed that INSTI-based regimens achieve superior viral suppression and maintain a high resistance barrier compared to non-INSTI regimens, supporting their continued role as first-line treatment for HIV-1 infection.

Long-acting injectable therapies represent a transformative shift in HIV-1 care. The ANRS0255 CARLAPOP study (PMID 42125948) evaluated the safety and efficacy of deltoid intramuscular long-acting cabotegravir and rilpivirine (CAB-LA) in people living with HIV switching from oral regimens. cabotegravir, the first long-acting injectable therapy approved for HIV-1 maintenance treatment when combined with rilpivirine, was further analyzed through population pharmacokinetic modeling (PMID 42170807) to characterize drug exposure during both oral and intramuscular administration. The ARTISTRY-1 randomized phase 3 trial (PMID 41763229) demonstrated that switching to a single-tablet bictegravir-lenacapavir regimen was effective for people unable to use standard single-tablet regimens due to resistance or drug-drug interactions. A phase 2 study (PMID 41720146) showed that lenacapavir combined with broadly neutralizing antibodies (bNAbs) teropavimab and zinlirvimab maintained virological suppression (HIV-1 RNA <50 copies/mL) for six months in susceptible patients, advancing the concept of long-acting, ART-free maintenance.

Novel drug classes and mechanisms are under active clinical development. MK-8527, a nucleoside reverse transcriptase translocation inhibitor, was evaluated in phase 1 studies (PMID 41830320) for both treatment and prevention of HIV-1 in ART-naive adults. A phase 1 pharmacokinetic study (PMID 42213486) evaluated potential drug-drug interactions between islatravir and lenacapavir, motivated by the challenge of long-term daily oral adherence leading to treatment failure or drug resistance. The fixed-dose combination of islatravir/lenacapavir was also evaluated for relative bioavailability and food effect (PMID 42053471), supporting development of long-acting oral regimens to reduce pill burden. Ainuovirine, a non-nucleoside reverse transcriptase inhibitor, had its absorption, distribution, metabolism, and excretion profile characterized in humans (PMID 41690529), supporting its consideration as an anchor antiretroviral agent. Perioperative pharmacokinetics of lenacapavir were investigated in a complex case (PMID 42048836) involving a patient with multidrug-resistant HIV-1 and severe hemophilia A undergoing liver transplantation, illustrating real-world pharmacological challenges.

Cure and reservoir research remains central to the field. A key obstacle is the persistence of HIV-1 proviral DNA integrated into CD4+ T cells, including those harboring genomically defective proviruses with immune-evasive protein expression profiles that sustain non-suppressible viremia through clonal expansion (PMID 41910264). Analytical treatment interruption cohort studies combined with multiomic analyses (PMID 41864210) have identified both cell-extrinsic and cell-intrinsic lymphocyte-mediated mechanisms governing HIV rebound, with insights into ART-free remission expanding through systematic review (PMID 42119366). Notably, the antidiabetic drug metformin — also studied as a mechanistic target of rapamycin kinase modulator — has shown capacity to induce DDIT4 and silence HIV in vitro, suggesting repurposing potential. A CRISPR/Cas-based lipid nanoparticle approach targeting CD4+ T cells demonstrated efficient HIV-1 DNA excision and reactivation blockade in latent cell lines (PMID 41769381), and hematopoietic stem cell gene editing was employed to engineer B lymphocytes producing long-lasting therapeutic levels of bNAbs against HIV-1 (PMID 41990179). In infants, VRC01 bNAb administration alongside early ART initiation showed that higher antibody concentrations correlated with greater HIV-1 DNA declines, though ART in infancy alone was insufficient for ART-free remission (PMID 42090482).

Immune pathogenesis research has illuminated several mechanisms of HIV-1-driven dysfunction. HIV Nef protein was shown to inhibit the WAVE2-ARP2/3 pathway in CD4+ T cells, impairing lamellipodial formation and immune function (PMID 41910361). Autoimmunity, promoted in part by systemic translocation of Staphylococcus aureus and its peptidoglycan components, was linked to poor immune reconstitution despite ART (PMID 41930968). Hypergammaglobulinemia, a B-cell abnormality present even in treated individuals, was characterized across both treated and untreated HIV populations (PMID 42166473). The broadly neutralizing antibody (bNAb) field explored how glycosylation on the HIV-1 envelope protein mediates dual resistance to CD4-binding site bNAbs (PMID 41930967), and gp41 target sequence analysis provided insights into persistent barriers to vaccine development (PMID 42065725). In population genetics, HIV-1 was shown to exert natural selection pressure on HLA-B alleles in KwaZulu-Natal, South Africa, an effect attenuated by widespread ART (PMID 42044322).

Comorbidities and aging have become central concerns as people with HIV (PWH) live longer. Longitudinal studies document progressive cognitive decline and structural brain changes in PWH (PMID 41542974), while a randomized controlled trial evaluated semaglutide — a glucagon-like peptide-1 agonist — for its effects on cognitive function, visceral adiposity, and inflammation in PWH (PMID 41098140). Excess visceral abdominal fat (EVAF) is described as prevalent even in those with normal BMI, with distinct therapeutic pathways including tesamorelin and GLP-1 receptor agonists (PMID 42139091). Cervical cancer risk remains substantially elevated in women with HIV-1, with both immunodeficiency and viremia independently associated with cervical precancer and cancer in South African women (PMID 41689274). Among those with HIV and advanced liver fibrosis or cirrhosis, hepatocellular carcinoma risk post-direct-acting antiviral treatment for HCV was quantified (PMID 41253696), as was the reduction in non-AIDS-defining malignancies with earlier ART initiation (PMID 41206033). C-reactive protein emerged as a predictive biomarker for hospitalization and mortality in patients with advanced HIV disease (CD4 ≤200 cells/μL) in Uganda (PMID 41057277). mitochondrial DNA fragment dynamics were characterized across acute and chronic HIV infection stages using both human and nonhuman primate models (PMID 41556528).

Global implementation, access, and equity are equally prominent themes. State AIDS Drug Assistance Programs (ADAPs) in the United States were shown to contribute meaningfully to viral suppression rates between 2015 and 2022 (PMID 41877607). Community-based programs targeting viral load suppression in HIV-positive orphaned and vulnerable children in Tanzania (PMID 42139209), alongside research on ART adherence determinants in Ghana and southern/eastern Africa (PMID 42113761, PMID 42166509), reflect the implementation science dimension of the global HIV response. The NIH has articulated future research directions toward ending HIV in the United States by 2030 (PMID 41628016), while qualitative research has examined barriers to palliative and end-of-life care for PWH (PMID 42134828), and well-being challenges among healthcare workers providing HIV services to children and adolescents in Africa (PMID 42139216).