RESUMO
Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide "megapools," circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in â¼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike, and N proteins each accounted for 11%-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a, and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2-reactive CD4+ T cells in â¼40%-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating "common cold" coronaviruses and SARS-CoV-2.
Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Epitopos de Linfócito T , Pneumonia Viral/imunologia , Betacoronavirus/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19 , Vacinas contra COVID-19 , Convalescença , Infecções por Coronavirus/sangue , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Reações Cruzadas , Humanos , Leucócitos Mononucleares/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas Virais/metabolismo , Vacinas Virais/imunologiaRESUMO
Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals ≥ 65 years old. Scarcity of naive T cells was also associated with aging and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between aging and impaired adaptive immune responses to SARS-CoV-2.
Assuntos
Imunidade Adaptativa , Antígenos Virais/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Betacoronavirus/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , SARS-CoV-2 , Índice de Gravidade de Doença , Adulto JovemRESUMO
The emergence of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy. Development of broadly effective coronavirus vaccines that can mitigate these threats is needed. Here, we utilized a targeted donor selection strategy to isolate a large panel of human broadly neutralizing antibodies (bnAbs) to sarbecoviruses. Many of these bnAbs are remarkably effective in neutralizing a diversity of sarbecoviruses and against most SARS-CoV-2 VOCs, including the Omicron variant. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor-binding domain (RBD). Consistent with targeting of conserved sites, select RBD bnAbs exhibited protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model in vivo. These bnAbs provide new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and provide a molecular basis for effective design of pan-sarbecovirus vaccines.
Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Neutralizantes , Anticorpos Antivirais , Anticorpos Amplamente Neutralizantes , COVID-19/prevenção & controle , Humanos , Glicoproteína da Espícula de CoronavírusRESUMO
Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and to more effectively respond to SARS-CoV-2 variants. The emergence of Omicron and subvariants of SARS-CoV-2 illustrates the limitations of solely targeting the receptor-binding domain (RBD) of the spike (S) protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors, which targets a conserved S2 region in the betacoronavirus spike fusion machinery. Select bnAbs showed broad in vivo protection against all three deadly betacoronaviruses, SARS-CoV-1, SARS-CoV-2, and MERS-CoV, which have spilled over into humans in the past two decades. Structural studies of these bnAbs delineated the molecular basis for their broad reactivity and revealed common antibody features targetable by broad vaccination strategies. These bnAbs provide new insights and opportunities for antibody-based interventions and for developing pan-betacoronavirus vaccines.
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COVID-19 , SARS-CoV-2 , Humanos , Anticorpos Amplamente Neutralizantes , Anticorpos Neutralizantes , Anticorpos AntiviraisRESUMO
The Last Gift is an observational HIV cure-related research study conducted with people with HIV at the end of life (EOL) at the University of California San Diego. Participants agree to voluntarily donate blood and other biospecimens while living and their bodies for a rapid research autopsy postmortem to better understand HIV reservoir dynamics throughout the entire body. The Last Gift study was initiated in 2017. Since then, 30 volunteers were enrolled who are either (1) terminally ill with a concomitant condition and have a prognosis of 6 months or less or (2) chronically ill with multiple comorbidities and nearing the EOL.Multiple ethical and logistical challenges have been revealed during this time; here, we share our lessons learnt and ethical analysis. Issues relevant to healthcare research include surrogate informed consent, personal and professional boundaries, challenges posed conducting research in a pandemic, and clinician burnout and emotional support. Issues more specific to EOL and postmortem research include dual roles of clinical care and research teams, communication between research personnel and clinical teams, legally required versus rapid research autopsy, identification of next of kin/loved ones and issues of inclusion. Issues specific to the Last Gift include logistics of body donation and rapid research autopsy, and disposition of the body as a study benefit.We recommend EOL research teams to have clear provisions around surrogate informed consent, rotate personnel to maintain boundaries, limit direct contact with staff associated with clinical care and have a clear plan for legally required versus research autopsies, among other recommendations.
Assuntos
Morte , Infecções por HIV , Humanos , Consentimento Livre e Esclarecido , Doente Terminal , ComunicaçãoRESUMO
BACKGROUND: Sex differences in human immunodeficiency virus (HIV) reservoir dynamics remain underexplored. METHODS: Longitudinal samples from virally suppressed midlife women (n = 59, median age 45 years) and age-matched men (nâ =â 31) were analyzed retrospectively. At each time point, we measured sex hormones (by means of enzyme-linked immunosorbent assay) and cellular HIV DNA and RNA (by means of digital droplet polymerase chain reaction). Number of inducible HIV RNA+ cells, which provides an upper estimate of the replication-competent reservoir, was quantified longitudinally in a different subset of 14 women, across well-defined reproductive stages. Mixed-effects models included normalized reservoir outcomes and sex, time since antiretroviral therapy (ART) initiation, and the sex-by-time interaction as predictors. RESULTS: At ART initiation, women and men had median (interquartile range [IQR]) CD4+ T-cell counts of 204/µL (83-306/µL) versus 238/µL (120-284/µL), respectively; median ages of 45 (42-48) versus 47 (43-51) years; and median follow-up times of 79.2/µL (60.5-121.1/µL) versus 66.2/µL (43.2-80.6/µL) months. We observed a significant decline of total HIV DNA over time in both men and women (Pâ <â .01). However, the rates of change differed significantly between the sexes (Pâ <â .01), with women having a significantly slower rate of decline than men, more pronounced with age. By contrast, the levels of inducible HIV RNA increased incrementally over time in women during reproductive aging (Pâ <â .01). CONCLUSIONS: In contrast to men, in whom the HIV reservoir steadily declines with aging, the HIV reservoir in women is more dynamic. Total HIV DNA (including intact and defective genomes) declines more slowly in women than in men, while the inducible HIV RNA+ reservoir, which is highly enriched in replication-competent virus, increases in women after menopause.
Assuntos
Infecções por HIV , Caracteres Sexuais , Envelhecimento , Linfócitos T CD4-Positivos , Feminino , HIV , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA , Estudos Retrospectivos , Carga ViralRESUMO
BACKGROUND: One of the next frontiers in HIV research is focused on finding a cure. A new priority includes people with HIV (PWH) with non-AIDS terminal illnesses who are willing to donate their bodies at the end-of-life (EOL) to advance the search towards an HIV cure. We endeavored to understand perceptions of this research and to identify ethical and practical considerations relevant to implementing it. METHODS: We conducted 20 in-depth interviews and 3 virtual focus groups among four types of key stakeholders in the United States (PWH, biomedical HIV cure researchers, HIV clinicians, and bioethicists) to obtain triangulated viewpoints because little was known about the ethics of this topic. Each group was queried as to ethical considerations, safeguards, and protections for conducting HIV cure-related research at the EOL to ensure this research remains acceptable. RESULTS: All four key stakeholder groups generally supported HIV cure-related research conducted at the EOL because of the history of altruism within the PWH community and the potential for substantial scientific knowledge to be gained. Our informants expressed that: (1) Strong stakeholder and community involvement are integral to the ethical and effective implementation, as well as the social acceptability of this research; (2) PWH approaching the EOL should not inherently be considered a vulnerable class and their autonomy must be respected when choosing to participate in HIV cure-related research at the EOL; (3) Greater diversity among study participants, as well as multi-disciplinary research teams, is necessitated by HIV cure-related research at the EOL; (4) The sensitive nature of this research warrants robust oversight to ensure a favorable risk/benefit balance and to minimize the possibility of therapeutic misconception or undue influence; and (5) Research protocols should remain flexible to accommodate participants' comfort and needs at the EOL. CONCLUSION: Because of the ethical issues presented by HIV cure-related research at the EOL, robust ethical safeguards are of utmost importance. The proposed ethical and practical considerations presented herein is a first step in determining the best way to maximize this research's impact and social value. More much inquiry will need to be directed towards understanding context-specific and cultural considerations for implementing EOL HIV cure research in diverse settings.
Assuntos
Infecções por HIV , Morte , Grupos Focais , Infecções por HIV/tratamento farmacológico , Humanos , Pesquisa Qualitativa , Pesquisadores , Estados UnidosRESUMO
Herein we measured CD4+ T-cell responses against common cold coronaviruses (CCC) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in high-risk health care workers (HCW) and community controls. We observed higher levels of CCC-reactive T cells in SARS-CoV-2-seronegative HCW compared to community donors, consistent with potential higher occupational exposure of HCW to CCC. We further show that SARS-CoV-2 T-cell reactivity of seronegative HCW was higher than community controls and correlation between CCC and SARS-CoV-2 responses is consistent with cross-reactivity and not associated with recent in vivo activation. Surprisingly, CCC T-cell reactivity was decreased in SARS-CoV-2-infected HCW, suggesting that exposure to SARS-CoV-2 might interfere with CCC responses, either directly or indirectly. This result was unexpected, but consistently detected in independent cohorts derived from Miami and San Diego. CD4+ T-cell responses against common cold coronaviruses (CCC) are elevated in SARS-CoV-2 seronegative high-risk health care workers (HCW) compared to COVID-19 convalescent HCW, suggesting that exposure to SARS-CoV-2 might interfere with CCC responses and/or cross-reactivity associated with a protective effect.
Assuntos
COVID-19/epidemiologia , COVID-19/imunologia , Pessoal de Saúde , SARS-CoV-2/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Anticorpos Antivirais , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , COVID-19/diagnóstico , COVID-19/virologia , Ensaio de Imunoadsorção Enzimática , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Imunofenotipagem , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Peptídeos/química , Peptídeos/imunologia , Vigilância em Saúde Pública , Estudos Soroepidemiológicos , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Cytomegalovirus (CMV) almost universally infects persons with HIV (PWH), and it is a driver of persistent inflammation and HIV persistence. The mechanisms underlying the association between CMV (and possibly other herpesviruses) and HIV persistence are unclear. Serially collected blood samples were obtained from men who have sex with men (MSM) who started antiretroviral therapy (ART) within 1 year of their estimated date of HIV infection (EDI). Total CMV and Epstein-Barr virus (EBV) DNA were quantified in peripheral blood mononuclear cells by droplet digital PCR (ddPCR). Deep sequencing of the HIV DNA partial env gene was performed, and the dynamics of viral diversity over time were analyzed in relation to CMV and EBV shedding status. In total, 37 MSM PWH were included and followed for a median of 23 months (IQR, 22 to 28). Participants started ART within a median of 3.1 months (IQR, 1.5 to 6.5) after EDI and remained virally suppressed thereafter. A total of 18 participants (48.6%) were classified as high EBV shedders, while 19 (51.4%) were classified as CMV shedders. In longitudinal analyses, normalized molecular diversity levels tended to increase over time among participants with detectable CMV and high EBV DNA (0.03 ± 0.02, P = 0.08), while they significantly declined among participants with no/low viral shedding (-0.04 ± 0.02, P = 0.047, interaction P < 0.01). Subclinical CMV and EBV shedding could contribute to the dynamics of the HIV DNA reservoir during suppressive ART. Whether persistent CMV/EBV replication could be targeted as a strategy to reduce the size of the latent HIV reservoir is an avenue that should be explored.IMPORTANCE As part of this study, we evaluated the molecular characteristics of the HIV DNA reservoir over time during antiretroviral treatment (ART) in relation to those of other chronic viral infections (i.e., cytomegalovirus [CMV] and Epstein-Barr virus [EBV]). We demonstrated that the presence of CMV and high-level EBV DNA in peripheral blood cells was associated with changes in HIV DNA molecular diversity. Specifically, HIV DNA molecular diversity increased over time among participants with detectable CMV and high-level EBV DNA, while it significantly declined among participants with no/low viral shedding. Although the current study design does not allow causality to be inferred, it does support the theory that persistent CMV and EBV shedding could contribute to the dynamics of the HIV DNA reservoir during suppressive ART, even when ART is initiated during the earliest phases of HIV infection.
Assuntos
Antirretrovirais/farmacologia , Citomegalovirus/genética , DNA Viral/análise , HIV-1/genética , Herpesvirus Humano 4/genética , Eliminação de Partículas Virais/genética , Coinfecção/virologia , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/virologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Herpesvirus Humano 4/efeitos dos fármacos , Homossexualidade Masculina , Humanos , Masculino , RNA Viral/sangue , Eliminação de Partículas Virais/efeitos dos fármacosRESUMO
BACKGROUND: Seminal human immunodeficiency virus (HIV) transmission from men to their partners remains the main driver of HIV epidemics worldwide. Semen is not merely a carrier of the virus, but also provides an immunological milieu that affects HIV transmission. METHODS: We collected blood and semen from people with HIV whose epidemiologically linked sexual partners either did or did not acquire HIV. Viral transmission was confirmed by phylogenetic linkage (HIV pol). We measured the concentration of 34 cytokines/chemokines by Luminex in the blood and semen of 21 source partners who transmitted HIV (transmitters) and 22 who did not transmit HIV (nontransmitters) to their sexual partners. Differences between cytokine profiles in transmitters versus nontransmitters were analyzed using the multivariate statistical technique of partial least square discriminant analysis. RESULTS: The cytokine profile in seminal fluid, but not in peripheral blood, was significantly different between men who have sex with men (MSM) who transmitted HIV and those who did not transmit HIV to their sexual partners (E = 19.77; P < .01). This difference persisted after excluding people with undetectable HIV RNA levels in nontransmitters. CONCLUSIONS: Seminal cytokine profiles correlated with transmission or nontransmission of HIV from the infected MSM to their partners, independently from seminal viral load. Seminal cytokine spectra might be a contributing determinant of sexual HIV transmission, thus providing new directions for the development of strategies aimed at preventing HIV transmission.
Assuntos
Citocinas/imunologia , Infecções por HIV/imunologia , Minorias Sexuais e de Gênero , Infecções por HIV/transmissão , HIV-1 , Homossexualidade Masculina , Humanos , Masculino , FilogeniaRESUMO
Most people living with HIV (PLWH) are coinfected with cytomegalovirus (CMV). Subclinical CMV replication is associated with immune dysfunction and with increased HIV DNA in antiretroviral therapy (ART)-naive and -suppressed PLWH. To identify immunological mechanisms by which CMV could favor HIV persistence, we analyzed 181 peripheral blood mononuclear cell (PBMC) samples from 64 PLWH starting ART during early HIV infection with subsequent virologic suppression up to 58 months. In each sample, we measured levels of CMV and Epstein-Barr virus (EBV) DNA by droplet digital PCR (ddPCR). We also measured expression of immunological markers for activation (HLA-DR+ CD38+), cycling (Ki-67+), degranulation (CD107a+), and the immune checkpoint protein PD-1 on CD4+ and CD8+ T cell memory subsets. Significant differences in percentages of lymphocyte markers by CMV/EBV shedding were identified using generalized linear mixed-effects models. Overall, CMV DNA was detected at 60/181 time points. At the time of ART initiation, the presence of detectable CMV DNA was associated with increased CD4+ T cell activation and CD107a expression and with increased CD8+ T cellular cycling and reduced CD107a expression on CD8+ T cells. While some effects disappeared during ART, greater CD4+ T cell activation and reduced CD107a expression on CD8+ T cells persisted when CMV was present (P < 0.01). In contrast, EBV was not associated with any immunological differences. Among the covariates, peak HIV RNA and CD4/CD8 ratio had the most significant effect on the immune system. In conclusion, our study identified immune differences in PLWH with detectable CMV starting early ART, which may represent an additional hurdle for HIV cure efforts.IMPORTANCE Chronic viral infections such as with HIV and CMV last a lifetime and can continually antagonize the immune system. Both viruses are associated with higher expression of inflammation markers, and recent evidence suggests that CMV may complicate efforts to deplete HIV reservoirs. Our group and others have shown that CMV shedding is associated with a larger HIV reservoir. Subclinical CMV replication could favor HIV persistence via bystander effects on our immune system. In this study, we collected longitudinal PBMC samples from people starting ART and measured immune changes associated with detectable CMV. We found that when CMV was detectable, CD4+ T cell activation was higher and CD8+ T cell degranulation was lower. Both results may contribute to the slower decay of the size of the reservoir during CMV replication, since activated CD4+ T cells are more vulnerable to HIV infection, while the loss of CD8+ T cell degranulation may impede the proper killing of infected cells.
Assuntos
Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Citomegalovirus/genética , Vírus de DNA/metabolismo , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Adulto , Fármacos Anti-HIV/uso terapêutico , Relação CD4-CD8 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Coinfecção , HIV-1 , Herpesvirus Humano 4 , Humanos , Ativação Linfocitária , Masculino , Receptor de Morte Celular Programada 1 , Minorias Sexuais e de Gênero , Replicação Viral , Eliminação de Partículas ViraisRESUMO
Modern antiretroviral therapy (ART) extends life expectancy for people living with HIV (PLWH). However, most older PLWH (≥50 years) "aged" with HIV and were exposed to historical HIV care practices and older, more toxic ART. In PLWH with exposure to older and multiple ART regimens, the drug interactions between ART frequently used in treatment-experienced persons and commonly used immunosuppressants remain a significant challenge. However, the advent of newer ART classes (eg, integrase non-strand transfer inhibitors) and more advanced HIV genetic resistance testing may allow optimization of ART regimens with minimal drug interactions. Here, we present a case series of three PLWH whose complicated ART interacted (or was at risk for interacting) with their post-liver transplant immunosuppression. After a review of their proviral DNA resistance testing, they successfully transitioned onto safer integrase non-strand transfer inhibitor-containing ART regimens without viral blips or evidence of organ rejection.
Assuntos
Fármacos Anti-HIV/farmacologia , Rejeição de Enxerto/prevenção & controle , Infecções por HIV/tratamento farmacológico , Imunossupressores/farmacologia , Transplante de Fígado/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Interações Medicamentosas , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Substituição de Medicamentos , Rejeição de Enxerto/imunologia , Infecções por HIV/complicações , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Pore-forming toxins are critical virulence factors for many bacterial pathogens and are central to Staphylococcus aureus-mediated killing of host cells. S. aureus encodes pore-forming bi-component leukotoxins that are toxic towards neutrophils, but also specifically target other immune cells. Despite decades since the first description of staphylococcal leukocidal activity, the host factors responsible for the selectivity of leukotoxins towards different immune cells remain unknown. Here we identify the human immunodeficiency virus (HIV) co-receptor CCR5 as a cellular determinant required for cytotoxic targeting of subsets of myeloid cells and T lymphocytes by the S. aureus leukotoxin ED (LukED). We further demonstrate that LukED-dependent cell killing is blocked by CCR5 receptor antagonists, including the HIV drug maraviroc. Remarkably, CCR5-deficient mice are largely resistant to lethal S. aureus infection, highlighting the importance of CCR5 targeting in S. aureus pathogenesis. Thus, depletion of CCR5(+) leukocytes by LukED suggests a new immune evasion mechanism of S. aureus that can be therapeutically targeted.
Assuntos
Toxinas Bacterianas/metabolismo , Exotoxinas/metabolismo , Receptores CCR5/metabolismo , Staphylococcus aureus/patogenicidade , Animais , Antagonistas dos Receptores CCR5 , Morte Celular , Células Cultivadas , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Humanos , Evasão da Resposta Imune , Memória Imunológica , Células Jurkat , Camundongos , Células Mieloides/citologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Staphylococcus aureus/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Meningitis caused by Acinetobacter species is a rare complication of neurosurgical procedures, although it is associated with high morbidity and mortality. Carbapenem-resistant Acinetobacter is particularly difficult to treat, considering the limited selection and tolerability of effective antimicrobials. Sulbactam-durlobactam was approved by the FDA in 2023 for treatment of hospital-acquired and ventilator-associated pneumonia due to susceptible strains of Acinetobacter, including carbapenem-resistant Acinetobacter baumannii. Here, we present a case of carbapenem-resistant Acinetobacter baumannii neurosurgical infection and meningitis successfully treated with sulbactam-durlobactam combination therapy.
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OBJECTIVE: We sought to determine if standard influenza and pneumococcal vaccines can be used to stimulate HIV reservoirs during antiretroviral therapy (ART). DESIGN: A prospective, randomized, double-blinded, placebo-controlled, crossover trial of two clinically recommended vaccines (influenza and pneumococcal). METHODS: Persons with HIV on ART ( N â=â54) were enrolled in the clinical trial. Blood was collected at baseline and days 2,4,7,14, and 30 postimmunizations. Levels of cellular HIV RNA and HIV DNA were measured by ddPCR. Expression of immunological markers on T cell subsets was measured by flow cytometry. Changes in unspliced cellular HIV RNA from baseline to day 7 postinjection between each vaccine and placebo was the primary outcome. RESULTS: Forty-seven participants completed at least one cycle and there were no serious adverse events related to the intervention. We observed no significant differences in the change in cellular HIV RNA after either vaccine compared with placebo at any timepoint. In secondary analyses, we observed a transient increase in total HIV DNA levels after influenza vaccine, as well as increased T cell activation and exhaustion on CD4 + T cells after pneumococcal vaccine. CONCLUSION: Clinically recommended vaccines were well tolerated but did not appear to stimulate the immune system strongly enough to elicit significantly noticeable HIV RNA transcription during ART.Clinicaltrials.gov identifier: NCT02707692.
Assuntos
Estudos Cross-Over , Infecções por HIV , Vacinas contra Influenza , Vacinas Pneumocócicas , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Masculino , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Feminino , Adulto , Pessoa de Meia-Idade , Método Duplo-Cego , Estudos Prospectivos , Placebos/administração & dosagem , RNA Viral/sangue , DNA Viral/sangue , Antirretrovirais/uso terapêutico , Influenza Humana/prevenção & controle , Influenza Humana/imunologia , Carga ViralRESUMO
A growing number of studies indicate that coronavirus disease 2019 (COVID-19) is associated with inflammatory sequelae, but molecular signatures governing the normal versus pathologic convalescence process have not been well-delineated. Here, we characterized global immune and proteome responses in matched plasma and saliva samples obtained from COVID-19 patients collected between 20 and 90 days after initial clinical symptoms resolved. Convalescent subjects showed robust total IgA and IgG responses and positive antibody correlations in saliva and plasma samples. Shotgun proteomics revealed persistent inflammatory patterns in convalescent samples including dysfunction of salivary innate immune cells, such as neutrophil markers (e.g., myeloperoxidase), and clotting factors in plasma (e.g., fibrinogen), with positive correlations to acute COVID-19 disease severity. Saliva samples were characterized by higher concentrations of IgA, and proteomics showed altered myeloid-derived pathways that correlated positively with SARS-CoV-2 IgA levels. Beyond plasma, our study positions saliva as a viable fluid to monitor normal and aberrant immune responses including vascular, inflammatory, and coagulation-related sequelae.
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OBJECTIVE: CMV coinfection contributes to sustained immune activation in people with chronic HIV. In particular, asymptomatic CMV shedding in semen has been associated with increased local and systemic immune activation, even during suppressive antiretroviral therapy (ART). However, the effect of seminal CMV shedding in people with HIV in the earliest phase of HIV infection is not known. METHODS: Using Luminex, we measured the concentration of 34 cytokines in the blood plasma of sixty-nine men who had sex with men with or without HIV and in subgroups of CMV shedders vs. non-shedders. Differences in blood plasma cytokines between groups were investigated using the multivariate supervised partial least squares discriminant analysis method. RESULTS: Independently of CMV, we found that concentrations of IP-10, MIG, MCP-1, I-TAC 10, IL-16, and MIP-1ß were modulated in the earliest phase of HIV infection compared with control individuals without HIV. In people with HIV, there was no difference in blood cytokines among CMV shedders vs. non-shedders. CONCLUSION: In early/acute HIV infection, asymptomatic CMV shedding in semen does not drive additional cytokine changes in blood. Early ART initiation should remain the priority, while the added benefit of CMV suppression during the various stages of HIV infection needs to be further investigated.
Assuntos
Coinfecção , Infecções por HIV , HIV-1 , Coinfecção/complicações , Citocinas , Humanos , Masculino , SêmenRESUMO
OBJECTIVE: HIV infection disrupts the cytokine network and this disruption is not completely reversed by antiretroviral therapy (ART). Characterization of cytokine changes in blood and genital secretions is important for understanding HIV pathogenesis and the mechanisms of HIV sexual transmission. Here, we characterized the cytokine network in individuals longitudinally sampled before they began ART and after achieving suppression of HIV RNA. METHODS: We measured concentrations of 34 cytokine/chemokines using multiplex bead-based assay in blood and seminal plasma of 19 men with HIV-1 prior to and after viral suppression. We used Partial Least Squares Discriminant Analysis (PLS-DA) to visualize the difference in cytokine pattern between the time points. Any cytokines with VIP scores exceeding 1 were deemed important in predicting suppression status and were subsequently tested using Wilcoxon Signed Rank Tests. RESULTS: PLS-DA projections in blood were fairly similar before and after viral suppression. In contrast, the difference in PLS-DA projection observed in semen emphasizes that the immunological landscape and immunological needs are very different before and after ART in the male genital compartment. When tested individually, four cytokines were significantly different across time points in semen (MIG, IL-15, IL-7, I-TAC), and two in blood (MIG and IP-10). CONCLUSION: Viral suppression with ART impacts the inflammatory milieu in seminal plasma. In contrast, the overall effect on the network of cytokines in blood was modest but consistent with prior analyses. These results identify specific changes in the cytokine networks in semen and blood as the immune system acclimates to chronic, suppressed HIV infection.
Assuntos
Citocinas , Infecções por HIV , HIV-1 , Sêmen , Quimiocinas/imunologia , Quimiocinas/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Infecções por HIV/sangue , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/imunologia , Humanos , Masculino , RNA Viral/genética , Sêmen/imunologia , Sêmen/metabolismo , Carga ViralRESUMO
BACKGROUND: We evaluated the association of inflammation and dysbosis on cervicovaginal fluid (CVF) tenofovir (TFV) concentrations in women taking oral tenofovir disoproxil fumarate/emtricitable for HIV pre-exposure prophylaxis (PrEP) in the United States. SETTING: Thirty-five women in a HIV PrEP implementation study attended their week 24 visit at a San Diego research clinic and provided CVF specimens. METHODS: Women in the Adherence Enhancement Guided by Individualized Texting and Drug Levels study had their CVF specimens evaluated for (1) sexually transmitted bacterial (Neisseria gonorrhoeae, Chlamydia trachomatis, Gardnerella, and Trichomonas vaginalis), viral (human papillomavirus, cytomegalovirus and herpes simplex virus-1/2) and fungal (Candida) infections; (2) microbiome composition by 16 S sequencing (V3-V4 region); and (3) cytokine profiles by enzyme-linked immunoassay (Interleukin-8, macrophage Inflammatory protein-1a, macrophage Inflammatory Protein-1b and interferon-γ-inducible protein-10). Univariate statistical analysis was used to determine factors associated with CVF TFV concentrations. CVF TFV of 100-1000 ng/mL benchmarked typical genital concentrations and TFV-diphosphate in dried blood spots of 700 fmol/punch was considered adequate adherence. RESULTS: Thirty-five women had CVF specimens collected. No factor was associated with CVF TFV concentrations or discordance of blood and vaginal concentrations. Among 27 participants assessed for vaginosis (Candida, Gardnerella or Trichomonas), women with Gardnerella (n = 11) were more likely to have high (>1000 ng/mL) CVF TFV concentrations (82% versus 33%, P = 0.02). CONCLUSIONS: Presence of genital viruses, cytokines, or vaginal community state types were not associated with low CVF TFV concentrations in cisgender women taking oral tenofovir disoproxil fumarate/emtricitable for PrEP. The surprising association observed between presence of Gardnerella and higher vaginal TFV concentrations needs further evaluation.