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1.
Methods Mol Biol ; 2552: 399-408, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36346605

RESUMO

Highly mutable pathogens pose daunting challenges for antibody design. The usual criteria of high potency and specificity are often insufficient to design antibodies that provide long-lasting protection. This is due, in part, to the ability of the pathogen to rapidly acquire mutations that permit them to evade the designed antibodies. To overcome these limitations, design of antibodies with a larger neutralizing breadth can be pursued. Such broadly neutralizing antibodies (bnAbs) should remain targeted to a specific epitope, yet show robustness against pathogen mutability, thereby neutralizing a higher number of antigens. This is particularly important for highly mutable pathogens, like the influenza virus and the human immunodeficiency virus (HIV). The protocol describes a method for computing the "breadth" of a given antibody, an essential aspect of antibody design.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Anticorpos Anti-HIV/genética , Anticorpos Neutralizantes , Epitopos
2.
Sci Rep ; 12(1): 18567, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36329160

RESUMO

Inhibitors of histone deacetylases (HDACis) are major latency reversing agent (LRA) candidates in 'shock and kill' strategies to eradicate the HIV reservoir in infected patients. The poor achievements of initial HDACi-based trials and subsequent studies have highlighted the need for more efficient approaches such as combinatory and immunostimulating therapies. Here we studied combinations of IL-15 with pan-HDACi (Vorinostat, Romidepsin, Panobinostat) or class I selective-HDACi (Entinostat) with or without a PKC agonist (Prostratin) for their impact on in vitro reactivation and NK cell-mediated suppression of latent HIV. Results showed that pan-HDACis but not Entinostat reduced NK cell viability and function; yet, combined IL-15 reverted the negative effects of pan-HDACis except for Panobinostat. All HDACis were ineffective at reactivating HIV in a CD4+ T cell model of latency, with pan-HDACis suppressing spontaneous and IL-15- or Prostratin-induced HIV release, while IL-15 + Prostratin combination showed maximal activity. Moreover, Panobinostat impaired STAT5 and NF-κB activation by IL-15 and Prostratin, respectively. Finally, by using effectors (NK) and targets (latently infected CD4+ T cells) equally exposed to drug combinations, we found that IL-15-mediated suppression of HIV reactivation by NK cells was inhibited by Panobinostat. Our data raise concerns and encouragements for therapeutic application of IL-15/LRA combinations.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Latência Viral , HIV-1/fisiologia , Panobinostat/farmacologia , Panobinostat/uso terapêutico , Infecções por HIV/tratamento farmacológico , Interleucina-15/farmacologia , Linfócitos T CD4-Positivos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Células Matadoras Naturais , Ativação Viral
3.
Front Cell Infect Microbiol ; 12: 976033, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36329822

RESUMO

Resistance to antifungal agents in vulvovaginal candidiasis has resulted in increasing morbidity among women globally. It is therefore crucial that new antimycotic agents are developed to counter this rising challenge. Q-Griffithsin (Q-GRFT) is a red algal lectin, manufactured in Nicotiana benthamiana. Griffithsin has well characterized broad spectrum antiviral activity and has demonstrated potent in vitro activity against multiple strains of Candida, including C. albicans. We have been working to incorporate Q-GRFT into topical microbicide products to prevent HIV-1 and HSV-2 transmission. The goal of this study was to evaluate the efficacy of a prototype Q-GRFT dosage form in prophylactic and therapeutic murine models of vaginal candidiasis, through microbiologic, histopathologic, and immune studies. In a preventive model, in comparison with infected controls, Q-GRFT treatment resulted in a lower fungal burden but did not alter the number of vaginal neutrophils and monocytes. In a therapeutic model, Q-GRFT enhanced fungal clearance when compared with infected untreated controls. Finally, histopathology demonstrated lower vaginal colonization with C. albicans following Q-GRFT treatment. Our results demonstrate that Q-GRFT has significant preventive and therapeutic activity in vaginal candidiasis offering additional benefit as a topical microbicide for prevention of HIV-1 and HSV-2 transmission.


Assuntos
Anti-Infecciosos Locais , Candidíase Vulvovaginal , HIV-1 , Camundongos , Feminino , Humanos , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Lectinas de Plantas , Candidíase Vulvovaginal/tratamento farmacológico , Candidíase Vulvovaginal/prevenção & controle , Modelos Animais de Doenças , Lectinas/farmacologia , Herpesvirus Humano 2
5.
Cell Rep ; 41(8): 111674, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36417867

RESUMO

A possible explanation for chronic inflammation in HIV-infected individuals treated with anti-retroviral therapy is hyperreactivity of myeloid cells due to a phenomenon called "trained immunity." Here, we demonstrate that human monocyte-derived macrophages originating from monocytes initially treated with extracellular vesicles containing HIV-1 protein Nef (exNef), but differentiating in the absence of exNef, release increased levels of pro-inflammatory cytokines after lipopolysaccharide stimulation. This effect is associated with chromatin changes at the genes involved in inflammation and cholesterol metabolism pathways and upregulation of the lipid rafts and is blocked by methyl-ß-cyclodextrin, statin, and an inhibitor of the lipid raft-associated receptor IGF1R. Bone-marrow-derived macrophages from exNef-injected mice, as well as from mice transplanted with bone marrow from exNef-injected animals, produce elevated levels of tumor necrosis factor α (TNF-α) upon stimulation. These phenomena are consistent with exNef-induced trained immunity that may contribute to persistent inflammation and associated co-morbidities in HIV-infected individuals with undetectable HIV load.


Assuntos
Vesículas Extracelulares , Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Camundongos , Animais , HIV-1/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética , Vesículas Extracelulares/metabolismo , Macrófagos/metabolismo , Inflamação/metabolismo
6.
Front Immunol ; 13: 878273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36420277

RESUMO

Follicular helper CD4+ T cells (TFH) are highly permissive to HIV and major foci of virus expression in both untreated and treated infection. Follicular regulatory CD4+ T cells (TFR) limit TFH numbers and function in vitro and in vivo. We evaluated the hypothesis that TFR suppress HIV replication in TFH using a well-established model of ex vivo HIV infection that employs tonsil cells from HIV uninfected individuals spinoculated with CXCR4- and CCR5-tropic HIV-GFP reporter viruses. Both CXCR4 and CCR5-tropic HIV replication were reduced in TFH cultured with TFR as compared to controls. Blocking antibodies to CD39, CTLA-4, IL-10, and TGF-beta failed to reverse suppression of HIV replication by TFR, and there were no sex differences in TFR suppressive activity. TFR reduced viability of TFH and even more so reduced HIV infected TFH as assessed by total and integrated HIV DNA. Exogenous IL-2 enhanced TFH viability and particularly numbers of GFP+ TFH in a concentration dependent manner. TFR reduced productively infected TFH at low and moderate IL-2 concentrations, and this was associated with decreases in extracellular IL-2. Both IL-2 expressing cells and larger numbers of FoxP3+CD4+ cells were detected in follicles and germinal centers of lymph nodes of people living with HIV. TFR may deplete TFH in vivo through restriction of IL-2 and thereby contribute to decay of HIV expressing cells in B cell follicles during HIV infection.


Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Células T Auxiliares Foliculares , Linfócitos T Reguladores , Interleucina-2
7.
BMJ Open ; 12(11): e067765, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36356989

RESUMO

INTRODUCTION: Cotreatment of HIV and tuberculosis (TB) reduces morbidity and mortality in coinfected patients. Availability of antiretroviral treatment (ART) drug options, including within drug classes, is important, particularly in high HIV/TB burden low and middle-income countries. METHODS AND ANALYSIS: This is a phase 2b, open-label, non-comparative randomised controlled trial to assess the antiretroviral activity of a fixed-drug, single tablet, combination of bictegravir (BIC) 50 mg/emtricitabine (FTC) 200 mg/tenofovir alafenamide (TAF) 25 mg (Biktarvy). The primary objective is to determine the efficacy, safety and pharmacokinetics of two times per day, coformulated BIC 50 mg/FTC 200 mg/TAF 25 mg in HIV-positive ART-naïve patients with TB who are receiving a rifampicin-based treatment regimen and to characterise viral suppression rates at week 24 through to week 48 in the BIC/FTC/TAF arm. We will enrol 120 patients randomised in a 2:1 ratio to the intervention or control arm of the study. A non-comparative contemporaneous control arm in which participants receive a dolutegravir-based regimen (standard of care) will also be enrolled. ETHICS AND DISSEMINATION: The University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and the South African Health Products Regulatory Authority (SAHPRA) have granted regulatory approval (trial reference numbers: BREC/00001300/2020 and SAHPRA 20200810). Trial results will be disseminated through conference presentations, peer-reviewed publications and the clinical trial registry. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov; Trial registration number: NCT04734652; South African National Clinical Trials Register (SANCTR DOH-27-012021-6789).


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Tuberculose , Humanos , Emtricitabina/uso terapêutico , Rifampina/uso terapêutico , Piridonas/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Adenina/uso terapêutico , Antirretrovirais/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Tuberculose/complicações , Tuberculose/tratamento farmacológico , Tuberculose/induzido quimicamente , Fumaratos/uso terapêutico , Fármacos Anti-HIV/uso terapêutico
8.
Top Antivir Med ; 30(4): 559-574, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36375130

RESUMO

The 2022 edition of the IAS-USA drug resistance mutations list updates the Figure last published in September 2019. The mutations listed are those that have been identified by specific criteria for evidence and drugs described. The Figure is designed to assist practitioners to identify key mutations associated with resistance to antiretroviral drugs, and therefore, in making clinical decisions regarding antiretroviral therapy.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , HIV-1/genética , Farmacorresistência Viral/genética , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Mutação
9.
Retrovirology ; 19(1): 25, 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36403071

RESUMO

BACKGROUND: Viroporins are virally encoded ion channels involved in virus assembly and release. Human immunodeficiency virus type 1 (HIV-1) and influenza A virus encode for viroporins. The human coronavirus SARS-CoV-2 encodes for at least two viroporins, a small 75 amino acid transmembrane protein known as the envelope (E) protein and a larger 275 amino acid protein known as Orf3a. Here, we compared the replication of HIV-1 in the presence of four different ß-coronavirus E proteins. RESULTS: We observed that the SARS-CoV-2 and SARS-CoV E proteins reduced the release of infectious HIV-1 yields by approximately 100-fold while MERS-CoV or HCoV-OC43 E proteins restricted HIV-1 infectivity to a lesser extent. Mechanistically, neither reverse transcription nor mRNA synthesis was involved in the restriction. We also show that all four E proteins caused phosphorylation of eIF2-α at similar levels and that lipidation of LC3-I could not account for the differences in restriction. However, the level of caspase 3 activity in transfected cells correlated with HIV-1 restriction in cells. Finally, we show that unlike the Vpu protein of HIV-1, the four E proteins did not significantly down-regulate bone marrow stromal cell antigen 2 (BST-2). CONCLUSIONS: The results of this study indicate that while viroporins from homologous viruses can enhance virus release, we show that a viroporin from a heterologous virus can suppress HIV-1 protein synthesis and release of infectious virus.


Assuntos
COVID-19 , HIV-1 , Humanos , Proteínas Viroporinas , HIV-1/genética , SARS-CoV-2 , Replicação Viral , Aminoácidos
10.
Proc Natl Acad Sci U S A ; 119(48): e2210584119, 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36413502

RESUMO

Antiretroviral therapy (ART) can attain prolonged undetectable HIV-1 in plasma and cerebrospinal fluid (CSF), but brain injury remains prevalent in people living with HIV-1 infection (PLHIV). We investigated cell-associated (CA)-HIV-1 RNA transcripts in cells in CSF and blood, using the highly sensitive Double-R assay, together with proton Magnetic Resonance Spectroscopy (1H MRS) of major brain metabolites, in sixteen PLHIV. 14/16 CSF cell samples had quantifiable CA-HIV-1 RNA, at levels significantly higher than in their PBMCs (median 9,266 vs 185 copies /106 CD4+ T-cells; p<0.0001). In individual PLHIV, higher levels of HIV-1 transcripts in CSF cells were associated with greater brain injury in the frontal white matter (Std ß=-0.73; p=0.007) and posterior cingulate (Std ß=-0.61; p=0.03). 18-colour flow cytometry revealed that the CSF cells were 91% memory T-cells, equally CD4+ and CD8+ T-cells, but fewer B cells (0.4 %), and monocytes (3.1%). CXCR3+CD49d+integrin ß7-, CCR5+CD4+ T-cells were highly enriched in CSF, compared with PBMC (p <0.001). However, CA-HIV-1 RNA could not be detected in 10/16 preparations of highly purified monocytes from PBMC, and was extremely low in the other six. Our data show that elevated HIV-1 transcripts in CSF cells were associated with brain injury, despite suppressive ART. The cellular source is most likely memory CD4+ T cells from blood, rather than trafficking monocytes. Future research should focus on inhibitors of this transcription to reduce local production of potentially neurotoxic and inflammatory viral products.


Assuntos
Lesões Encefálicas , Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , HIV-1/genética , Linfócitos T CD4-Positivos , Leucócitos Mononucleares , Infecções por HIV/tratamento farmacológico
11.
Front Immunol ; 13: 1014515, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405707

RESUMO

The risk of active tuberculosis disease is 15-21 times higher in those coinfected with human immunodeficiency virus-1 (HIV) compared to tuberculosis alone, and tuberculosis is the leading cause of death in HIV+ individuals. Mechanisms driving synergy between Mycobacterium tuberculosis (Mtb) and HIV during coinfection include: disruption of cytokine balances, impairment of innate and adaptive immune cell functionality, and Mtb-induced increase in HIV viral loads. Tuberculosis granulomas are the interface of host-pathogen interactions. Thus, granuloma-based research elucidating the role and relative impact of coinfection mechanisms within Mtb granulomas could inform cohesive treatments that target both pathogens simultaneously. We review known interactions between Mtb and HIV, and discuss how the structure, function and development of the granuloma microenvironment create a positive feedback loop favoring pathogen expansion and interaction. We also identify key outstanding questions and highlight how coupling computational modeling with in vitro and in vivo efforts could accelerate Mtb-HIV coinfection discoveries.


Assuntos
Coinfecção , Infecções por HIV , HIV-1 , Tuberculose , Humanos , Biologia de Sistemas , Granuloma , Infecções por HIV/complicações
12.
Front Immunol ; 13: 1029167, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405722

RESUMO

Highly mutable infectious disease pathogens (hm-IDPs) such as HIV and influenza evolve faster than the human immune system can contain them, allowing them to circumvent traditional vaccination approaches and causing over one million deaths annually. Agent-based models can be used to simulate the complex interactions that occur between immune cells and hm-IDP-like proteins (antigens) during affinity maturation-the process by which antibodies evolve. Compared to existing experimental approaches, agent-based models offer a safe, low-cost, and rapid route to study the immune response to vaccines spanning a wide range of design variables. However, the highly stochastic nature of affinity maturation and vast sequence space of hm-IDPs render brute force searches intractable for exploring all pertinent vaccine design variables and the subset of immunization protocols encompassed therein. To address this challenge, we employed deep reinforcement learning to drive a recently developed agent-based model of affinity maturation to focus sampling on immunization protocols with greater potential to improve the chosen metrics of protection, namely the broadly neutralizing antibody (bnAb) titers or fraction of bnAbs produced. Using this approach, we were able to coarse-grain a wide range of vaccine design variables and explore the relevant design space. Our work offers new testable insights into how vaccines should be formulated to maximize protective immune responses to hm-IDPs and how they can be minimally tailored to account for major sources of heterogeneity in human immune responses and various socioeconomic factors. Our results indicate that the first 3 to 5 immunizations, depending on the metric of protection, should be specially tailored to achieve a robust protective immune response, but that beyond this point further immunizations require only subtle changes in formulation to sustain a durable bnAb response.


Assuntos
Vacinas contra a AIDS , Infecções por HIV , HIV-1 , Humanos , Anticorpos Anti-HIV , Anticorpos Neutralizantes , Anticorpos Amplamente Neutralizantes , Infecções por HIV/prevenção & controle
13.
PLoS One ; 17(11): e0277606, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36409695

RESUMO

BACKGROUND: The main international guidelines indicate DTG/3TC therapy as one of the preferred regimens for people living with HIV (PLWH), due to its observed efficacy in randomized clinical trials. However, information in real-life cohorts is relatively scarce for first-line use. METHODS: A retrospective multicenter study of adult PLWH starting DTG+3TC as a first-line regimen before January 31st, 2020. Virological failure (VF) was defined as 2 consecutive HIV RNA viral load (VL) >50 copies/mL. RESULTS: 135 participants were included. Treatment was started without knowing baseline drug resistance testing (bDRT) results in 71.9% of cases, with baseline resistance mutations being later confirmed in 17 patients (12.6%), two of them with presence of M184V mutation. Effectiveness at week 48 was 85.2% (CI95%: 78.1-90.7%) (ITT missing = failure [M = F]) and 96.6% (CI 95%: 91.6-99.1%) (per-protocol analysis). Six patients (4.4%) discontinued treatment. One developed not confirmed VF after discontinuing treatment due to poor adherence; no resistance-associated mutations emerged. Three discontinued treatments due to central nervous system side effects (2.2%), and two due to a medical decision after determining the M184V mutation in bDRT. Finally, 14 (10.4%) were lost to follow-up, most of them due to the COVID-19 pandemic. CONCLUSIONS: In a real-life multicenter cohort of ART-naïve PLWH, treatment initiation with DTG + 3TC showed high effectiveness and favorable safety results, comparable to those of randomized clinical trials, without treatment-emergent resistance being observed through week 48. Starting treatment before receiving the results of baseline drug resistance testing did not have an impact on the regimen's effectiveness.


Assuntos
Fármacos Anti-HIV , COVID-19 , Infecções por HIV , HIV-1 , Adulto , Humanos , Lamivudina/farmacologia , Fármacos Anti-HIV/efeitos adversos , Pandemias , HIV-1/genética , Antirretrovirais/uso terapêutico
14.
PLoS One ; 17(11): e0277231, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36409740

RESUMO

There are limited data regarding bone health in older people living with HIV (PWH), especially those of Asian ethnicity. We aimed to determine whether BMD in well-suppressed HIV-infected men and women aged ≥ 50 years are different from HIV-uninfected controls. In a cross-sectional study, BMD by dual-energy X-ray absorptiometry and calciotropic hormones were measured. A total of 481 participants were consecutively enrolled (209 HIV+ men, 88 HIV- men, 126 HIV+ women and 58 HIV- women). PWH were on average 2.5 years younger [men: 55.0 vs. 57.5 yr; women: 54.0 vs. 58.0 yr] and had lower body mass index (BMI) [men: 23.2 vs. 25.1 kg/m2; women: 23.1 vs. 24.7 kg/m2] compared to the controls. The median duration since HIV diagnosis was 19 (IQR 15-21) years in men and 18 (IQR 15-21) years in women. Three-quarters of PWH had been treated with tenofovir disoproxil fumarate-containing antiretroviral therapy for a median time of 7.4 (IQR 4.5-8.9) years in men and 8.2 (IQR 6.1-10) years in women. In an unadjusted model, HIV+men had significantly lower BMD (g/cm2) at the total hip and femoral neck whereas there was a tend toward lower BMD in HIV+women. After adjusting for age, BMI, and other traditional osteoporotic risk factors, BMD of virologically suppressed older PWH did not differ from participants without HIV (P>0.1). PWH had lower serum 25(OH)D levels but this was not correlated with BMD. In conclusion, BMD in well-suppressed PWH is not different from non-HIV people, therefore, effective control of HIV infection and minimization of other traditional osteoporosis risk factors may help maintain good skeletal health and prevent premature bone loss in Asian PWH. Clinical trial registration: Clinicaltrials.gov # NCT00411983.


Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Masculino , Feminino , Humanos , Idoso , Pessoa de Meia-Idade , Densidade Óssea , Estudos Transversais , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Asiáticos , Absorciometria de Fóton
15.
Clin Infect Dis ; 75(Supplement_4): S498-S501, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36410378

RESUMO

The landscape for the development of therapeutics for prevention and treatment of human immunodeficiency virus (HIV)-1 infection has pivoted towards long-acting antiretrovirals (LA-ARVs). LA-ARVs have the potential to transform global implementation of HIV-1 prevention and treatment strategies. The ability to identify potential knowledge gaps early in development, proactively address missing information or data gaps, and strategically leverage all the available information is the key to streamline the development of safe and effective LA-ARV therapeutics. The purpose of this article is to discuss some potential considerations for development of LA-ARVs. Three possible drug development scenarios are briefly discussed and include developing (1) a novel LA-ARV, (2) a novel LA formulation of an approved oral ARV, and (3) an LA pro-drug of an approved oral ARV. For each of these scenarios, we briefly describe what type(s) of information may be helpful and discuss potential opportunities to leverage available information. Additionally, we discuss some unique LA-ARV drug development considerations, including the use of an oral lead-in, and assessing the impact of residual ARV exposures on subsequent regimens and evaluation of LA-ARVs in specific populations. We strongly believe that efficient integration of multidisciplinary knowledge can advance the development, availability, and accessibility of therapeutics not only for HIV-1 prevention and treatment but also for other chronic viral infections.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Saúde Pública , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Antirretrovirais/uso terapêutico
16.
Clin Infect Dis ; 75(Supplement_4): S530-S540, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36410387

RESUMO

Broadly neutralizing antibodies directed against human immunodeficiency virus (HIV) offer promise as long-acting agents for prevention and treatment of HIV. Progress and challenges are discussed. Lessons may be learned from the development of monoclonal antibodies to treat and prevent COVID-19.


Assuntos
Antineoplásicos Imunológicos , COVID-19 , Infecções por HIV , HIV-1 , Humanos , Anticorpos Anti-HIV , Anticorpos Monoclonais/uso terapêutico
17.
BMC Infect Dis ; 22(1): 867, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36411423

RESUMO

BACKGROUND: Highly active anti-retroviral therapy (HAART) can successfully suppress human immunodeficiency virus (HIV) viral replication and reconstruct immune function reconstruction in HIV-1-infected patients. However, about 15-30% of HIV-1-infected patients still fail to recover their CD4+ T cell counts after HAART treatment, which means immune reconstruction failure. Pyroptosis plays an important role in the death of CD4+ T cells in HIV-1- infected patients. The study aims to explore the association between the expression of pyroptosis in peripheral blood and immune function reconstruction in HIV-1- infected patients. METHODS: One hundred thirty-five HIV-1-infected patients including immunological non-responders (INR) group, immunological responders (IR) group and normal immune function control (NC) group were analyzed. The expression of GSDMD and Caspase-1 in peripheral blood of HIV-1-infected patients were measured by qPCR. The concentrations of GSDMD, Caspase-1, IL-1ß and IL-18 in the peripheral serum were quantified by ELISA. The associations between the expression of pyroptosis in peripheral blood and immune function reconstruction were analyzed using multivariate logistic models. RESULTS: The relative expression of GSDMD mRNA and caspase-1 mRNA in peripheral blood, as well as the expression of IL-18 cytokine in the INR, were significantly higher than those in the IR and NC (P < 0.05). There was no significant difference in the expression of IL-1ß cytokine (P > 0.05). Multivariate logistic analysis showed that the patients with baseline CD4+ T cell counts less than 100 cells/µL (aOR 7.051, 95% CI 1.115-44.592, P = 0.038), high level of expression of Caspase-1mRNA (aOR 2.803, 95% CI 1.065-7.377, P = 0.037) and IL-18 cytokine (aOR 10.131, 95% CI 1.616-63.505, P = 0.013) had significant poor CD4+ T cell recovery. CONCLUSIONS: The baseline CD4+ T cell counts less than 100 cells/µL, high relative expression of Caspase-1 mRNA, and high expression of IL-18 cytokine are associated factors that affect the reconstruction of immune function.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Estudos Transversais , Interleucina-18/genética , Piroptose , Caspase 1 , RNA Mensageiro/análise
18.
J Virol ; 96(22): e0124822, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36326273

RESUMO

Rare HLA alleles such as HLA-B57 are associated with slow progression to AIDS. However, the evidence for the advantage of rare protective alleles is limited, and the mechanism is still unclear. Although the prevalence of HLA-B*67:01 is only 1.2% in Japan, HLA-B*67:01-positive (HLA-B*67:01+) individuals had the lowest plasma viral load (pVL) and highest CD4 count in HIV-1 clade B-infected Japanese individuals. We investigated the mechanism of immunological control of HIV-1 by a rare protective allele, HLA-B*67:01. We identified six novel HLA-B*67:01-restricted epitopes and found that T cells specific for four epitopes were significantly associated with good clinical outcomes, pVL and/or CD4 count. The wild type or cross-reactive sequences of three protective and immunodominant Pol and Gag epitopes were found in around 95% of the circulating HIV-1, indicating that T cells specific for three conserved or cross-reactive epitopes contributed to good clinical outcomes. One escape mutation (Nef71K) in the Nef protective epitope, which was selected by T cells restricted by either HLA allele in the HLA-B*67:01-C*07:02 haplotype, affected the HLA-B*67:01-restricted RY11-specific T-cell recognition. These results imply that the further accumulation of the Nef71K mutation in the population will negatively affect the control of HIV-1 replication by RY11-specific CD8+ T cells in HIV-1-infected HLA-B*67:01+ individuals. The present study demonstrated that conserved or cross-reactive epitope-specific T cells mainly contribute to control of HIV-1 by a rare protective allele, HLA-B*67:01. IMPORTANCE HLA-B57 is a relatively rare allele around world and the strongest protective HLA allele in Caucasians and African black individuals infected with HIV-1. Previous studies suggested that the advantage of this allele in HIV-1 disease progression is due to a strong functional ability of HLA-B57-restricted Gag-specific T cells and lower fitness of mutant viruses selected by the T cells. HLA-B*57 is a very rare allele and has not been reported as a protective allele in Asian countries, whereas a rare allele, HLA-B*67:01, was shown to be a protective allele in Japan. Therefore, the analysis of HLA-B*67:01-restricted T cells is important to clarify the mechanism of immunological control of HIV-1 by a rare protective HLA allele in Asia. We found that HLA-B*67:01-restricted T cells specific for three conserved or cross-reactive Gag and Pol epitopes are associated with good clinical outcomes in HLA-B*67:01+ individuals. It is expected that T cells specific for conserved or cross-reactive epitopes contribute to a curing treatment.


Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , HIV-1/genética , Alelos , Linfócitos T CD8-Positivos , Replicação Viral , Antígenos HLA-B/genética , Soropositividade para HIV/genética , Epitopos , Progressão da Doença , Epitopos de Linfócito T/genética
19.
Commun Biol ; 5(1): 1265, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36400835

RESUMO

Antibodies against the carboxy-terminal section of the membrane-proximal external region (C-MPER) of the HIV-1 envelope glycoprotein (Env) are considered as nearly pan-neutralizing. Development of vaccines capable of producing analogous broadly neutralizing antibodies requires deep understanding of the mechanism that underlies C-MPER recognition in membranes. Here, we use the archetypic 10E8 antibody and a variety of biophysical techniques including single-molecule approaches to study the molecular recognition of C-MPER in membrane mimetics. In contrast to the assumption that an interfacial MPER helix embodies the entire C-MPER epitope recognized by 10E8, our data indicate that transmembrane domain (TMD) residues contribute to binding affinity and specificity. Moreover, anchoring to membrane the helical C-MPER epitope through the TMD augments antibody binding affinity and relieves the effects exerted by the interfacial MPER helix on the mechanical stability of the lipid bilayer. These observations support that addition of TMD residues may result in more efficient and stable anti-MPER vaccines.


Assuntos
HIV-1 , HIV-1/química , Proteína gp41 do Envelope de HIV/química , Proteína gp41 do Envelope de HIV/metabolismo , Anticorpos Anti-HIV/química , Epitopos , Bicamadas Lipídicas/química
20.
Top Antivir Med ; 30(2): 419-425, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36346700

RESUMO

The Conference on Retroviruses and Opportunistic Infections (CROI) 2022, which was held as a virtual conference, continues to serve as the preeminent forum that features research advances in HIV-1 and its associated coinfections. The conference has extended its area of coverage to include research advances in SARS- CoV-2. As pointed out in the presentation from Hatziioannou in the New Investigators workshop, there has been an explosion in research activity on SARS-CoV-2 that has eclipsed that for HIV-1. In the past 12 months, there were approximately 6600 publications on HIV-1 and approximately 64,000 on SARS-CoV-2. Although these numbers include review articles, they reveal the tremendous response by researchers to the existential threats posed by lentiviruses and coronaviruses. This poses challenges for any conference committee tasked with selecting abstracts for presentation from the large number submitted for consideration. CROI organizers have consistently been able to assemble a program that, through invited presentations, abstract-driven talks, posters, interactive sessions, workshops, and symposia, showcases the most recent research advances.


Assuntos
Pesquisa Biomédica , COVID-19 , Infecções por HIV , HIV-1 , Infecções por Retroviridae , Humanos , SARS-CoV-2
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