Efficacy and safety of raltegravir plus lamivudine maintenance therapy.

BACKGROUND: Decreasing medication burden with raltegravir plus lamivudine in virologically suppressed persons with HIV (PWH) maintained efficacy and was well tolerated at 24 weeks, but more comprehensive data over longer follow-up are required. METHODS: Prospective 48 week extension phase of the raltegravir plus lamivudine arm from a previous 24 week pilot randomized clinical trial in which virologically suppressed PWH were randomized 2:1 to switch to fixed-dose combination 150 mg lamivudine/300 mg raltegravir twice daily or to continue therapy. In this 48 week extension phase, raltegravir was dosed at 1200 mg/day and lamivudine 300 mg/day. Primary outcome was the proportion of PWH with treatment failure at Week 48. Secondary outcomes were changes in ultrasensitive plasma HIV RNA, HIV DNA in CD4 cells, serum IL-6, ultrasensitive C-reactive protein and sCD14, body composition, sleep quality, quality of life and adverse effects. RESULTS: Between May 2018 and June 2019, 33 PWH were enrolled. One participant experienced virological failure without resistance mutations and re-achieved sustained virological suppression without therapy discontinuation, and two others discontinued therapy due to adverse effects. Treatment failure was 9% (95% CI 2%-24%) and 3% (95% CI 0%-17%) in the ITT and on-treatment populations. There were significant changes between baseline and Week 48 in serum cytokines but not in other secondary outcomes. CONCLUSIONS: Switching to raltegravir and lamivudine in PWH with virological suppression maintains efficacy and is well tolerated. This maintenance regimen might be a cost-effective option for PWH at risk of drug-drug interactions or needing to avoid specific toxicities of certain antiretroviral drugs or their negative impact on comorbidities.

Exploring the HIV-1 Rev Recognition Element (RRE)-Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs.

Human immunodeficiency virus-type 1 (HIV-1) remains one of the leading contributors to the global burden of disease, and novel antiretroviral agents with alternative mechanisms are needed to cure this infection. Here, we describe an exploratory attempt to optimize the antiretroviral properties of benfluron, a cytostatic agent previously reported to exhibit strong anti-HIV activity likely based on inhibitory actions on virus transcription and Rev-mediated viral RNA export. After obtaining six analogs designed to modify the benzo[c]fluorenone system of the parent molecule, we examined their antiretroviral and toxicity properties together with their capacity to recognize the Rev Recognition Element (RRE) of the virus RNA and inhibit the RRE-Rev interaction. The results indicated that both the benzo[c] and cyclopentanone components of benfluron are required for strong RRE-Rev target engagement and antiretroviral activity and revealed the relative impact of these moieties on RRE affinity, RRE-Rev inhibition, antiviral action and cellular toxicity. These data provide insights into the biological properties of the benzo[c]fluorenone scaffold and contribute to facilitating the design of new anti-HIV agents based on the inhibition of Rev function.

Novel HIV-1 RNA biogenesis inhibitors identified by virtual pharmacophore-based screening.

The complex between the Rev protein of HIV-1 and the Rev Recognition Element (RRE) within the virus RNA promotes nuclear export of unspliced or incompletely spliced viral transcripts and is required for virus transmission. Here, we have screened a virtual collection of compounds using a pharmacophore based on the chemical similarity of previously characterized inhibitors to identify new chemical scaffolds blocking the RRE-Rev interaction. The best molecules discovered with this strategy inhibited the complex by binding to the RRE and exhibited substantial antiretroviral activity (between 0.582 and 11.3 µM EC50 values) likely associated to inhibitory actions on viral transcription and Rev function. These results have allowed us to identify structural features required for RRE-Rev inhibition as well as to add new compounds to the pool of possible candidates for developing antiretroviral agents based on blockage of HIV-1 RNA biogenesis.

Persistent Immunity against SARS-CoV-2 in Individuals with Oncohematological Diseases Who Underwent Autologous or Allogeneic Stem Cell Transplantation after Vaccination.

The high morbimortality due to SARS-CoV-2 infection in oncohematological diseases (OHD) and hematopoietic stem cell transplant (HSCT) recipients in the pre-vaccine era has made vaccination a priority in this group. After HSCT, the immune responses against common vaccines such as tetanus, varicella, rubella, and polio may be lost. However, the loss of immunity developed by COVID-19 vaccination after HSCT has not been completely defined. In this study, both humoral and cellular immunity against SARS-CoV-2 were analyzed in 29 individuals with OHD who were vaccinated before receiving allogeneic (n = 11) or autologous (n = 18) HSCT. All participants had low but protective levels of neutralizing IgGs against SARS-CoV-2 after HSCT despite B-cell lymphopenia and immaturity. Although antibody-dependent cellular cytotoxicity was impaired, direct cellular cytotoxicity was similar to healthy donors in participants with autologous-HSCT, in contrast to individuals with allogeneic-HSCT, which severely deteriorated. No significant changes were observed in the immune response before and after HSCT. During follow-up, all reported post-HSCT SARS-CoV-2 infections were mild. This data emphasizes that COVID-19 vaccination is effective, necessary, and safe for individuals with OHD and also supports the persistence of some degree of immune protection after HSCT, at least in the short term, when patients cannot yet be revaccinated.

Immunomodulatory Activity of the Tyrosine Kinase Inhibitor Dasatinib to Elicit NK Cytotoxicity against Cancer, HIV Infection and Aging.

Tyrosine kinase inhibitors (TKIs) have been extensively used as a treatment for chronic myeloid leukemia (CML). Dasatinib is a broad-spectrum TKI with off-target effects that give it an immunomodulatory capacity resulting in increased innate immune responses against cancerous cells and viral infected cells. Several studies reported that dasatinib expanded memory-like natural killer (NK) cells and γδ T cells that have been related with increased control of CML after treatment withdrawal. In the HIV infection setting, these innate cells are associated with virus control and protection, suggesting that dasatinib could have a potential role in improving both the CML and HIV outcomes. Moreover, dasatinib could also directly induce apoptosis of senescence cells, being a new potential senolytic drug. Here, we review in depth the current knowledge of virological and immunogenetic factors associated with the development of powerful cytotoxic responses associated with this drug. Besides, we will discuss the potential therapeutic role against CML, HIV infection and aging.

Longer intervals between SARS-CoV-2 infection and mRNA-1273 doses improve the neutralization of different variants of concern.

The humoral immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern elicited by vaccination was evaluated in COVID-19 recovered individuals (Rec) separated 1-3 months (Rec2m) or 4-12 months (Rec9m) postinfection and compared to the response in naïve participants. Antibody-mediated immune responses were assessed in 66 participants by three commercial immunoassays and a SARS-CoV-2 lentiviral-based pseudovirus neutralization assay. Immunoglobulin (Ig) levels against SARS-CoV-2 spike were lower in naïve participants after two doses than in Rec after a single dose (p < 0.05). After two doses in Rec, levels of total Ig to receptor-binding domain were significantly increased in Rec9m compared to Rec2m (p < 0.001). The neutralizing potency observed in Rec9m was consistently higher than in Rec2m against variants of concern (VOCs) Alpha, Beta, Delta, and BA.1 sublineage of Omicron with 2.2-2.8-fold increases. Increasing the interval between SARS-CoV-2 infection and the vaccination with messenger RNA-based vaccines to more than 3 months generates a more efficient heterologous humoral immune response against VOCs by allowing enough time to mount a strong recall memory B cell response.

Treatment with integrase inhibitors alters SARS-CoV-2 neutralization levels measured with HIV-based pseudotypes in people living with HIV.

The presence of neutralizing antibodies (NAbs) is a major correlate of protection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Thus, different in vitro pseudoviruses-based assays have been described to detect NAbs against SARS-CoV-2. However, the determination of NAbs against SARS-CoV-2 in people living with HIV (PLWH) through HIV-based pseudoparticles could be influenced by cross-neutralization activity or treatment, impeding accurate titration of NAbs. Two assays were compared using replication-defective HIV or VSV-based particles pseudotyped with SARS-CoV-2 spike to measure NAbs in COVID-19-recovered and COVID-19-naïve PLWH. The assay based on HIV-pseudoparticles displayed neutralization activity in all COVID-19-recovered PLWH with a median neutralizing titer 50 (NT50) of 1417.0 (interquartile range [IQR]: 450.3-3284.0), but also in 67% of COVID-19-naïve PLWH (NT50: 631.5, IQR: 16.0-1535.0). Regarding VSV-pseudoparticles system, no neutralization was observed in COVID-19-naïve PLWH as expected, whereas in comparison with HIV-pseudoparticles assay lower neutralization titers were measured in 75% COVID-19-recovered PLWH (NT50: 100.5; IQR: 20.5-1353.0). Treatment with integrase inhibitors was associated with inaccurate increase in neutralization titers when HIV-based pseudoparticles were used. IgG purification and consequent elimination of drugs from samples avoided the interference with retroviral cycle and corrected the lack of specificity observed in HIV-pseudotyped assay. This study shows methodological alternatives based on pseudoviruses systems to determine specific SARS-CoV-2 neutralization titers in PLWH.

Pharmacokinetics, the Immunological Impact, and the Effect on HIV Ex-Vivo Infectivity of Maraviroc, Raltegravir, and Lopinavir in Men Who Have Sex with Men Using Postexposure Prophylaxis.

Most of the studies using the colorectal tissue explants challenge model have been conducted after one single dose and before reaching a steady state. We consider that longer exposure as in 28-day postexposure prophylaxis (PEP) course and in an at-risk setting, such as after a sexual risk exposure to HIV could give us valuable information about these drugs. In a substudy we assessed pharmacokinetics, changes on immune system and ex-vivo rectal mucosal susceptibility to HIV-1 infection after taking maraviroc (MVC), raltegravir (RAL), and ritonavir-boosted lopinavir (LPV/r) PEP-based regimens in 30 men who have sex with men. Participants received 28 days of twice-daily MVC (n = 11), RAL (n = 10) or LPV/r (n = 9) all with tenofovir/emtricitabine (TDF/FTC) backbone. Blood, rectal fluid, and rectal tissue samples were collected at days 7, 28, and 90 after starting PEP. The samples obtained at day 90 were considered baseline. All studied antiretrovirals were quantifiable at 7 and 28 days in all tissues. Activation markers were increased in CD4 mucosal mononuclear cells (MMCs) after 28 days of MVC: CD38 + 68.5 versus 85.1, p = .008 and CD38+DR +16.1 versus 26.7, p = .008. Exposure to MVC at both endpoints (7 and 28 days) was associated with significant suppression of HIV-1BAL (p = .005 and p = .028), but we did not observe this effect with RAL or LPV/r. Merging together changes in MMC in all arms, we found a positive correlation in the CD8 T cell lineage between the infectivity at day 7 and activation (CD38+ r = 0.43, p = .025, DR + r = 0.547, p = .003 and 38+DR+ r = 0.526, p = .05), senescence (CD57+CD28- r = 0.479, p = .012), naive cells (RA+CCR7+ r = 0.484, p = .01), and CCR5 expression (r = 0.593, p = .001). We conclude that MVC in combination with TDF/FTC was associated with viral suppression in rectal explants and that overall ex-vivo HIV infectivity correlated with activation and senescence in CD8 MMCs.

Immunological and virological findings in a patient with exceptional post-treatment control: a case report.

BACKGROUND: Although antiretroviral therapy (ART) is effective in suppressing viral replication, HIV-1 persists in reservoirs and rebounds after ART has been stopped. However, a very few people (eg, elite and post-treatment controllers) are able to maintain viral loads below detection limits without ART, constituting a realistic model for long-term HIV remission. Here, we describe the HIV control mechanisms of an individual who showed exceptional post-treatment control for longer than 15 years. METHODS: We report the case of a Hispanic woman aged 59 years with sexually acquired acute HIV infection, who was included in an immune-mediated primary HIV infection trial involving a short course of ciclosporine A, interleukin-2, granulocyte macrophage colony-stimulating factor, and pegylated interferon alfa, followed by analytical treatment interruption. We did the following viral assays: total and integrated HIV-1 DNA in CD4 T cells and rectal tissue, quantitative viral outgrowth assay, HIV-1 infectivity in peripheral blood mononuclear cells and CD4 T-cell cultures and viral inhibitory activity by natural killer (NK) and CD8 T cells. NK and T-cell phenotypes were determined by flow cytometry. HLA, killer cell immunoglobulin-like receptors, Δ32CCR5, and NKG2C alleles were genotyped. FINDINGS: After ART and immunomodulatory treatment, the person maintained undetectable plasma viral load for 15 years. HIV-1 subtype was CFR_02AG, CCR5-tropic. We found progressive reductions in viral reservoir during the 15-year treatment interruption: total HIV DNA (from 4573·50 copies per 106 CD4 T cells to 95·33 copies per 106 CD4 T cells) and integrated DNA (from 85·37 copies per 106 CD4 T cells to 5·25 copies per 106 CD4 T cells). Viral inhibition assays showed strong inhibition of in vitro HIV replication in co-cultures of CD4 T cells with autologous NK or CD8 T cells at 1:2 ratio (75% and 62%, respectively). Co-cultures with NK and CD8 T cells resulted in 93% inhibition. We detected higher-than-reference levels of both NKG2C-memory-like NK cells (46·2%) and NKG2C γδ T cells (64·9%) associated with HIV-1 control. INTERPRETATION: We described long-term remission in a woman aged 59 years who was treated during primary HIV infection and has maintained undetectable viral load for 15 years without ART. Replication-competent HIV-1 was isolated. NKG2C-memory-like NK cells and γδ T cells were associated with the control viral replication. Strategies promoting these cells could bring about long-term HIV remission. FUNDING: Fondo Europeo para el Desarrollo Regional (FEDER), SPANISH AIDS Research Network (RIS), Fondo de Investigación Sanitaria (FIS), HIVACAT, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CERCA Programme/Generalitat de Catalunya, la Caixa Foundation, and Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC). TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Genetic Study of SARS-CoV-2 Non Structural Protein 12 in COVID-19 Patients Non Responders to Remdesivir.

Remdesivir (RDV) was the first antiviral drug approved by the FDA to treat severe coronavirus disease-2019 (COVID-19) patients. RDV inhibits SARS-CoV-2 replication by stalling the non structural protein 12 (nsp12) subunit of the RNA-dependent RNA polymerase (RdRp). No evidence of global widespread RDV-resistance mutations has been reported, however, defining genetic pathways to RDV resistance and determining emergent mutations prior and subsequent antiviral therapy in clinical settings is necessary. This study identified 57/149 (38.3%) patients who did not respond to one course (5-days) (n = 36/111, 32.4%) or prolonged (5 to 20 days) (n = 21/38, 55.3%) RDV therapy by subgenomic RNA detection. Genetic variants in the nsp12 gene were detected in 29/49 (59.2%) non responder patients by Illumina sequencing, including the de novo E83D mutation that emerged in an immunosuppressed patient after receiving 10 + 8 days of RDV, and the L838I detected at baseline and/or after prolonged RDV treatment in 9/49 (18.4%) non responder subjects. Although 3D protein modeling predicted no interference with RDV, the amino acid substitutions detected in the nsp12 involved changes on the electrostatic outer surface and in secondary structures that may alter antiviral response. It is important for health surveillance to study potential mutations associated with drug resistance as well as the benefit of RDV retreatment, especially in immunosuppressed patients and in those with persistent replication. IMPORTANCE This study provides clinical and microbiologic data of an extended population of hospitalized patients for COVID-19 pneumonia who experienced treatment failure, detected by the presence of subgenomic RNA (sgRNA). The genetic variants found in the nsp12 pharmacological target of RDV bring into focus the importance of monitoring emergent mutations, one of the objectives of the World Health Organization (WHO) for health surveillance. These mutations become even more crucial as RDV keeps being prescribed and new molecules are being repurposed for the treatment of COVID-19. The present article offers new perspectives for the clinical management of non responder patients treated and retreated with RDV and emphasizes the need of further research of the benefit of combinatorial therapies and RDV retreatment, especially in immunosuppressed patients with persistent replication after therapy.

Strong Humoral but Not Cellular Immune Responses against SARS-CoV-2 in Individuals with Oncohematological Disease Who Were Treated with Rituximab before Receiving a Vaccine Booster.

The humoral immune response developed after receiving the full vaccination schedule against COVID-19 is impaired in individuals who received anti-CD20 therapy 6-9 months before vaccination. However, there is little information about the cellular immune responses elicited in these individuals. In this study, we analyzed the humoral and cellular immune responses in 18 individuals with hematological disease who received the last dose of rituximab 13.8 months (IQR 9.4-19) before the booster dose. One month after receiving the booster dose, the seroconversion rate in the rituximab-treated cohort increased from 83.3% to 88.9% and titers of specific IgGs against SARS-CoV-2 increased 1.53-fold (p = 0.0098), while the levels of neutralizing antibodies increased 3.03-fold (p = 0.0381). However, the cytotoxic activity of peripheral blood mononuclear cells (PBMCs) from rituximab-treated individuals remained unchanged, and both antibody-dependent cellular cytotoxicity (ADCC) and direct cellular cytotoxicity (CDD) were reduced 1.7-fold (p = 0.0047) and 2.0-fold (p = 0.0086), respectively, in comparison with healthy donors. Breakthrough infections rate was higher in our cohort of rituximab-treated individuals (33.33%), although most of the infected patients (83.4%) developed a mild form of COVID-19. In conclusion, our findings confirm a benefit in the humoral, but not in the cellular, immune response in rituximab-treated individuals after receiving a booster dose of an mRNA-based vaccine against COVID-19.

Elite controllers long-term non progressors present improved survival and slower disease progression.

Different phenotypes exhibiting no evidences of disease progression have been described in ART-naïve HIV-1 positive individuals. Long-term non progressors (LTNP) and elite controllers (EC) are low frequent examples of immunological and virological control in HIV-1 positive subjects, respectively. The combination of both phenotypes is even less frequent and studied despite being considered as models of HIV-1 functional cure. A multicenter, prospective study in retrospect including clinical and epidemiological data collected from 313 LTNP of 21 Spanish hospitals was carried out. LTNPs maintaining CD4+ T cell counts over 500 cells/µl and viral loads (VL) under 10,000 copies/mL for at least 10 years in the absence of antiretroviral therapy were followed for a median of 20.8 years (IQR = 15.6-25.5). A 52.1% were considered EC (undetectable VL) and LTNP (EC-LTNP) and a total of 171 (54.8%) and 42 (13.5%) out of the 313 participants maintained LTNP status for at least 20 and 30 years, respectively. EC-LTNP showed lower CD4+ T cell count loss (9.9 vs 24.2 cells/µl/year), higher CD4/CD8 ratio (0.01 vs - 0.09 in ratio), and lesser VL increase (no increase vs 197.2 copies/mL/year) compared with LTNPs with detectable VL (vLTNP). Survival probabilities for all-cause mortality at 30 years from HIV + diagnosis were 0.90 for EC-LTNP and 0.70 for vLTNP (p = 2.0 × 10-3), and EC-LTNP phenotype was the only factor associated with better survival in multivariate analyses (HR = 0.28; 95% CI 0.10-0.79). The probability to preserve LTNP status at 30 years was 0.51 for EC-LTNP and 0.18 for vLTNP (p < 2.2 × 10-16). Risk factors associated to the loss of LTNP status was: higher age at diagnosis and the increase of VL, whereas the increase of CD4+ T cell counts and CD4/CD8 ratio, the initial EC-LTNP phenotype and HCV coinfection were protective factors. EC-LTNP phenotype was associated with improved survival and slower disease progression compared with other phenotypes of LTNP. EC-LTNP individuals represent one of the most favorable phenotypes of immune activation against HIV-1 found in nature and, therefore, are strong candidates to be considered a model of functional cure of HIV-1 infection.

Highly Efficient Autologous HIV-1 Isolation by Coculturing Macrophage With Enriched CD4+ T Cells From HIV-1 Patients.

We described a novel HIV autologous isolation method based in coculturing macrophages and CD4+T-cell-enriched fractions from peripheral blood collected from antiretroviral-treated (ART) HIV patients. This method allows the isolation of high viral titers of autologous viruses, over 1010HIV RNA copies/ml, and reduces the time required to produce necessary amounts for virus for use as antigens presented by monocyte-derived myeloid cells in HIV therapeutic vaccine approaches. By applying these high titer and autologous virus produced in the patient-derived cells, we intended to elicit a boost of the immunological system response in HIV therapeutic vaccines in clinical trials.

Immune response and reactogenicity after immunization with two-doses of an experimental COVID-19 vaccine (CVnCOV) followed by a third-fourth shot with a standard mRNA vaccine (BNT162b2): RescueVacs multicenter cohort study.

Background: There is no evidence to date on immunogenic response among individuals who participated in clinical trials of COVID-19 experimental vaccines redirected to standard national vaccination regimens. Methods: This multicentre, prospective controlled cohort study included subjects who received a COVID-19 experimental vaccine (CVnCoV)(test group, TG) - and unvaccinated subjects (control group, CG), selected among individuals to be vaccinated according to the Spanish vaccination program. All study subjects received BNT162b2 as a standard national vaccination schedule, except 8 (from CG) who received mRNA-1273 and were excluded from immunogenicity analyses. Anti-RBD antibodies level and neutralising titres (NT50) against G614, Beta, Mu, Delta and Omicron variants were analysed. Reactogenicity was also assessed. Findings: 130 participants (TG:92; CG:38) completed standard vaccination. In TG, median (IQR) of anti-RBD antibodies after first BNT162b2 dose were 10740·0 BAU/mL (4466·0-12500) compared to 29·8 BAU/mL (14·5-47·8) in CG (p <0·0001). Median NT50 (IQR) of G614 was 2674·0 (1865·0-3997·0) in TG and 63·0 (16·0-123·1) in CG (p <0·0001). After second BNT162b2 dose, anti-RBD levels increased to ≥12500 BAU/mL (11625·0-12500) in TG compared to 1859·0 BAU/mL (915·4-3820·0) in CG (p <0·0001). NT50 was 2626·5 (1756·0-5472·0) and 850·4 (525·1-1608·0), respectively (p <0·0001). Variant-specific (Beta, Mu, Omicron) response was also assessed. Most frequent adverse reactions were headache, myalgia, and local pain. No severe AEs were reported. Interpretation: Heterologous BNT162b2 as third and fourth doses in previously suboptimal immunized individuals elicit stronger immune response than that obtained with two doses of BNT162b2. This apparent benefit was also observed in variant-specific response. No safety concerns arose. Funding: Partly funded by the Institute of Health Carlos-III and COVID-19 Fund, co-financed by the European Regional Development Fund (FEDER) "A way to make Europe".

Immunogenic dynamics and SARS-CoV-2 variant neutralisation of the heterologous ChAdOx1-S/BNT162b2 vaccination: Secondary analysis of the randomised CombiVacS study.

Background: The CombiVacS study was designed to assess immunogenicity and reactogenicity of the heterologous ChAdOx1-S/BNT162b2 combination, and 14-day results showed a strong immune response. The present secondary analysis addresses the evolution of humoral and cellular response up to day 180. Methods: Between April 24 and 30, 2021, 676 adults primed with ChAdOx1-S were enrolled in five hospitals in Spain, and randomised to receive BNT162b2 as second dose (interventional group [IG]) or no vaccine (control group [CG]). Individuals from CG received BNT162b2 as second dose and also on day 28, as planned based on favourable results on day 14. Humoral immunogenicity, measured by immunoassay for SARS-CoV-2 receptor binding domain (RBD), antibody functionality using pseudovirus neutralisation assays for the reference (G614), Alpha, Beta, Delta, and Omicron variants, as well as cellular immune response using interferon-γ and IL-2 immunoassays were assessed at day 28 after BNT162b2 in both groups, at day 90 (planned only in the interventional group) and at day 180 (laboratory data cut-off on Nov 19, 2021). This study was registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739). Findings: In this secondary analysis, 664 individuals (441 from IG and 223 from CG) were included. At day 28 post vaccine, geometric mean titres (GMT) of RBD antibodies were 5616·91 BAU/mL (95% CI 5296·49-5956·71) in the IG and 7298·22 BAU/mL (6739·41-7903·37) in the CG (p < 0·0001). RBD antibodies titres decreased at day 180 (1142·0 BAU/mL [1048·69-1243·62] and 1836·4 BAU/mL [1621·62-2079·62] in the IG and CG, respectively; p < 0·0001). Neutralising antibodies also waned from day 28 to day 180 in both the IG (1429·01 [1220·37-1673·33] and 198·72 [161·54-244·47], respectively) and the CG (1503·28 [1210·71-1866·54] and 295·57 [209·84-416·33], respectively). The lowest variant-specific response was observed against Omicron-and Beta variants, with low proportion of individuals exhibiting specific neutralising antibody titres (NT50) >1:100 at day 180 (19% and 22%, respectively). Interpretation: Titres of RBD antibodies decay over time, similar to homologous regimes. Our findings suggested that delaying administration of the second dose did not have a detrimental effect after vaccination and may have improved the response obtained. Lower neutralisation was observed against Omicron and Beta variants at day 180. Funding: Funded by Instituto de Salud Carlos III (ISCIII).

HIV and aging, biological mechanisms, and therapies: What do we know?

Aging, a time-dependent loss of physiological function, and its drivers are turning into a significant topic of researchas the population's mean age increases. Epigenetic alterations, telomere shortening or dysfunction, mitogenic stress,oxidative stress, or accumulation of DNA damage can drive the cell to senescence a permanent cell cycle arrest sometimes associated with a secretory phenotype and inflammatory consequences in the surrounding tissue. The amount of senescent cellsgrows over time in older organisms and may induce tissue inflammation and threaten overall tissue homeostasis, favoring aging. Senolytic and senomorphic therapeuticsare an emerging approach to eliminate senescent cells or to block their secretoryphenotypes respectively. Given that people living with HIV suffer non-AIDS comorbidities in a higher prevalence than the general population, aging is accentuated among them. Inflammation biomarkers may be helpful to assess prognosis or act as surrogate endpoints for studies of strategies focused on reversal of HIV-associated accelerated aging. This review summarizes the latest findings in aging and its major drivers, under the light of HIV infection. Since the number of older PLWH is currently rising, it will be of great importance to address and treat their age-related conditions, as well as to better decipher their biological mechanisms.

Omic Technologies in HIV: Searching Transcriptional Signatures Involved in Long-Term Non-Progressor and HIV Controller Phenotypes.

This article reviews the main discoveries achieved by transcriptomic approaches on HIV controller (HIC) and long-term non-progressor (LTNP) individuals, who are able to suppress HIV replication and maintain high CD4+ T cell levels, respectively, in the absence of antiretroviral therapy. Different studies using high throughput techniques have elucidated multifactorial causes implied in natural control of HIV infection. Genes related to IFN response, calcium metabolism, ribosome biogenesis, among others, are commonly differentially expressed in LTNP/HIC individuals. Additionally, pathways related with activation, survival, proliferation, apoptosis and inflammation, can be deregulated in these individuals. Likewise, recent transcriptomic studies include high-throughput sequencing in specific immune cell subpopulations, finding additional gene expression patterns associated to viral control and/or non-progression in immune cell subsets. Herein, we provide an overview of the main differentially expressed genes and biological routes commonly observed on immune cells involved in HIV infection from HIC and LTNP individuals, analyzing also different technical aspects that could affect the data analysis and the future perspectives and gaps to be addressed in this field.

The ex vivo pharmacology of HIV-1 antiretrovirals differs between macaques and humans.

Non-human primates (NHP) are widely used for the pre-clinical assessment of antiretrovirals (ARVs) for HIV treatment and prevention. However, the utility of these models is questionable given the differences in ARV pharmacology between humans and macaques. Here, we report a model based on ex vivo ARV exposure and the challenge of mucosal tissue explants to define pharmacological differences between NHPs and humans. For colorectal and cervicovaginal explants in both species, high concentrations of tenofovir (TFV) and maraviroc were predictive of anti-viral efficacy. However, their combinations resulted in increased inhibitory potency in NHP when compared to human explants. In NHPs, higher TFV concentrations were measured in colorectal versus cervicovaginal explants (p = 0.042). In humans, this relationship was inverted with lower levels in colorectal tissue (p = 0.027). TFV-resistance caused greater loss of viral fitness for HIV-1 than SIV. This, tissue explants provide an important bridge to refine and appropriately interpret NHP studies.

Transcriptomic Evidence of the Immune Response Activation in Individuals With Limb Girdle Muscular Dystrophy Dominant 2 (LGMDD2) Contributes to Resistance to HIV-1 Infection.

LGMDD2 is a rare form of muscular dystrophy characterized by one of the three heterozygous deletions described within the TNPO3 gene that result in the addition of a 15-amino acid tail in the C-terminus.TNPO3 is involved in the nuclear import of splicing factors and acts as a host cofactor for HIV-1 infection by mechanisms not yet deciphered. Further characterization of the crosstalk between HIV-1 infection and LGMDD2 disease may contribute to a better understanding of both the cellular alterations occurring in LGMDD2 patients and the role of TNPO3 in the HIV-1 cycle. To this regard, transcriptome profiling of PBMCs from LGMDD2 patients carrying the deletion c.2771delA in the TNPO3 gene was compared to healthy controls. A total of 545 differentially expressed genes were detected between LGMDD2 patients and healthy controls, with a high representation of G protein-coupled receptor binding chemokines and metallopeptidases among the most upregulated genes in LGMDD2 patients. Plasma levels of IFN-ß and IFN-γ were 4.7- and 2.7-fold higher in LGMDD2 patients, respectively. An increase of 2.3-fold in the expression of the interferon-stimulated gene MxA was observed in activated PBMCs from LGMDD2 patients after ex vivo HIV-1 pseudovirus infection. Thus, the analysis suggests a pro-inflammatory state in LGMDD2 patients also described for other muscular dystrophies, that is characterized by the alteration of IL-17 signaling pathway and the consequent increase of metallopeptidases activity and TNF response. In summary, the increase in interferons and inflammatory mediators suggests an antiviral environment and resistance to HIV-1 infection but that could also impair muscular function in LGMDD2 patients, worsening disease evolution. Biomarkers of disease progression and therapeutic strategies based on these genes and mechanisms should be further investigated for this type of muscular dystrophy.

Elevated α-Ketoglutaric Acid Concentrations and a Lipid-Balanced Signature Are the Key Factors in Long-Term HIV Control.

Long-term elite controllers (LTECs) are a fascinating small subset of HIV individuals with viral and immunological HIV control in the long term that have been designated as models of an HIV functional cure. However, data on the LTEC phenotype are still scarce, and hence, the metabolomics and lipidomics signatures in the LTEC-extreme phenotype, LTECs with more than 10 years of viral and immunological HIV control, could be pivotal to finding the keys for functional HIV remission. Metabolomics and lipidomics analyses were performed using high-resolution mass spectrometry (ultra-high-performance liquid chromatography-electrospray ionization-quadrupole time of flight [UHPLC-(ESI) qTOF] in plasma samples of 13 patients defined as LTEC-extreme, a group of 20 LTECs that lost viral and/or immunological control during the follow-up study (LTEC-losing) and 9 EC patients with short-term viral and immunological control (less than 5 years; no-LTEC patients). Long-term viral and immunological HIV-1 control was found to be strongly associated with elevated tricarboxylic acid (TCA) cycle function. Interestingly, of the nine metabolites identified in the TCA cycle, α-ketoglutaric acid (p = 0.004), a metabolite implicated in the activation of the mTOR complex, a modulator of HIV latency and regulator of several biological processes, was found to be a key metabolite in the persistent control. On the other hand, a lipidomics panel combining 45 lipid species showed an optimal percentage of separation and an ability to differentiate LTEC-extreme from LTEC-losing, revealing that an elevated lipidomics plasma profile could be a predictive factor for the reignition of viral replication in LTEC individuals.