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1.
Proc Natl Acad Sci U S A ; 119(43): e2211467119, 2022 10 25.
Article in English | MEDLINE | ID: covidwho-2077262

ABSTRACT

Through a screen that combines functional and evolutionary analyses, we identified tripartite motif protein (Trim69), a poorly studied member of the Trim family, as a negative regulator of HIV-1 infection in interferon (IFN)-stimulated myeloid cells. Trim69 inhibits the early phases of infection of HIV-1, but also of HIV-2 and SIVMAC in addition to the negative and positive-strand RNA viruses vesicular stomatitis virus and severe acute respiratory syndrome coronavirus 2, with magnitudes that depend on the combination between cell type and virus. Mechanistically, Trim69 associates directly to microtubules and its antiviral activity is linked to its ability to promote the accumulation of stable microtubules, a program that we uncover to be an integral part of antiviral IFN-I responses in myeloid cells. Overall, our study identifies Trim69 as the antiviral innate defense factor that regulates the properties of microtubules to limit viral spread and highlights the cytoskeleton as an unappreciated battleground in the host-pathogen interactions that underlie viral infections.


Subject(s)
HIV Infections , Tripartite Motif Proteins , Ubiquitin-Protein Ligases , Virus Replication , Humans , Immunity, Innate , Interferons/immunology , Microtubules/metabolism , Tripartite Motif Proteins/genetics , Tripartite Motif Proteins/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , HIV Infections/immunology
2.
Nat Commun ; 13(1): 4888, 2022 08 19.
Article in English | MEDLINE | ID: covidwho-2000886

ABSTRACT

Efforts to cure HIV have focused on reactivating latent proviruses to enable elimination by CD8+ cytotoxic T-cells. Clinical studies of latency reversing agents (LRA) in antiretroviral therapy (ART)-treated individuals have shown increases in HIV transcription, but without reductions in virologic measures, or evidence that HIV-specific CD8+ T-cells were productively engaged. Here, we show that the SARS-CoV-2 mRNA vaccine BNT162b2 activates the RIG-I/TLR - TNF - NFκb axis, resulting in transcription of HIV proviruses with minimal perturbations of T-cell activation and host transcription. T-cells specific for the early gene-product HIV-Nef uniquely increased in frequency and acquired effector function (granzyme-B) in ART-treated individuals following SARS-CoV-2 mRNA vaccination. These parameters of CD8+ T-cell induction correlated with significant decreases in cell-associated HIV mRNA, suggesting killing or suppression of cells transcribing HIV. Thus, we report the observation of an intervention-induced reduction in a measure of HIV persistence, accompanied by precise immune correlates, in ART-suppressed individuals. However, we did not observe significant depletions of intact proviruses, underscoring challenges to achieving (or measuring) HIV reservoir reductions. Overall, our results support prioritizing the measurement of granzyme-B-producing Nef-specific responses in latency reversal studies and add impetus to developing HIV-targeted mRNA therapeutic vaccines that leverage built-in LRA activity.


Subject(s)
CD8-Positive T-Lymphocytes , COVID-19 Vaccines , COVID-19 , HIV Infections , HIV-1 , BNT162 Vaccine , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Granzymes , HIV Infections/immunology , Humans , RNA, Messenger/genetics , RNA, Messenger/therapeutic use , SARS-CoV-2 , Vaccination , Vaccines, Synthetic , Virus Latency , mRNA Vaccines , nef Gene Products, Human Immunodeficiency Virus/genetics
3.
Infection ; 50(4): 1013-1017, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1971886

ABSTRACT

PURPOSE: SARS-CoV-2 infection produces lymphopenia and CD4+ T-cell decrease, which could lead to a higher risk of bacterial co-infection or impair immunological evolution in people living with HIV (PLWH). METHODS: We investigated the rate of co-infection and superinfection, and the evolution of CD4+ count and CD4+/CD8+ ratio, in hospitalized PLWH with COVID-19. RESULTS: From March to December 2020, 176 PLWH had symptomatic COVID-19 and 62 required hospitalization (median age, 56 years, 89% males). At admission, 7% and 13% of patients had leukocytosis or increased procalcitonin values and 37 (60%) received empiric antibiotic therapy, but no bacterial co-infection was diagnosed. There were seven cases of superinfection (12%), and one case of P. jiroveci pneumonia during ICU stay. No significant change in CD4+ count or CD4+/CD8+ ratio was observed after discharge. CONCLUSION: Bacterial co-infection is not frequent in PLWH with COVID-19. Immune recovery is observed in most of patients after the disease.


Subject(s)
COVID-19 , HIV Infections , Bacterial Infections/epidemiology , COVID-19/epidemiology , COVID-19/immunology , Coinfection/epidemiology , Female , HIV Infections/epidemiology , HIV Infections/immunology , Humans , Immunosuppression Therapy/statistics & numerical data , Male , Middle Aged , Opportunistic Infections/epidemiology , Risk Assessment
4.
Front Immunol ; 13: 833310, 2022.
Article in English | MEDLINE | ID: covidwho-1902989

ABSTRACT

Immune checkpoints (ICPs) consist of paired receptor-ligand molecules that exert inhibitory or stimulatory effects on immune defense, surveillance, regulation, and self-tolerance. ICPs exist in both membrane and soluble forms in vivo and in vitro. Imbalances between inhibitory and stimulatory membrane-bound ICPs (mICPs) in malignant cells and immune cells in the tumor immune microenvironment (TIME) have been well documented. Blockades of inhibitory mICPs have emerged as an immense breakthrough in cancer therapeutics. However, the origin, structure, production regulation, and biological significance of soluble ICPs (sICPs) in health and disease largely remains elusive. Soluble ICPs can be generated through either alternative mRNA splicing and secretion or protease-mediated shedding from mICPs. Since sICPs are found in the bloodstream, they likely form a circulating immune regulatory system. In fact, there is increasing evidence that sICPs exhibit biological functions including (1) regulation of antibacterial immunity, (2) interaction with their mICP compartments to positively or negatively regulate immune responses, and (3) competition with their mICP compartments for binding to the ICP blocking antibodies, thereby reducing the efficacy of ICP blockade therapies. Here, we summarize current data of sICPs in cancer and infectious diseases. We particularly focus on sICPs in COVID-19 and HIV infection as they are the two ongoing global pandemics and have created the world's most serious public health challenges. A "storm" of sICPs occurs in the peripheral circulation of COVID-19 patients and is associated with the severity of COVID-19. Similarly, sICPs are highly dysregulated in people living with HIV (PLHIV) and some sICPs remain dysregulated in PLHIV on antiretroviral therapy (ART), indicating these sICPs may serve as biomarkers of incomplete immune reconstitution in PLHIV on ART. We reveal that HIV infection in the setting of alcohol misuse exacerbates sICP dysregulation as PLHIV with heavy alcohol consumption have significantly elevated plasma levels of many sICPs. Thus, both stimulatory and inhibitory sICPs are present in the bloodstream of healthy people and their balance can be disrupted under pathophysiological conditions such as cancer, COVID-19, HIV infection, and alcohol misuse. There is an urgent need to study the role of sICPs in immune regulation in health and disease.


Subject(s)
Alcoholism/immunology , COVID-19/immunology , HIV Infections/immunology , HIV-1/physiology , Neoplasms/immunology , SARS-CoV-2/physiology , Biomarkers/blood , Humans , Immune Checkpoint Proteins/blood , Severity of Illness Index
5.
Nature ; 606(7913): 375-381, 2022 06.
Article in English | MEDLINE | ID: covidwho-1890198

ABSTRACT

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.


Subject(s)
Anti-HIV Agents , Antibodies, Neutralizing , HIV Antibodies , HIV Infections , HIV-1 , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Anti-HIV Agents/immunology , Anti-HIV Agents/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/adverse effects , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Broadly Neutralizing Antibodies/administration & dosage , Broadly Neutralizing Antibodies/adverse effects , Broadly Neutralizing Antibodies/immunology , Broadly Neutralizing Antibodies/therapeutic use , Double-Blind Method , HIV Antibodies/administration & dosage , HIV Antibodies/adverse effects , HIV Antibodies/immunology , HIV Antibodies/therapeutic use , HIV Infections/drug therapy , HIV Infections/immunology , HIV Infections/virology , HIV-1/drug effects , HIV-1/immunology , HIV-1/isolation & purification , Humans , Viral Load/drug effects , Viremia/drug therapy , Viremia/immunology , Viremia/virology
6.
Front Immunol ; 12: 820126, 2021.
Article in English | MEDLINE | ID: covidwho-1715000

ABSTRACT

This study aims to assess the immunological response and impact on virological control of the mRNA vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among people living with HIV (PLWH). In this single-center observational study, all PLWH were offered vaccination with mRNA1273 or BNT162b2. Both anti-N and anti-S1-receptor binding domain (RBD) antibodies were measured together with HIV-1 RNA levels after the first dose (M0) and then at 1 (M1), 2 (M2) and 6 (M6) months later. A total of 131 individuals (median age: 54 years [IQR: 47.0-60.5]; male: 70.2%; median baseline CD4 T-cell: 602/µl [IQR 445.0-825.5]; median nadir CD4 T-cells 223/µl [IQR 111.0-330.0]) were included. All participants were positive for anti-RBD antibodies at 30 days, 60 days and 6 months after the first dose, with no statistical difference between those with HIV-1 RNA below or >20 copies/ml. HIV-1 RNA data were collected for 128 patients at baseline and 30 days after the first dose; for 124 individuals, 30 days after the second dose; and for 83 patients, 6 months after the first dose. Nineteen (14.8%) of 128 had detectable HIV-1 RNA (>20 copies/ml) at M0, 13/128 (10.2%) at M1 (among which 5 were newly detectable), 15/124 (12.1%) at M2 (among which 5 were newly detectable), and 8/83 (9.6%) at M6. No serious adverse effects were reported. All participants elicited antibodies after two doses of mRNA vaccines, with only a minor impact on HIV-1 RNA levels over a 6-month period.


Subject(s)
/immunology , CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , HIV Infections/immunology , HIV-1/physiology , RNA, Viral/analysis , SARS-CoV-2/physiology , Adult , Aged , Antibodies, Viral/blood , Antibody Formation , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Immunity, Heterologous , Male , Middle Aged , Phosphoproteins/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination
7.
Viruses ; 14(2)2022 01 28.
Article in English | MEDLINE | ID: covidwho-1667345

ABSTRACT

This study compared the immunogenicity of inactivated SARS-CoV-2 vaccines between people living with HIV (PLWH) and HIV-negative individuals. We recruited 120 PLWH and 53 HIV-negative individuals aged 18-59 years who had received an inactivated SARS-CoV-2 vaccine in two Chinese cities between April and June 2021. Blood samples were tested for immunogenicity of the inactivated SARS-CoV-2 vaccines. The prevalence and severity of adverse events associated with SARS-CoV-2 vaccines were similar between PLWH and HIV-negative individuals. The seropositivity of neutralizing activity against authentic SARS-CoV-2, of the total amount of antibody (total antibody) and of S-IgG were 71.3%, 81.9%, and 92.6%, respectively, among fully vaccinated PLWH. Among all participants, PLWH had lower neutralizing activity, total antibody, S-IgG, and T-cell-specific immune response levels, compared to HIV-negative individuals, after controlling for types of vaccine, time interval between first and second dose, time after receiving the second dose, and sociodemographic factors. PLWH with a longer interval since HIV diagnosis, who received their second dose 15-28 days prior to study commencement, and who had an interval of ≥21 days between first and second dose had higher neutralizing activity levels. The immunogenicity of the inactivated SARS-CoV-2 vaccines was lower among PLWH as compared to HIV-negative individuals. Vaccination guideline specific for PLWH should be developed.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/immunology , COVID-19/epidemiology , COVID-19/immunology , HIV Infections/epidemiology , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Vaccines, Inactivated/immunology , Adolescent , Adult , Antibodies, Neutralizing/blood , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , China/epidemiology , Cross-Sectional Studies , Female , HIV Infections/complications , HIV Infections/immunology , Humans , Male , Middle Aged , Vaccination , Vaccines, Inactivated/administration & dosage , Young Adult
9.
Lancet HIV ; 8(11): e701-e710, 2021 11.
Article in English | MEDLINE | ID: covidwho-1541051

ABSTRACT

BACKGROUND: Factors affecting outcomes of SARS-CoV-2 infection in people living with HIV are unclear. We assessed the factors associated with SARS-CoV-2 diagnosis and severe outcomes among people living with HIV. METHODS: We did a retrospective cohort study using data from the PISCIS cohort of people with HIV in Catalonia (Spain) between March 1 and Dec 15, 2020. We linked PISCIS data with integrated health-care, clinical, and surveillance registries through the Public Data Analysis for Health Research and Innovation Program of Catalonia (PADRIS) to obtain data on SARS-CoV-2 diagnosis, chronic comorbidities, as well as clinical and mortality outcomes. Participants were aged at least 16 years in care at 16 hospitals in Catalonia. Factors associated with SARS-CoV-2 diagnoses and severe outcomes were assessed using univariable and multivariable Cox regression models. We estimated the effect of immunosuppression on severe outcomes (hospital admission for >24 h with dyspnoea, tachypnoea, hypoxaemia, asphyxia, or hyperventilation; or death) using Kaplan-Meier survival analysis. FINDINGS: We linked 20 847 (72·8%) of 28 666 participants in the PISCIS cohort with PADRIS data; 13 142 people had HIV. 749 (5·7%) people with HIV were diagnosed with SARS-CoV-2: their median age was 43·5 years (IQR 37·0-52·7), 131 (17·5%) were female, and 618 (82·5%) were male. 103 people with HIV (13·8%) were hospitalised, seven (0·9%) admitted to intensive care, and 13 (1·7%) died. SARS-CoV-2 diagnosis was more common among migrants (adjusted hazard ratio 1·55, 95% CI 1·31-1·83), men who have sex with men (1·42, 1·09-1·86), and those with four or more chronic comorbidities (1·46, 1·09-1·97). Age at least 75 years (5·2, 1·8-15·3), non-Spanish origin (2·1, 1·3-3·4), and neuropsychiatric (1·69, 1·07-2·69), autoimmune disease (1·92, 1·14-3·23), respiratory disease (1·84, 1·09-3·09), and metabolic disease (2·59, 1·59-4·23) chronic comorbidities were associated with increased risk of severe outcomes. A Kaplan-Meier estimator showed differences in the risk of severe outcomes according to CD4 cell count in patients with detectable HIV RNA (p=0·039) but no differences were observed in patients with undetectable HIV RNA (p=0·15). INTERPRETATION: People living with HIV with detectable HIV viraemia, chronic comorbidities, and some subpopulations could be at increased risk of severe outcomes from COVID-19. These groups should be prioritised in clinical management and SARS-CoV-2 vaccination programmes. FUNDING: Fundació "la Caixa". TRANSLATIONS: For the Catalan, Spanish and Russian translations of the Summary see Supplementary Materials section.


Subject(s)
COVID-19/immunology , COVID-19/mortality , HIV Infections/complications , HIV Infections/immunology , Immunoglobulin G/blood , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , COVID-19/complications , COVID-19/epidemiology , COVID-19 Testing , COVID-19 Vaccines , Cohort Studies , Female , HIV Infections/drug therapy , HIV Infections/epidemiology , Humans , Immunologic Factors , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Socioeconomic Factors , Spain/epidemiology
10.
Cells ; 10(11)2021 11 16.
Article in English | MEDLINE | ID: covidwho-1523883

ABSTRACT

While the risk of SARS-CoV-2 infection and/or COVID-19 disease progression in the general population has been largely assessed, its impact on HIV-positive individuals remains unclear. We present clinical and immunological data collected in a cohort of HIV-infected young individuals during the first wave of COVID-19 pandemic. SARS-CoV-2 RNA, virus-specific antibodies, as well as the expression of factors involved in the anti-viral immune response were analyzed. Moreover, we set up an in vitro coinfection assay to study the mechanisms correlated to the coinfection process. Our results did not show any increased risk of severe COVID-19 in HIV-positive young individuals. In those subjects who contracted SARS-CoV-2 infection, an increase in IL-10 expression and production was observed. Furthermore, in the in vitro coinfection assay, we revealed a reduction in SARS-CoV-2 replication associated to an upregulation of IL-10. We speculate that IL-10 could play a crucial role in the course of SARS-CoV-2 infection in HIV-positive individuals. These results might help defining clinical management of HIV/SARS-CoV-2 co-infected young individuals, or putative indications for vaccination schedules in this population.


Subject(s)
COVID-19/immunology , Coinfection/immunology , HIV Infections/immunology , Adolescent , Adult , COVID-19/virology , Child , Child, Preschool , Coinfection/virology , HIV Infections/virology , Humans , Infant , Inflammation , Interleukin-10/blood , Interleukin-10/genetics , Male , RNA, Messenger/blood , SARS-CoV-2/immunology , Young Adult
11.
Front Immunol ; 12: 768695, 2021.
Article in English | MEDLINE | ID: covidwho-1523709

ABSTRACT

A major barrier to human immunodeficiency virus (HIV-1) cure is the latent viral reservoir, which persists despite antiretroviral therapy (ART), including across the non-dividing myeloid reservoir which is found systemically in sanctuary sites across tissues and the central nervous system (CNS). Unlike activated CD4+ T cells that undergo rapid cell death during initial infection (due to rapid viral replication kinetics), viral replication kinetics are delayed in non-dividing myeloid cells, resulting in long-lived survival of infected macrophages and macrophage-like cells. Simultaneously, persistent inflammation in macrophages confers immune dysregulation that is a key driver of co-morbidities including cardiovascular disease (CVD) and neurological deficits in people living with HIV-1 (PLWH). Macrophage activation and dysregulation is also a key driver of disease progression across other viral infections including SARS-CoV-2, influenza, and chikungunya viruses, underscoring the interplay between macrophages and disease progression, pathogenesis, and comorbidity in the viral infection setting. This review discusses the role of macrophages in persistence and pathogenesis of HIV-1 and related comorbidities, SARS-CoV-2 and other viruses. A special focus is given to novel immunomodulatory targets for key events driving myeloid cell dysregulation and reservoir maintenance across a diverse array of viral infections.


Subject(s)
HIV Infections/immunology , Immunologic Factors/immunology , Macrophages/immunology , Virus Diseases/immunology , COVID-19/immunology , HIV-1/immunology , Humans , SARS-CoV-2/immunology
12.
Int Immunopharmacol ; 102: 108383, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1521087

ABSTRACT

BACKGROUNDS: To date, the effects of SARS-CoV-2 vaccines on people living with HIV (PLWH) were mainly focused on messenger RNA (mRNA) and adenovirus vector-based vaccines, and little is known about the effects of inactivated virus-based vaccine. This study was designed to determine the effects of inactivated SARS-CoV-2 vaccines on PLWH. METHODS: Twenty-four HIV-positive individuals and 24 healthy donors (HD) were respectively recruited from Malipo Country People's Hospital and community in Kunming city. Enumeration of lymphocyte and CD4+CD45RO+ memory T cells were evaluated by flow cytometry. Competitive ELISA was used to measure the level of Anti-SARS-CoV-2 neutralization antibody. Spearman or Pearson correlation analysis was used to analyze the relationship between laboratory indicators and neutralization antibodies in PLWH. T-cell responses (Th1, Th2, Th17, Treg) and intracellular expression of cytokines (IL-2 and TNF-α) in CD4 or CD8 were induced by spike protein in SARS-CoV-2 (SARS-2-S) and further measured by intracellular staining. RESULTS: CD4, B cells, CD4+CD45RO+ memory T cells in peripheral blood of PLWH are dramatically decreased in comparison with HD. Importantly, PLWH display comparable neutralizing antibody positive rate to HD after inoculation with inactivated SARS-CoV-2 vaccine. However, PLWH showed weaker responses to vaccines exhibited by lower levels of neutralizing antibodies. Correlation analysis shows that this is possibly caused by low number of CD4 and B cells. Furthermore, SARS-2-S-induced Th2 and Th17 responses are also decreased in PLWH, while no influences on Treg and other cytokines (IL-2, TNF-α and IFN-γ) observed. CONCLUSIONS: PLWH and HD have comparable neutralizing antibodies positive rates, but PLWH display weaker responses to inactivated SARS-CoV-2 vaccines in magnitude, which suggests that a booster dose or dose adjustment are required for HIV-infected individuals, especially for those with lower counts of CD4 T and B cells.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , HIV Infections/immunology , Vaccines, Inactivated/immunology , Adult , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Female , HIV Infections/blood , HIV Infections/complications , Healthy Volunteers , Humans , Immunogenicity, Vaccine , Male , Middle Aged , SARS-CoV-2/immunology , Th17 Cells/immunology , Th2 Cells/immunology , Vaccines, Inactivated/administration & dosage
13.
Nat Commun ; 12(1): 5839, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1454764

ABSTRACT

There is an urgent need to understand the nature of immune responses against SARS-CoV-2, to inform risk-mitigation strategies for people living with HIV (PLWH). Here we show that the majority of PLWH with ART suppressed HIV viral load, mount a detectable adaptive immune response to SARS-CoV-2. Humoral and SARS-CoV-2-specific T cell responses are comparable between HIV-positive and negative subjects and persist 5-7 months following predominately mild COVID-19 disease. T cell responses against Spike, Membrane and Nucleoprotein are the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. We further show that the overall magnitude of SARS-CoV-2-specific T cell responses relates to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH. These findings suggest that inadequate immune reconstitution on ART, could hinder immune responses to SARS-CoV-2 with implications for the individual management and vaccine effectiveness in PLWH.


Subject(s)
HIV Infections/immunology , HIV Infections/virology , Immunity, Humoral , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Adult , Aged , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antibody Formation/immunology , Antigens, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Cohort Studies , Female , Genome, Human , HIV Infections/blood , Humans , Interferon-gamma/metabolism , Male , Middle Aged , Phenotype , Species Specificity , Tissue Donors
14.
Elife ; 102021 10 05.
Article in English | MEDLINE | ID: covidwho-1450948

ABSTRACT

There are conflicting reports on the effects of HIV on COVID-19. Here, we analyzed disease severity and immune cell changes during and after SARS-CoV-2 infection in 236 participants from South Africa, of which 39% were people living with HIV (PLWH), during the first and second (Beta dominated) infection waves. The second wave had more PLWH requiring supplemental oxygen relative to HIV-negative participants. Higher disease severity was associated with low CD4 T cell counts and higher neutrophil to lymphocyte ratios (NLR). Yet, CD4 counts recovered and NLR stabilized after SARS-CoV-2 clearance in wave 2 infected PLWH, arguing for an interaction between SARS-CoV-2 and HIV infection leading to low CD4 and high NLR. The first infection wave, where severity in HIV negative and PLWH was similar, still showed some HIV modulation of SARS-CoV-2 immune responses. Therefore, HIV infection can synergize with the SARS-CoV-2 variant to change COVID-19 outcomes.


Subject(s)
COVID-19/complications , COVID-19/immunology , HIV Infections/complications , HIV Infections/immunology , Immunity, Cellular , Severity of Illness Index , Adult , Aged , CD4 Lymphocyte Count , Female , Humans , Male , Middle Aged , SARS-CoV-2 , South Africa
15.
Viruses ; 13(9)2021 09 10.
Article in English | MEDLINE | ID: covidwho-1430973

ABSTRACT

Monocytes are key modulators in acute viral infections, determining both inflammation and development of specific B- and T-cell responses. Recently, these cells were shown to be associated to different SARS-CoV-2 infection outcome. However, their role in acute HIV-1 infection remains unclear. We had the opportunity to evaluate the mononuclear cell compartment in an early hyper-acute HIV-1 patient in comparison with an untreated chronic HIV-1 and a cohort of SARS-CoV-2 infected patients, by high dimensional flow cytometry using an unsupervised approach. A distinct polarization of the monocyte phenotype was observed in the two viral infections, with maintenance of pro-inflammatory M1-like profile in HIV-1, in contrast to the M2-like immunosuppressive shift in SARS-CoV-2. Noticeably, both acute infections had reduced CD14low/-CD16+ non-classical monocytes, with depletion of the population expressing Slan (6-sulfo LacNac), which is thought to contribute to immune surveillance through pro-inflammatory properties. This depletion indicates a potential role of these cells in acute viral infection, which has not previously been explored. The inflammatory state accompanied by the depletion of Slan+ monocytes may provide new insights on the critical events that determine the rate of viral set-point in acute HIV-1 infection and subsequent impact on transmission and reservoir establishment.


Subject(s)
Amino Sugars/immunology , COVID-19/immunology , HIV Infections/immunology , HIV-1/immunology , Monocytes/immunology , Adult , Aged , Cohort Studies , Female , Humans , Leukocyte Count , Male , Middle Aged , Young Adult
16.
Cell Rep ; 37(1): 109793, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1415261

ABSTRACT

The mortality risk of coronavirus disease 2019 (COVID-19) patients has been linked to the cytokine storm caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding the inflammatory responses shared between COVID-19 and other infectious diseases that feature cytokine storms may therefore help in developing improved therapeutic strategies. Here, we use integrative analysis of single-cell transcriptomes to characterize the inflammatory signatures of peripheral blood mononuclear cells from patients with COVID-19, sepsis, and HIV infection. We identify ten hyperinflammatory cell subtypes in which monocytes are the main contributors to the transcriptional differences in these infections. Monocytes from COVID-19 patients share hyperinflammatory signatures with HIV infection and immunosuppressive signatures with sepsis. Finally, we construct a "three-stage" model of heterogeneity among COVID-19 patients, related to the hyperinflammatory and immunosuppressive signatures in monocytes. Our study thus reveals cellular and molecular insights about inflammatory responses to SARS-CoV-2 infection and provides therapeutic guidance to improve treatments for subsets of COVID-19 patients.


Subject(s)
COVID-19/blood , COVID-19/immunology , HIV Infections/blood , Leukocytes, Mononuclear/metabolism , SARS-CoV-2/immunology , Sepsis/blood , Transcriptome , COVID-19/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Cytokines/blood , Data Analysis , Datasets as Topic , HIV Infections/immunology , HIV-1/immunology , Humans , Inflammation/blood , Leukocytes, Mononuclear/immunology , Sepsis/immunology , Single-Cell Analysis
18.
Mol Syst Biol ; 17(9): e10243, 2021 09.
Article in English | MEDLINE | ID: covidwho-1395372

ABSTRACT

Systems serology provides a broad view of humoral immunity by profiling both the antigen-binding and Fc properties of antibodies. These studies contain structured biophysical profiling across disease-relevant antigen targets, alongside additional measurements made for single antigens or in an antigen-generic manner. Identifying patterns in these measurements helps guide vaccine and therapeutic antibody development, improve our understanding of diseases, and discover conserved regulatory mechanisms. Here, we report that coupled matrix-tensor factorization (CMTF) can reduce these data into consistent patterns by recognizing the intrinsic structure of these data. We use measurements from two previous studies of HIV- and SARS-CoV-2-infected subjects as examples. CMTF outperforms standard methods like principal components analysis in the extent of data reduction while maintaining equivalent prediction of immune functional responses and disease status. Under CMTF, model interpretation improves through effective data reduction, separation of the Fc and antigen-binding effects, and recognition of consistent patterns across individual measurements. Data reduction also helps make prediction models more replicable. Therefore, we propose that CMTF is an effective general strategy for data exploration in systems serology.


Subject(s)
AIDS Serodiagnosis , COVID-19 Serological Testing , COVID-19/immunology , Data Interpretation, Statistical , HIV Infections/immunology , AIDS Serodiagnosis/methods , AIDS Serodiagnosis/statistics & numerical data , Antibodies, Viral/blood , Antibodies, Viral/metabolism , COVID-19 Serological Testing/methods , COVID-19 Serological Testing/statistics & numerical data , Humans , Immunity, Humoral , Killer Cells, Natural/immunology , Logistic Models , Receptors, Fc/immunology , Receptors, IgG/immunology
19.
Int J Med Sci ; 18(3): 846-851, 2021.
Article in English | MEDLINE | ID: covidwho-1389719

ABSTRACT

In the last 50 years we have experienced two big pandemics, the HIV pandemic and the pandemic caused by SARS-CoV-2. Both pandemics are caused by RNA viruses and have reached us from animals. These two viruses are different in the transmission mode and in the symptoms they generate. However, they have important similarities: the fear in the population, increase in proinflammatory cytokines that generate intestinal microbiota modifications or NETosis production by polymorphonuclear neutrophils, among others. They have been implicated in the clinical, prognostic and therapeutic attitudes.


Subject(s)
COVID-19/epidemiology , HIV Infections/epidemiology , HIV-1/pathogenicity , Pandemics/history , SARS-CoV-2/pathogenicity , COVID-19/immunology , COVID-19/psychology , COVID-19/transmission , Cytokines/blood , Cytokines/immunology , Extracellular Traps/immunology , Extracellular Traps/metabolism , Fear , Global Burden of Disease/statistics & numerical data , HIV Infections/immunology , HIV Infections/psychology , HIV Infections/transmission , HIV-1/immunology , HIV-1/isolation & purification , History, 20th Century , History, 21st Century , Host-Pathogen Interactions/immunology , Humans , Inflammation Mediators/blood , Inflammation Mediators/immunology , Mortality , Neutrophils/immunology , Neutrophils/metabolism , Pandemics/statistics & numerical data , Prognosis , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification
20.
Sci Adv ; 7(31)2021 07.
Article in English | MEDLINE | ID: covidwho-1388435

ABSTRACT

Rationally designed protein subunit vaccines are being developed for a variety of viruses including influenza, RSV, SARS-CoV-2, and HIV. These vaccines are based on stabilized versions of the primary targets of neutralizing antibodies on the viral surface, namely, viral fusion glycoproteins. While these immunogens display the epitopes of potent neutralizing antibodies, they also present epitopes recognized by non-neutralizing or weakly neutralizing ("off-target") antibodies. Using our recently developed electron microscopy polyclonal epitope mapping approach, we have uncovered a phenomenon wherein off-target antibodies elicited by HIV trimer subunit vaccines cause the otherwise highly stabilized trimeric proteins to degrade into cognate protomers. Further, we show that these protomers expose an expanded suite of off-target epitopes, normally occluded inside the prefusion conformation of trimer, that subsequently elicit further off-target antibody responses. Our study provides critical insights for further improvement of HIV subunit trimer vaccines for future rounds of the iterative vaccine design process.


Subject(s)
AIDS Vaccines/immunology , HIV Antibodies/chemistry , HIV Infections/immunology , HIV-1/chemistry , env Gene Products, Human Immunodeficiency Virus/chemistry , AIDS Vaccines/chemistry , Animals , COVID-19/immunology , Female , HIV Antibodies/immunology , HIV-1/immunology , Humans , Macaca mulatta , Rabbits , SARS-CoV-2/chemistry , SARS-CoV-2/immunology , env Gene Products, Human Immunodeficiency Virus/immunology
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