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1.
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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2.
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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3.
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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Influence of maternal use of tenofovir disoproxil fumarate or zidovudine in Vietnamese pregnant women with HIV on infant growth, renal function, and bone health.
Kinai, E, Nguyen, HDT, Do, HQ, Matsumoto, S, Nagai, M, Tanuma, J, Nguyen, KV, Pham, TN, Oka, S
PloS one. 2021;(4):e0250828
Abstract
Tenofovir disoproxil fumarate (TDF) is still widely prescribed for human immunodeficiency virus (HIV)-infected pregnant women, despite its renal and bone toxicity. Although TDF-exposed infants often show transient growth impairment, it is not clear whether maternal TDF causes infantile rickets via maternal/fetal renal dysfunction in Asian populations. This prospective observational study was conducted in Vietnam and involved pregnant HIV-infected women treated with TDF-based regimen (TDF group) or zidovudine-based regimen (AZT-group). At birth, 3, 12, and 18 months of age, and included body length, weight, head circumference, serum alkaline phosphatase (ALP), creatinine, calcium, phosphorus, urine-β2-microglobulin (U-BMG), percentage of tubular reabsorption of phosphate (%TRP), and radiographic wrist score for rickets. Age-adjusted multivariate linear regression analysis evaluated the association of TDF/AZT use during pregnancy with fetal renal function and bone health. The study included 63 mother-infant pairs (TDF group = 53, AZT group = 10). In the mothers, detectable U-BMG (>252 μg/L) was observed more frequently in the TDF- than AZT group (89 vs 50%, p<0.001), but other renal/bone parameters were similar. In infants, maternal TDF use was not associated with growth impairment, renal dysfunction, or abnormal bone findings, but with a slightly higher ALP levels (p = 0.019). However, shorter length was associated with maternal AZT (p = 0.021), and worse radiographic scores were associated with LPV/r (p = 0.024). In Vietnamese population, TDF usage during pregnancy was not associated with infant transient rickets, growth impairment, or renal dysfunction, despite mild maternal tubular impairment. Maternal AZT and LPV/r influenced infant growth and bone health, though further studies are needed to confirm this finding.
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Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells.
New-Aaron, M, Thomes, PG, Ganesan, M, Dagur, RS, Donohue, TM, Kusum, KK, Poluektova, LY, Osna, NA
Biomolecules. 2021;(10)
Abstract
Although the causes of hepatotoxicity among alcohol-abusing HIV patients are multifactorial, alcohol remains the least explored "second hit" for HIV-related hepatotoxicity. Here, we investigated whether metabolically derived acetaldehyde impairs lysosomes to enhance HIV-induced hepatotoxicity. We exposed Cytochrome P450 2E1 (CYP2E1)-expressing Huh 7.5 (also known as RLW) cells to an acetaldehyde-generating system (AGS) for 24 h. We then infected (or not) the cells with HIV-1ADA then exposed them again to AGS for another 48 h. Lysosome damage was assessed by galectin 3/LAMP1 co-localization and cathepsin leakage. Expression of lysosome biogenesis-transcription factor, TFEB, was measured by its protein levels and by in situ immunofluorescence. Exposure of cells to both AGS + HIV caused the greatest amount of lysosome leakage and its impaired lysosomal biogenesis, leading to intrinsic apoptosis. Furthermore, the movement of TFEB from cytosol to the nucleus via microtubules was impaired by AGS exposure. The latter impairment appeared to occur by acetylation of α-tubulin. Moreover, ZKSCAN3, a repressor of lysosome gene activation by TFEB, was amplified by AGS. Both these changes contributed to AGS-elicited disruption of lysosome biogenesis. Our findings indicate that metabolically generated acetaldehyde damages lysosomes and likely prevents their repair and restoration, thereby exacerbating HIV-induced hepatotoxicity.
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Adherence to a Supplemented Mediterranean Diet Drives Changes in the Gut Microbiota of HIV-1-Infected Individuals.
Pastor-Ibáñez, R, Blanco-Heredia, J, Etcheverry, F, Sánchez-Palomino, S, Díez-Fuertes, F, Casas, R, Navarrete-Muñoz, MÁ, Castro-Barquero, S, Lucero, C, Fernández, I, et al
Nutrients. 2021;(4)
Abstract
OBJECTIVE The health effects of a supplemented Mediterranean diet (SMD) with extra-virgin olive oil (EVOO) and nuts are well documented in non-HIV-infected individuals. We hypothesised that the benefits of an SMD could be mediated by changes in the gut microbiota, even in those with an altered intestinal microbiota such as people living with HIV. DESIGN Individuals living with HIV (n = 102) were randomised to receive an SMD with 50 g/day of EVOO and 30 g/day of walnuts (SMD group) or continue with their regular diet (control group) for 12 weeks. METHODS Adherence to the Mediterranean diet was assessed using the validated 14-item MD-Adherence-Screener (MEDAS) from the PREDIMED study. A sub-study classifying the participants according to their MEDAS scores was performed. RESULTS The lipid profile was improved in the SMD group vs. that in the control group (delta-total cholesterol and delta-B-lipoprotein). The immune activation (CD4+HLADR+CD38+ and CD8+HLADR+CD38+ cells) and IFN-γ-producing T-cells significantly decreased at week 12 compared to the baseline in the SMD group but not in the control group. The gut microbiota in those from the high-adherence group presented significantly high diversity and richness at the end of the intervention. Succinivibrio and Bifidobacterium abundances were influenced by the adherence to the MD and significantly correlated with Treg cells. CONCLUSION The Mediterranean diet improved metabolic parameters, immune activation, Treg function, and the gut microbiota composition in HIV-1-infected individuals. Further, Mediterranean diet increased the Bifidobacterium abundances after the intervention, and it was associated to a beneficial profile.
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Brief Report: Improvement in Metabolic Health Parameters at Week 48 After Switching From a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen to the 2-Drug Regimen of Dolutegravir/Lamivudine: The TANGO Study.
van Wyk, J, Ait-Khaled, M, Santos, J, Scholten, S, Wohlfeiler, M, Ajana, F, Jones, B, Nascimento, MC, Tenorio, AR, Smith, DE, et al
Journal of acquired immune deficiency syndromes (1999). 2021;(2):794-800
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Abstract
BACKGROUND In TANGO, switching to dolutegravir/lamivudine was noninferior at 48 weeks to continuing 3-/4-drug tenofovir alafenamide-based regimens in virologically suppressed individuals with HIV-1. Antiretroviral agents have been associated with weight gain and metabolic complications. SETTING One hundred thirty-four centers; 10 countries. METHODS We assessed weight; fasting lipids, glucose, and insulin; and prevalence of insulin resistance and metabolic syndrome at baseline and week 48 in TANGO participant subgroups by boosting agent use in baseline regimens (boosted and unboosted). RESULTS In each treatment group, 74% of participants used boosted regimens at baseline. In boosted and unboosted subgroups, weight and fasting glucose changes at week 48 were small and similar between treatment groups. Overall and in the boosted subgroup, greater decreases from baseline were observed with dolutegravir/lamivudine in fasting total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P < 0.001), triglycerides (P < 0.001), total cholesterol/high-density lipoprotein cholesterol ratio (overall, P = 0.017; boosted, P = 0.007), and insulin (boosted, P = 0.005). Prevalence of HOMA-IR ≥2 was significantly lower at week 48 with dolutegravir/lamivudine overall [adjusted odds ratio (aOR), 0.59; 95% confidence interval (CI), 0.40 to 0.87; P = 0.008] and in the boosted subgroup [aOR, 0.56; 95% CI, 0.36 to 0.88; P = 0.012] but not in the unboosted subgroup [aOR, 0.70; 95% CI, 0.31 to 1.58; P = 0.396]. Prevalence of metabolic syndrome at week 48 was low and consistent between treatment groups overall, with differences trending to favor dolutegravir/lamivudine in the unboosted subgroup [aOR, 0.41; 95% CI, 0.15 to 1.09; P = 0.075]. CONCLUSION Generally, switching from 3-/4-drug tenofovir alafenamide-based regimens to dolutegravir/lamivudine improved metabolic parameters, particularly when switching from boosted regimens. Because of smaller sample size in the unboosted subgroup, results warrant further investigation.
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Impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in a randomized clinical trial.
Stranix-Chibanda, L, Tierney, C, Sebikari, D, Aizire, J, Dadabhai, S, Zanga, A, Mukwasi-Kahari, C, Vhembo, T, Violari, A, Theron, G, et al
PloS one. 2021;(2):e0246272
Abstract
OBJECTIVES We set out to evaluate the effect of postnatal exposure to tenofovir-containing antiretroviral therapy on bone mineral density among breastfeeding women living with HIV. DESIGN IMPAACT P1084s is a sub-study of the PROMISE randomized trial conducted in four African countries (ClinicalTrials.gov number NCT01066858). METHODS IMPAACT P1084s enrolled eligible mother-infant pairs previously randomised in the PROMISE trial at one week after delivery to receive either maternal antiretroviral therapy (Tenofovir disoproxil fumarate / Emtricitabine + Lopinavir/ritonavir-maternal TDF-ART) or administer infant nevirapine, with no maternal antiretroviral therapy, to prevent breastmilk HIV transmission. Maternal lumbar spine and hip bone mineral density were measured using dual-energy x-ray absorptiometry (DXA) at postpartum weeks 1 and 74. We studied the effect of the postpartum randomization on percent change in maternal bone mineral density in an intention-to-treat analysis with a t-test; mean and 95% confidence interval (95%CI) are presented. RESULTS Among 398/400 women included in this analysis, baseline age, body-mass index, CD4 count, mean bone mineral density and alcohol use were comparable between study arms. On average, maternal lumbar spine bone mineral density declined significantly through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference (95%CI) -2.86 (-4.03, -1.70) percentage points (p-value <0.001). Similarly, maternal hip bone mineral density declined significantly more through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference -2.29% (-3.20, -1.39) (p-value <0.001). Adjusting for covariates did not change the treatment effect. CONCLUSIONS Bone mineral density decline through week 74 postpartum was greater among breastfeeding HIV-infected women randomized to receive maternal TDF-ART during breastfeeding compared to those mothers whose infants received nevirapine prophylaxis.
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Nef Obtained from Individuals with HIV-1 Vary in Their Ability to Antagonize SERINC3- and SERINC5-Mediated HIV-1 Restriction.
Kruize, Z, van Nuenen, AC, van Wijk, SW, Girigorie, AF, van Dort, KA, Booiman, T, Kootstra, NA
Viruses. 2021;(3)
Abstract
Nef is a multifunctional viral protein that has the ability to downregulate cell surface molecules, including CD4 and major histocompatibility complex class I (MHC-I) and, as recently shown, also members of the serine incorporator family (SERINC). Here, we analyzed the impact of naturally occurring mutations in HIV-1 Nef on its ability to counteract SERINC restriction and the clinical course of infection. HIV-1 Nef sequences were obtained from 123 participants of the Amsterdam Cohort Studies and showed multiple amino acid variations and mutations. Most of the primary Nef proteins showed increased activity to counteract SERINC3 and SERINC5 as compared to NL4-3 Nef. Several mutations in Nef were associated with either an increased or decreased infectivity of Bal26-pseudotyped HIV-1 produced in the presence of SERINC3 or SERINC5. The 8R, 157N and R178G Nef mutations were shown to have an effect on disease progression. Survival analysis showed an accelerated disease progression of individuals infected with HIV-1 carrying arginine or asparagine at position 8 or 157 in Nef, respectively, or the R178G Nef mutation. Here, we observed that naturally occurring mutations in Nef affect the ability of Nef to counteract SERINC3- and SERINC5-mediated inhibition of viral infectivity. The majority of these Nef mutations had no significant effect on HIV-1 pathogenesis and only the 8R, 157N and R178G mutations were associated with disease course.
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Brief Report: Impact of ART on Maternal Health After Cessation of Breastfeeding.
Brummel, SS, Taha, TE, Angelidou, KN, Saidi, F, Atuhaire, P, Dula, D, Moodley, D, Matubu, A, Chareka, G, Nevrekar, N, et al
Journal of acquired immune deficiency syndromes (1999). 2021;(4):450-454
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Abstract
IMPAACT PROMISE 1077BF/FF was a sequentially randomized study of pregnant and postpartum women living with HIV to investigate the efficacy and safety of antiretroviral therapy (ART). This Maternal Health Component investigated efficacy for the risk of developing AIDS or death; and safety among women randomized to continue ART (CTART N = 289) or discontinue ART (N = 268) after cessation of breastfeeding or after confirmation of infant infection. No AIDS-defining illnesses were reported during follow-up in either arm. Adverse events of grade 3 or higher were more frequent in the CTART arm [hazard ratio = 1.78, 95% confidence interval: (1.05 to 3.02), P-value = 0.03]. The difference in adverse events in the 2 groups was mostly driven by moderate weight loss for women on the CTART arm.