Search Results (62)

The Intact Proviral DNA Assay (IPDA) is widely used to quantify genome-intact HIV proviruses in people living with HIV, but viral sequence diversity has been observed to cause assay failures due to primer/probe mismatches. Adapted for subtype C, IPDA-BC is a modified version of the IPDA validated on South African HIV-1 subtype C. India is also impacted by subtype C, but IPDA performance within-subtype across geographical regions is not well studied. We analyzed Indian (IN) and South African (ZA) subtype C sequences in silico, hypothesizing that IPDA-BC may underperform with IN viruses. Primer/probe binding was predicted using three increasingly stringent nucleotide mismatch criteria, whose sensitivity and specificity were evaluated against experimental IPDA outcomes. Phylogenetic analyses confirmed that IN and ZA subtype C sequences form distinct clusters with significant compartmentalization (p < 0.003). Across criteria, up to 6–10% decreases in primer/probe binding were observed in IN versus ZA, with the env forward primer being the most affected. These criteria showed low sensitivity (18–53%) and variable specificity (67–100%) in predicting experimental outcomes. In conclusion, even within subtype, HIV-1 variation across geographical regions may impact IPDA performance, underscoring the need for improved predictive models to guide assay design for global HIV cure research. Full article

Background/Objectives: End-of-life (EOL) HIV cure research, which studies HIV persistence through pre- and post-mortem tissue collection, has focused primarily on people living with HIV (PLWH) with a prognosis of six months or less. However, the perspectives of long-term survivors (LTS) diagnosed before the advent of effective antiretroviral treatment (ART) remain underexplored. Understanding their motivations and concerns about EOL cure research is essential for creating inclusive and ethical research frameworks. Methods: Between 2023 and 2024, we conducted in-depth qualitative interviews with 16 PLWH aged 60 and older from diverse backgrounds across the United States, recruited through community-based organizations and HIV networks. We used inductive thematic analysis to explore LTS’ perspectives on EOL HIV research. Results: Participants included cisgender men (56.25%) and women (43.75%) with diverse racial identities. While participants supported EOL HIV cure research, their willingness to participate varied, influenced by awareness, logistics, and ethical concerns. Altruism-motivated participation, but misconceptions about procedures and concerns over bodily integrity represented potential barriers. Some viewed blood draws and leukaphereses as routine, while others expressed hesitancy with biopsies and post-mortem tissue retrieval. HIV stigma, historical mistrust, and cultural beliefs also played a role in willingness to participate. LTS emphasized the need for decentralized research sites, travel support, and financial safeguards. Conclusions: To include LTS in EOL HIV cure research, a community-driven approach is needed, focusing on clear communication, ethical considerations, logistical support, and linkages to EOL care. Addressing misconceptions and building trust, particularly within groups traditionally underrepresented in research, is essential to expanding participation. Full article

Despite the success of antiretroviral therapy (ART) in suppressing viral replication in the blood, HIV persists in the central nervous system (CNS) and causes chronic neurocognitive impairment, a hallmark of HIV-associated neurocognitive disorders (HAND). This review looks at the complex interactions among HIV, the blood–brain barrier (BBB), neuroinflammation, and the roles of viral proteins, immune cell trafficking, and pro-inflammatory mediators in establishing and maintaining latent viral reservoirs in the CNS, particularly microglia and astrocytes. Key findings show disruption of the BBB, monocyte infiltration, and activation of CNS-resident cells by HIV proteins like Tat and gp120, contributing to the neuroinflammatory environment and neuronal damage. Advances in epigenetic regulation of latency have identified targets like histone modifications and DNA methylation, and new therapeutic strategies like latency-reversing agents (LRAs), gene editing (CRISPR/Cas9), and nanoparticle-based drug delivery also offer hope. While we have made significant progress in understanding the molecular basis of HIV persistence in the CNS, overcoming the challenges of BBB penetration and neuroinflammation is key to developing effective therapies. Further research into combination therapies and novel drug delivery systems will help improve outcomes for HAND patients and bring us closer to a functional cure for HIV. Full article

The cytoplasmic human Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) cytidine deaminases G and F (A3G and A3F) can block the spread of human immunodeficiency virus (HIV). HIV counteracts this cell-intrinsic defense through a viral protein called viral infectivity factor (Vif). Vif causes proteasomal degradation of A3G and A3F proteins (A3G/F) in HIV-producing cells to ensure infectivity of virions subsequently released from these cells. Here, we optimized a lead compound reported previously to boost cellular levels of A3G. The modified analogs designed, synthesized, and evaluated here inhibit cell-mediated post-translational degradation of A3G/F, whether Vif is present or not. This increases A3G/F incorporation into Vif-positive virions to decrease viral infectivity. The compounds and processes described here can facilitate the development of new anti-HIV therapeutics whose host-targeted effect may not be evaded by resistance-conferring mutations in HIV Vif. Full article

A proviral reservoir persists within the central nervous system (CNS) of people with HIV, but its characteristics remain poorly understood. Research has primarily focused on cerebrospinal fluid (CSF), as acquiring brain tissue is challenging. We examined size, cellular tropism, and infection-dynamics of the viral reservoir in post-mortem brain tissue from five individuals on and off antiretroviral therapy (ART) across three brain regions. Microglia-enriched fractions (CD11b⁺) were isolated and levels of intact proviral DNA were quantified (IPDA). Full-length envelope reporter viruses were generated and characterized in CD4⁺ T cells and monocyte-derived microglia. HIV DNA was observed in microglia-enriched fractions of all individuals, but intact proviruses were identified only in one ART-treated individual, representing 15% of the total proviruses. Phenotypic analyses of clones from this individual showed that 80% replicated efficiently in microglia and CD4⁺ T cells, while the remaining viruses replicated only in CD4⁺ T cells. No region-specific effects were observed. These results indicate a distinct HIV brain reservoir in microglia for all individuals, although intact proviruses were detected in only one. Given the unique immune environment of the CNS, the characteristics of microglia, and the challenges associated with targeting these cells, the CNS reservoir should be considered in cure strategies. Full article

Although combination antiretroviral therapy (ART) has been a landmark achievement for the treatment of human immunodeficiency virus (HIV), an HIV cure has remained elusive. Elimination of latent HIV reservoirs that persist throughout HIV infection is the most challenging barrier to an HIV cure. The progressive HIV infection is marked by the increasing size and diversity of latent HIV reservoirs until an effective immune response is mobilized, which can control but not eliminate HIV infection. The stalemate between HIV replication and the immune response is manifested by the establishment of a viral set point. ART initiation during the early stage limits HIV reservoir development, preserves immune function, improves the quality of life, and may lead to ART-free viral remission in a few people living with HIV (PLWH). However, for the overwhelming majority of PLWH, early ART initiation alone does not cure HIV, and lifelong ART is needed to sustain viral suppression. A critical area of research is focused on determining whether HIV could be functionally cured if additional treatments are provided alongside early ART. Several HIV interventions including Block and Lock, Shock and Kill, broadly neutralizing antibody (bNAb) therapy, adoptive CD8+ T cell therapy, and gene therapy have demonstrated delayed viral rebound and/or viral remission in animal models and/or some PLWH. Whether or not their application during early infection can improve the success of HIV remission is less studied. Herein, we review the current state of clinical and investigative HIV interventions and discuss their potential to improve the likelihood of post-treatment remission if initiated during early infection. Full article

The human immunodeficiency virus type 1 (HIV-1) epidemic has been a major public health threat on a global scale since the early 1980s. Despite the introduction of combination antiretroviral therapy (cART), the incidence of new HIV-1 infections continues to rise in some regions around the world. Thus, with the continuous transmission of HIV-1 and the lack of a cure, it is imperative for molecular epidemiological studies to be performed, to monitor the infection and ultimately be able to control the spread of this virus. This work provides a comprehensive molecular epidemiological analysis of the HIV-1 infection in Cyprus, through examining 305 HIV-1 sequences collected between 9 March 2017 and 14 October 2021. Employing advanced statistical and bioinformatic techniques, the research delved deeply into understanding the transmission dynamics of the HIV-1 epidemic in Cyprus, as well as the monitoring of HIV-1’s genetic diversity and the surveillance of transmitted drug resistance. The characterization of Cyprus’s HIV-1 epidemic revealed a diverse landscape, comprising 21 HIV-1 group M pure subtypes and circulating recombinant forms (CRFs), alongside numerous uncharacterized recombinant strains. Subtypes A1 and B emerged as the most prevalent strains, followed by CRF02_AG. The findings of this study also revealed high levels of transmitted drug resistance (TDR) patterns, raising concerns for the efficacy of cART. The demographic profiles of individuals involved in HIV-1 transmission underscored the disproportionate burden borne by young to middle-aged Cypriot males, particularly those in the MSM community, who reported contracting the virus in Cyprus. An assessment of the spatiotemporal evolutionary dynamics illustrated the global interconnectedness of HIV-1 transmission networks, implicating five continents in the dissemination of strains within Cyprus: Europe, Africa, Asia, North America, and Oceania. Overall, this study advances the comprehension of the HIV-1 epidemic in Cyprus and highlights the importance of understanding HIV-1’s transmission dynamics through continuous surveillance efforts. Furthermore, this work emphasizes the critical role of state-of-the-art bioinformatics analyses in addressing the challenges posed by HIV-1 transmission globally, laying the groundwork for public health interventions aimed at curbing its spread and improving patient outcomes. Full article

microRNAs have emerged as essential regulators of health and disease, attracting significant attention from researchers across diverse disciplines. Following their identification as noncoding oligonucleotides intricately involved in post-transcriptional regulation of protein expression, extensive efforts were devoted to elucidating and validating their roles in fundamental metabolic pathways and multiple pathologies. Viral infections are significant modifiers of the host microRNAome. Specifically, the Human Immunodeficiency Virus (HIV), which affects approximately 39 million people worldwide and has no definitive cure, was reported to induce significant changes in host cell miRNA profiles. Identifying and understanding the effects of the aberrant microRNAome holds potential for early detection and therapeutic designs. This review presents a comprehensive overview of the impact of HIV on host microRNAome. We aim to review the cause-and-effect relationship between the HIV-induced aberrant microRNAome that underscores miRNA’s therapeutic potential and acknowledge its limitations. Full article

Human Immunodeficiency Virus (HIV) remains a significant global health challenge with approximately 38 million people currently having the virus worldwide. Despite advances in treatment development, the virus persists in the human population and still leads to new infections. The virus has a powerful ability to mutate and hide from the human immune system in reservoirs of the body. Current standard treatment with antiretroviral therapy effectively controls viral replication but requires lifelong adherence and does not eradicate the virus. This review explores the potential of Advanced Therapy Medicinal Products as novel therapeutic approaches to HIV, including cell therapy, immunisation strategies and gene therapy. Cell therapy, particularly chimeric antigen receptor T cell therapy, shows promise in preclinical studies for targeting and eliminating HIV-infected cells. Immunisation therapies, such as broadly neutralising antibodies are being investigated to control viral replication and reduce reservoirs. Despite setbacks in recent trials, vaccines remain a promising avenue for HIV therapy development. Gene therapy using technologies like CRISPR/Cas9 aims to modify cells to resist HIV infection or eliminate infected cells. Challenges such as off-target effects, delivery efficiency and ethical considerations persist in gene therapy for HIV. Future directions require further research to assess the safety and efficacy of emerging therapies in clinical trials. Combined approaches may be necessary to achieve complete elimination of the HIV reservoir. Overall, advanced therapies offer new hope for advancing HIV treatment and moving closer to a cure. Full article

Background: Although antiretroviral therapy (ART) effectively halts disease progression in HIV infection, the complete eradication of the virus remains elusive. Additionally, challenges such as long-term ART toxicity, drug resistance, and the demanding regimen of daily and lifelong adherence required by ART highlight the imperative need for alternative therapeutic and preventative approaches. In recent years, broadly neutralizing antibodies (bNAbs) have emerged as promising candidates, offering potential for therapeutic, preventative, and possibly curative interventions against HIV infection. Objective: This review aims to provide a comprehensive overview of the current state of knowledge regarding the passive immunization of bNAbs in HIV-1-infected individuals. Main findings: Recent findings from clinical trials have highlighted the potential of bNAbs in the treatment, prevention, and quest for an HIV-1 cure. While monotherapy with a single bNAb is insufficient in maintaining viral suppression and preventing viral escape, ultimately leading to viral rebound, combination therapy with potent, non-overlapping epitope-targeting bNAbs have demonstrated prolonged viral suppression and delayed time to rebound by effectively restricting the emergence of escape mutations, albeit largely in individuals with bNAb-sensitive strains. Additionally, passive immunization with bNAb has provided a “proof of concept” for antibody-mediated prevention against HIV-1 acquisition, although complete prevention has not been obtained. Therefore, further research on the use of bNAbs in HIV-1 treatment and prevention remains imperative. Full article

Human Immunodeficiency Virus type 1 (HIV-1) latency represents a significant hurdle in finding a cure for HIV-1 infections, despite tireless research efforts. This challenge is partly attributed to the intricate nature of HIV-1 latency, wherein various host and viral factors participate in multiple physiological processes. While substantial progress has been made in discovering therapeutic targets for HIV-1 transcription, targets for the post-transcriptional regulation of HIV-1 infections have received less attention. However, cumulative evidence now suggests the pivotal contribution of post-transcriptional regulation to the viral latency in both in vitro models and infected individuals. In this review, we explore recent insights on post-transcriptional latency in HIV-1 and discuss the potential of its therapeutic targets, illustrating some host factors that restrict HIV-1 at the post-transcriptional level. Full article

Early gene therapy studies held great promise for the cure of heritable diseases, but the occurrence of various genotoxic events led to a pause in clinical trials and a more guarded approach to progress. Recent advances in genetic engineering technologies have reignited interest, leading to the approval of the first gene therapy product targeting genetic mutations in 2017. Gene therapy (GT) can be delivered either in vivo or ex vivo. An ex vivo approach to gene therapy is advantageous, as it allows for the characterization of the gene-modified cells and the selection of desired properties before patient administration. Autologous cells can also be used during this process which eliminates the possibility of immune rejection. This review highlights the various stages of ex vivo gene therapy, current research developments that have increased the efficiency and safety of this process, and a comprehensive summary of Human Immunodeficiency Virus (HIV) gene therapy studies, the majority of which have employed the ex vivo approach. Full article

Combination antiretroviral therapy (cART) has significantly improved the prognosis of individuals living with human immunodeficiency virus (HIV). Acquired immunodeficiency syndrome has transformed from a fatal disease to a treatable chronic infection. Currently, effective and safe anti-HIV drugs are available. Although cART can reduce viral production in the body of the patient to below the detection limit, it cannot eliminate the HIV provirus integrated into the host cell genome; hence, the virus will be produced again after cART discontinuation. Therefore, research into a cure (or remission) for HIV has been widely conducted. In this review, we focus on drug development targeting cells latently infected with HIV and assess the progress including our current studies, particularly in terms of the “Shock and Kill”, and “Block and Lock” strategies. Full article

The treatment of human immunodeficiency virus (HIV-1) has evolved since the establishment of combination antiretroviral therapy (ART) in the 1990s, providing HIV-infected individuals with approaches that suppress viral replication, prevent acquired immunodeficiency syndrome (AIDS) throughout their lifetime with continuous therapy, and halt HIV transmission. However, despite the success of these regimens, the global HIV epidemic persists, prompting a comprehensive exploration of potential strategies for an HIV cure. Here, we offer a consolidated overview of cell-based therapies for HIV-1, focusing on CAR-T cell approaches, gene editing, and immune modulation. Persistent challenges, including CAR-T cell susceptibility to HIV infection, stability, and viral reservoir control, underscore the need for continued research. This review synthesizes current knowledge, highlighting the potential of cellular therapies to address persistent challenges in the pursuit of an HIV cure. Full article

Infectious agents, notably viruses, can cause or increase the risk of cancer occurrences. These agents often disrupt normal cellular functions, promote uncontrolled proliferation and growth, and trigger chronic inflammation, leading to cancer. Approximately 20% of all cancer cases in humans are associated with an infectious pathogen. The International Agency for Research on Cancer (IARC) recognizes seven viruses as direct oncogenic agents, including Epstein–Barr Virus (EBV), Kaposi’s Sarcoma-associated herpesvirus (KSHV), human T-cell leukemia virus type-1 (HTLV-1), human papilloma virus (HPV), hepatitis C virus (HCV), hepatitis B virus (HBV), and human immunodeficiency virus type 1 (HIV-1). Most viruses linked to increased cancer risk are typically transmitted through contact with contaminated body fluids and high-risk behaviors. The risk of infection can be reduced through vaccinations and routine testing, as well as recognizing and addressing risky behaviors and staying informed about public health concerns. Numerous strategies are currently in pre-clinical phases or undergoing clinical trials for targeting cancers driven by viral infections. Herein, we provide an overview of risk factors associated with increased cancer incidence in people living with HIV (PLWH) as well as other chronic viral infections, and contributing factors such as aging, toxicity from ART, coinfections, and comorbidities. Furthermore, we highlight both antibody- and cell-based strategies directed against virus-induced cancers while also emphasizing approaches aimed at discovering cures or achieving complete remission for affected individuals. Full article