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1.
Anti-HIV antibody development up to 1 year after antiretroviral therapy initiation in acute HIV infection.
Mitchell, JL, Pollara, J, Dietze, K, Edwards, RW, Nohara, J, N'guessan, KF, Zemil, M, Buranapraditkun, S, Takata, H, Li, Y, et al
The Journal of clinical investigation. 2022;(1)
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Abstract
Early initiation of antiretroviral therapy (ART) in acute HIV infection (AHI) is effective at limiting seeding of the HIV viral reservoir, but little is known about how the resultant decreased antigen load affects long-term Ab development after ART. We report here that Env-specific plasma antibody (Ab) levels and Ab-dependent cellular cytotoxicity (ADCC) increased during the first 24 weeks of ART and correlated with Ab levels persisting after 48 weeks of ART. Participants treated in AHI stage 1 had lower Env-specific Ab levels and ADCC activity on ART than did those treated later. Importantly, participants who initiated ART after peak viremia in AHI developed elevated cross-clade ADCC responses that were detectable 1 year after ART initiation, even though clinically undetectable viremia was reached by 24 weeks. These data suggest that there is more germinal center (GC) activity in the later stages of AHI and that Ab development continues in the absence of detectable viremia during the first year of suppressive ART. The development of therapeutic interventions that can enhance earlier development of GCs in AHI and Abs after ART initiation could provide important protection against the viral reservoir that is seeded in individuals treated early in the disease.
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2.
Engineered Zinc Finger Protein Targeting 2LTR Inhibits HIV Integration in Hematopoietic Stem and Progenitor Cell-Derived Macrophages: In Vitro Study.
Chupradit, K, Khamaikawin, W, Sakkhachornphop, S, Puaninta, C, Torbett, BE, Borwornpinyo, S, Hongeng, S, Wattanapanitch, M, Tayapiwatana, C
International journal of molecular sciences. 2022;(4)
Abstract
Human hematopoietic stem/progenitor cell (HSPC)-based gene therapy is a promising direction for curing HIV-1-infected individuals. The zinc finger protein (2LTRZFP) designed to target the 2-LTR-circle junction of HIV-1 cDNA was previously reported as an intracellular antiviral molecular scaffold that prevents HIV integration. Here, we elucidate the efficacy and safety of using 2LTRZFP in human CD34+ HSPCs. We transduced 2LTRZFP which has the mCherry tag (2LTRZFPmCherry) into human CD34+ HSPCs using a lentiviral vector. The 2LTRZFPmCherry-transduced HSPCs were subsequently differentiated into macrophages. The expression levels of pro-apoptotic proteins of the 2LTRZFPmCherry-transduced HSPCs showed no significant difference from those of the non-transduced control. Furthermore, the 2LTRZFPmCherry-transduced HSPCs were successfully differentiated into mature macrophages, which had normal phagocytic function. The cytokine secretion assay demonstrated that 2LTRZFPmCherry-transduced CD34+ derived macrophages promoted the polarization towards classically activated (M1) subtypes. More importantly, the 2LTRZFPmCherry transduced cells significantly exhibited resistance to HIV-1 integration in vitro. Our findings demonstrate that the 2LTRZFPmCherry-transduced macrophages were found to be functionally and phenotypically normal, with no adverse effects of the anti-HIV-1 scaffold. Our data suggest that the anti-HIV-1 integrase scaffold is a promising antiviral molecule that could be applied to human CD34+ HSPC-based gene therapy for AIDS patients.
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3.
Cholesterol-Mediated Clustering of the HIV Fusion Protein gp41 in Lipid Bilayers.
Tran, N, Oh, Y, Sutherland, M, Cui, Q, Hong, M
Journal of molecular biology. 2022;(2):167345
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Abstract
The envelope glycoprotein (Env) of the human immunodeficient virus (HIV-1) is known to cluster on the viral membrane surface to attach to target cells and cause membrane fusion for HIV-1 infection. However, the molecular structural mechanisms that drive Env clustering remain opaque. Here, we use solid-state NMR spectroscopy and molecular dynamics (MD) simulations to investigate nanometer-scale clustering of the membrane-proximal external region (MPER) and transmembrane domain (TMD) of gp41, the fusion protein component of Env. Using 19F solid-state NMR experiments of mixed fluorinated peptides, we show that MPER-TMD trimers form clusters with interdigitated MPER helices in cholesterol-containing membranes. Inter-trimer 19F-19F cross peaks, which are indicative of spatial contacts within ∼2 nm, are observed in cholesterol-rich virus-mimetic membranes but are suppressed in cholesterol-free model membranes. Water-peptide and lipid-peptide cross peaks in 2D 1H-19F correlation spectra indicate that the MPER is well embedded in model phosphocholine membranes but is more exposed to the surface of the virus-mimetic membrane. These experimental results are reproduced in coarse-grained and atomistic molecular dynamics simulations, which suggest that the effects of cholesterol on gp41 clustering is likely via indirect modulation of the MPER orientation. Cholesterol binding to the helix-turn-helix region of the MPER-TMD causes a parallel orientation of the MPER with the membrane surface, thus allowing MPERs of neighboring trimers to interact with each other to cause clustering. These solid-state NMR data and molecular dynamics simulations suggest that MPER and cholesterol cooperatively govern the clustering of gp41 trimers during virus-cell membrane fusion.
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4.
Detecting Selection in the HIV-1 Genome during Sexual Transmission Events.
Seifert, D, Joos, B, Braun, DL, Oberle, CS, Schenkel, CD, Kuster, H, Grube, C, Böni, J, Yerly, S, Aubert, V, et al
Viruses. 2022;(2)
Abstract
Little is known about whether and how variation in the HIV-1 genome affects its transmissibility. Assessing which genomic features of HIV-1 are under positive or negative selection during transmission is challenging, because very few virus particles are typically transmitted, and random genetic drift can dilute genetic signals in the recipient virus population. We analyzed 30 transmitter-recipient pairs from the Zurich Primary HIV Infection Study and the Swiss HIV Cohort Study using near full-length HIV-1 genomes. We developed a new statistical test to detect selection during transmission, called Selection Test in Transmission (SeTesT), based on comparing the transmitter and recipient virus population and accounting for the transmission bottleneck. We performed extensive simulations and found that sensitivity of detecting selection during transmission is limited by the strong population bottleneck of few transmitted virions. When pooling individual test results across patients, we found two candidate HIV-1 genomic features for affecting transmission, namely amino acid positions 3 and 18 of Vpu, which were significant before but not after correction for multiple testing. In summary, SeTesT provides a general framework for detecting selection based on genomic sequencing data of transmitted viruses. Our study shows that a higher number of transmitter-recipient pairs is required to improve sensitivity of detecting selection.
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HIV-1 integrase strand transfer inhibitors: a review of current drugs, recent advances and drug resistance.
Mbhele, N, Chimukangara, B, Gordon, M
International journal of antimicrobial agents. 2021;(5):106343
Abstract
Antiretroviral therapy has been imperative in controlling the human immunodeficiency virus (HIV) epidemic. Most low- and middle-income countries have used nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors extensively in the treatment of HIV. However, integrase strand transfer inhibitors (INSTIs) are becoming more common. Since their identification as a promising therapeutic drug, significant progress has been made that has led to the approval of five INSTIs by the US Food and Drug Administration (FDA), i.e. dolutegravir (DTG), raltegravir (RAL), elvitegravir (EVG), bictegravir (BIC) and cabotegravir (CAB). INSTIs have been shown to effectively halt HIV-1 replication and are commended for having a higher genetic barrier to resistance compared with NRTIs and NNRTIs. More interestingly, DTG has shown a higher genetic barrier to resistance compared with RAL and EVG, and CAB is being used as the first long-acting agent in HIV-1 treatment. Considering the increasing interest in INSTIs for HIV-1 treatment, we focus our review on the retroviral integrase, development of INSTIs and their mode of action. We also discuss each of the INSTI drugs, including potential drug resistance and known side effects.
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Search for new therapeutics against HIV-1 via dual inhibition of RNase H and integrase: current status and future challenges.
Kharkwal, H, Kumar, BK, Murugesan, S, Singhvi, G, Avasthi, P, Goyal, A, Jamalis, J, Chander, S
Future medicinal chemistry. 2021;(3):269-286
Abstract
Reverse transcriptase and integrase are key enzymes that play a pivotal role in HIV-1 viral maturation and replication. Reverse transcriptase consists of two active sites: RNA-dependent DNA polymerase and RNase H. The catalytic domains of integrase and RNase H share striking similarity, comprising two aspartates and one glutamate residue, also known as the catalytic DDE triad, and a Mg2+ pair. The simultaneous inhibition of reverse transcriptase and integrase can be a rational drug discovery approach for combating the emerging drug resistance problem. In the present review, the dual inhibition of RNase H and integrase is systematically discussed, including rationality of design, journey of development, advancement and future perspective.
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Reversal of Viral Latency and Induction of Gag-Specific T-Cell Responses in HIV-1-Infected Adults Through Cyclic Treatment Interruption of Rosuvastatin: A Proof-of-Concept Study.
Hsieh, SM, Pan, SC, Huang, YS, Chang, SC
Journal of acquired immune deficiency syndromes (1999). 2021;(4):500-508
Abstract
BACKGROUND HIV-1 infection remains incurable through combination antiretroviral therapy. Previous studies have shown statins have immunomodulatory effects, and interruption of statins may cause an immune rebound. METHODS In this proof-of-concept study, we longitudinally assessed the impact of immune rebound by cyclic treatment-interruption (CTI) of rosuvastatin on the reversal of HIV latency. The HIV-1-infected persons with stable viral control were considered to be enrolled for CTI of rosuvastatin with a fixed 12-week interval for 72 weeks (3 treatment-interruption cycles). HIV-1 Gag-specific T-cell responses, cell-associated RNA, and proviral DNA were determined. RESULTS From Feb 2017 to Dec 2019, 10 subjects were enrolled. During the 72-week follow-up, their CD4+ T-cell counts did not significantly change, and plasma HIV RNA remained undetectable. Transient but remarkable increases in levels of cell-associated RNA, Gag-specific interferon-γ production from CD4+ T cells and Gag-specific CD8+ cytotoxic capacity were detected shortly after stopping rosuvastatin in every cycle of CTI of rosuvastatin. Furthermore, there was a 2.63-fold reduction (range, 1.41-4.82) in proviral DNA levels (P = 0.005) during the 72-week follow-up. A significant linear association was demonstrated between their nadir CD4+ T-cell counts and the fold decrease in proviral DNA levels (R = 0.81, P = 0.004). CONCLUSION It may be possible to reverse viral latency in CD4+ T cells, activate Gag-specific T cells, and reduce viral reservoir size through CTI of rosuvastatin in HIV-1-infected subjects with stable combination antiretroviral therapy, especially in those with nadir CD4+ T-cell counts > 350 cells/μL.
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Brief Report: Efficacy and Safety of Bictegravir/Emtricitabine/Tenofovir Alafenamide in Females Living With HIV: An Integrated Analysis of 5 Trials.
Orkin, C, Ajana, F, Kityo, C, Koenig, E, Natukunda, E, Gandhi-Patel, B, Wang, H, Liu, Y, Wei, X, White, K, et al
Journal of acquired immune deficiency syndromes (1999). 2021;(4):393-398
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Abstract
BACKGROUND We characterized the efficacy and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in a broad population of pediatric/adolescent/adult/elderly females living with HIV (FWH). SETTING Integrated analysis. METHODS Available data from 5 trials were integrated. Week 48 virologic suppression (HIV-1 RNA <50 copies/mL), resistance, adverse events (AEs), and laboratory parameters were assessed. RESULTS Three hundred and seventy-three FWH [304 virologically suppressed; 69 antiretroviral therapy (ART)-naive] received B/F/TAF [data from comparator regimens available for 306 individuals (236 virologically suppressed and 70 ART-naive participants)]. Virologic suppression rates with B/F/TAF at week 48 were high regardless of age in participants virologically suppressed at baseline (≥95%) and in ART-naive participants (≥87%). Virologic suppression rates were similar in B/F/TAF and comparator regimens (both virologically suppressed and ART-naive groups). Treatment-emergent resistance was not detected in the B/F/TAF group. AEs considered related to study drugs were experienced by 9.2% (B/F/TAF) and 5.5% (comparator regimen) of virologically suppressed participants and 15.9% (B/F/TAF) and 31.4% (comparator regimen) of ART-naive participants. For virologically suppressed and ART-naive FWH combined, only 1 of the 373 B/F/TAF-treated and 2 of the 306 comparator-regimen participants discontinued because of AEs (none were bone/renal/hepatic AEs); grade 3/4 AEs were experienced by 5.1% (B/F/TAF) and 7.8% (comparator regimen); and grade 3/4 elevation of low-density lipoprotein/total cholesterol occurred in 2.7%/0.3% (B/F/TAF) and 5.9%/2.0% (comparator regimen). At week 48, median changes from baseline estimated glomerular filtration rate in adults were <5 mL/min; results were similar in B/F/TAF and comparator-regimen groups. CONCLUSION B/F/TAF treatment was effective and well tolerated over 48 weeks, confirming B/F/TAF as an option for a broad population of FWH.
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HIV-1 Envelope Spike MPER: From a Vaccine Target to a New Druggable Pocket for Novel and Effective Fusion Inhibitors.
Luque, FJ, Camarasa, MJ
ChemMedChem. 2021;(1):105-107
Abstract
Here we highlight a sound and unique work reported by Chen and co-workers entitled "HIV-1 fusion inhibitors targeting the membrane-proximal external region of Env spikes" (Xiao et al., Nat. Chem. Biol. 2020, 16, 529). In this article, the authors identify, by means of a clever antibody-guided strategy, several small molecules as fusion inhibitors of HIV-1 replication acting at the membrane proximal external region (MPER) of the HIV-1 envelope (Env) spike. MPER, which was previously recognized as a vaccine target, emerges as a novel druggable target for the discovery of HIV-1 fusion inhibitors. The compounds (exemplified by dequalinium and dequalinium-inspired analogues) prevent the conformational changes of Env from the prefusion species to the intermediate states required for membrane fusion. This work not only paves the way to novel, specific and useful anti-HIV-1 inhibitors, but also discloses new therapeutic strategies against other infectious diseases.
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A Structural Perspective of the Role of IP6 in Immature and Mature Retroviral Assembly.
Obr, M, Schur, FKM, Dick, RA
Viruses. 2021;(9)
Abstract
The small cellular molecule inositol hexakisphosphate (IP6) has been known for ~20 years to promote the in vitro assembly of HIV-1 into immature virus-like particles. However, the molecular details underlying this effect have been determined only recently, with the identification of the IP6 binding site in the immature Gag lattice. IP6 also promotes formation of the mature capsid protein (CA) lattice via a second IP6 binding site, and enhances core stability, creating a favorable environment for reverse transcription. IP6 also enhances assembly of other retroviruses, from both the Lentivirus and the Alpharetrovirus genera. These findings suggest that IP6 may have a conserved function throughout the family Retroviridae. Here, we discuss the different steps in the viral life cycle that are influenced by IP6, and describe in detail how IP6 interacts with the immature and mature lattices of different retroviruses.