Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting: the RV217 acute infection cohort study.

BACKGROUND: The CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the mechanisms remain unclear. The difficulty in elucidating the evolutionary origin of the earliest X4 viruses limits our understanding of this phenomenon. METHODS: We tracked the evolution of the transmitted/founder (T/F) HIV-1 in RV217 participants identified in acute infection. The origin of the X4 viruses was elucidated by single genome amplification, deep sequencing and coreceptor assay. Mutations responsible for coreceptor switch were confirmed by mutagenesis. Viral susceptibility to neutralization was determined by neutralization assay. Virus CD4 subset preference was demonstrated by sequencing HIV-1 RNA in sorted CD4 subsets. FINDINGS: We demonstrated that the earliest X4 viruses evolved de novo from the T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive the X4 variants to replicate mainly in the central memory (CM) and naïve CD4 subsets. Likely due to the smaller viral burst size of the CM and naïve subsets, the X4 variants existed at low frequency in plasma. The origin of the X4 viruses preceded accelerated CD4 decline. All except one X4 virus identified in the current study lost the conserved V3 N301 glycan site. INTERPRETATIONS: The findings demonstrate co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting which have implications for HIV-1 therapeutics and functional cure. The observations provide evidence that coreceptor switch can function as an evolutionary mechanism of immune evasion. FUNDING: Institute of Human Virology, National Institutes of Health, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Thai Red Cross AIDS Research Centre, Gilead Sciences, Merck, and ViiV Healthcare.

Angiomatosis bacilar y sarcoma de Kaposi en lesión cutánea de paciente VIH positivo / Bacillary angiomatosis and Kaposi's sarcoma in skin lesion of HIV positive patient

La angiomatosis bacilar (AB) es una enfermedad infec-ciosa poco frecuente, causada por bacterias del género Bartonella spp. transmitidas por vectores como pulgas, piojos y mosquitos. En el ser humano provoca diferentes síndromes clínicos. En pacientes con infección por el virus de inmunodeficiencia humana (VIH) con recuento de LT CD4 + <100 cél/µL se asocia a lesiones angiomatosas con neovascularización que comprometen la piel y, en menor medida, mucosas, hígado, bazo y huesos.El sarcoma de Kaposi (SK) es una neoplasia caracteriza-da por hiperplasia vascular multifocal de origen endotelial relacionada con el herpes virus humano 8. También puede afectar piel, mucosas y vísceras, siendo la variante epidé-mica una enfermedad marcadora de la infección avanzada por VIH. El principal diagnóstico diferencial clínico para las lesiones cutáneas y mucosas del SK es la AB.Presentamos un paciente con enfermedad VIH/sida que desarrolló AB y SK en forma concomitante en la misma lesión cutánea

Bacillary angiomatosis (BA) is a rare infectious disease, caused by bacteria of the genus Bartonella spp, transmitted by vectors such as fleas, lice and mosquitoes. It causes different clinical syndromes in humans. In patients with human immunodeficiency virus (HIV) infection with an LT CD4 + <100 cell/µL count, it is associated with the development of angiomatous lesions with neovascularization involving the skin and, with less frequency, mucous membranes, liver, spleen and bones. Kaposi's sarcoma (KS) is a neoplasm characterized by multifocal vascular hyperplasia of endothelial origin related to human herpes virus 8. It can also compromiso the skin, mucous membranes and viscera, with the epidemic variant being a marker disease of advanced HIV infection. The main clinical differential diagnosis for KS skin and mucosal lesions is the BA.Herein we present a patient with HIV/AIDS disease that developed BA and KS concomitantly in the same skin lesion

Sarcoma de Kaposi del tracto gastrointestinal. Reporte de presentación en colon / Kaposi's sarcoma of the gastrointestinal tract. Report of presentation in colon

El sarcoma de Kaposi (SK) es una neoplasia maligna angioproliferativa de bajo grado, causada por la infección por virus herpes humano tipo 8 (HHV-8). El tracto gastrointestinal está involucrado en el 40% de los casos y constituye la neoplasia maligna gastrointestinal más común en pacientes con sida. Se presenta el caso de un paciente 32 años con antecedente de VIH de larga data, sin tratamiento, que relató episodios de proctorragia intermitente y pérdida de peso en los últimos dos meses. Presentaba lesiones cutáneas elevadas en forma de placas violáceas que predominaban en tronco y miembros superiores. Se realizó videocolonoscopía, la que evidenció en el área próxima a la válvula ileocecal y en el colon ascendente, lesiones sobreelevadas, eritematosas, friables y sangrantes, las cuales se biopsiaron. El estudio anatomopatológico reportó un perfil inmunohistoquímico compatible con SK. Al momento de la escritura de este artículo el paciente se encontraba bajo tratamiento quimioterápico (doxorrubicina liposomal, seis ciclos) e iniciando tratamiento antirretroviral (lamivudina ­ tenofovir ­ dolutegravir). Se presenta el siguiente caso para destacar la importancia del enfoque multidisciplinario del paciente con VIH/sida y fundamentalmente el rol de la endoscopía digestiva tanto alta como baja en pacientes con dolor abdominal, sangrado digestivo u otros síntomas abdominales, con el fin de descartar patologías del tracto gastrointestinal y, particularmente, el SK

Kaposi's sarcoma (KS) is a low-grade angioproliferative malignancy caused by infection with human herpes virus -8. The gastrointestinal tract is involved in 40% of cases, being the most common gastrointestinal malignancy in patients with AIDS. We present the case of a 32-year-old patient with a long-standing history of HIV without treatment, who reported episodes of intermittent proctorrhagia and weight loss in the last two months. He presented raised skin lesions in the form of violaceous plaques that predominate on the trunk and upper limbs. A videocolonoscopy was performed, revealing raised, erythematous, friable, bleeding lesions near the ileocecal valve and in the ascending colon, which were biopsied. The anatomopathological study shows an immunohistochemical profile compatible with KS. At the time of writing this article, the patient was under chemotherapy treatment (liposomal doxorubicin, 6 cycles) and starting antiretroviral treatment (lamivudine - tenofovir - dolutegravir). The following case is presented to highlight the importance of the multidisciplinary approach of the patient with HIV / AIDS and fundamentally the role of both upper and lower digestive endoscopy in those cases that present with abdominal pain, digestive bleeding and other abdominal symptoms, in order to rule out gastrointestinal tract pathologies and particularly KS

Utilidad del recuento de unidades formadoras de colonia de Cryptococcus sp. en líquido cefalorraquídeo de pacientes con criptococosis meníngea asociada al sida / Cryptococcus' colony forming unit count usefulness

Antecedentes: El recuento de unidades formadoras de colonia (UFC) de Cryptococcus en el líquido cefalorraquídeo (LCR) sería un marcador fiable para el pronóstico del paciente y una herramienta simple y económica. Objetivo: Evaluar la utilidad del recuento de UFC de Cryptococcus spp. y compararlo con las variaciones de antígeno capsular de Cryptococcus (AgCr) en LCR.Materiales y métodos: Se realizó la revisión de historias clínicas de pacientes con meningoencefalitis por Cryptococcus asociada con el sida en nuestro centro, entre febrero de 2016 y julio de 2020. Se evaluaron los valores de UFC y AgCr en LCR durante la evolución de la micosis. Resultados y discusión: Se analizaron datos de 94 episodios clínicos de 85 pacientes, con un total de 297 observaciones de muestras de LCR. Se evidenció el valor del recuento de UFC por ser un marcador de viabilidad y de carga fúngica. El recuento de UFC bajo no necesariamente coexistió con un nivel bajo de AgCr. Con respecto a la evolución en el tiempo, la mayoría de los pacientes fueron diagnosticados con una alta carga fúngica y su descenso ocurrió más rápido que el del AgCr, por lo que reflejaría la mejora del paciente, permitiendo tomar conductas al respecto.Palabras clave: Criptococosis, carga fúngica, ufc/mL.

Background. The Cryptococcus' colony-forming unit (CFU) count in cerebrospinal fluid (CSF) would be a reliable marker for patient prognosis and a simple and inexpensive tool. Objectives: To evaluate the usefulness of the CFU count of Cryptococcus spp. And to compare it with the variations of Cryptococcus' capsular antigen (CrAg) in CSF.Materials and methods. Clinical records of patients with aids-related meningoencephalitis caused by Cryptococcusassisted in our center between February 2016 and July 2020 were reviewed. CFU count and CrAg values in CSF were evaluated during the evolution of the mycosis.Results and Discussion. Data from 94 clinical episodes of 85 patients with a total of 297 observations of CSF samples were analyzed.The importance of using the CFU count was evidenced as it is a viability and fungal load marker.Low CFU count did not necessarily coexist with low CrAg.Regarding the evolution over time, most of the patients were diagnosed with a high fungal load and its decrease occurred faster than that the one of AgCr. This would reflect the improvement of the patient, allowing behaviors to be taken in this regard

Host-Level Susceptibility and IRF1 Expression Influence the Ability of IFN-γ to Inhibit KSHV Infection in B Lymphocytes.

Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with vascular endothelial cell tumor, Kaposi's sarcoma (KS) and lymphoproliferative disorder, multicentric Castleman's disease (MCD), primary effusion lymphoma (PEL) and KSHV inflammatory cytokine syndrome (KICS). Dysregulation of proinflammatory cytokines is found in most KSHV associated diseases. However, little is known about the role of host microenvironment in the regulation of KSHV establishment in B cells. In the present study, we demonstrated that IFN-γ has a strong inhibitory effect on KSHV infection but only in a subset of tonsil-derived lymphocyte samples that are intrinsically more susceptible to infection, contain higher proportions of naïve B cells, and display increased levels of IRF1 and STAT1-pY701. The effect of IFN-γ in responsive samples was associated with increased frequencies of germinal center B cells (GCB) and decreased infection of plasma cells, suggesting that IFN-γ-mediated modulation of viral dynamics in GC can inhibit the establishment of KSHV infection.

AIDS patient with severe T cell depletion achieved control but not clearance of SARS-CoV-2 infection.

A late presenter AIDS patient with severe T cell depletion presented non-severe COVID-19 symptoms, with prolonged viral shedding. Our case report supports the hypothesis that an effective T cell response may be dispensable for the control of COVID-19 progression to severe forms, while it may be necessary for SARS-CoV-2 clearance.

CD3+T, CD4+T, CD8+T, and CD4+T/CD8+T Ratio and Quantity of γδT Cells in Peripheral Blood of HIV-Infected/AIDS Patients and Its Clinical Significance.

OBJECTIVE: To investigate the quantity of CD4+T, CD4+T, CD8+T, and γδT cells in peripheral blood of HIV-infected/AIDS patients as well as to explore the possible role of CD4/CD8 ratio and γδT cells in the progression of HIV/AIDS, aimed at providing evidence for the diagnosis and treatment of AIDS. METHODS: The quantity levels of CD3+T cells, CD4+T cells, CD8+T cells, and γδT cells in peripheral blood of 46 HIV-infected/AIDS patients and 30 healthy controls were detected by using flow cytometry. RESULTS: The count of CD3+T, CD4+T, CD8+T, and γδT cells ( x ¯ ± s , A/µl) in the peripheral blood was 1183.64 ± 132.58, 278.39 ± 122.38, 863.13 ± 82.38, and 22.53 ± 1.74 in the experimental group as well as 1456.46 ± 124.37, 788.74 ± 189.67, 569.61 ± 46.49, and 10.96 ± 0.28 in the control group, respectively. The p values of the two groups were <0.005 after the t-test, revealing a statistically significant difference. The proportion of CD3+T, CD4+T, CD8+T, and γδT cells in total lymphocytes in the two groups ( x ¯ ± s , %) was 71.83 ± 5.37, 13.39 ± 2.23, 62.93 ± 5.81, and 3.67 ± 0.87 in the experimental group, respectively. In the control group, the values were expressed as 66.72 ± 5.48, 42.77 ± 3.38, 31.41 ± 3.62, and 1.73 ± 0.36, respectively. After performing the t-test, p values in the two groups were <0.005 except CD3+T, with statistically significant differences. Besides, CD4/CD8 was 0.33 ± 0.11 in the experimental group and 1.48 ± 0.29 in the control group, t = 26.528, p < 0.001, exhibiting a significant statistical difference. CONCLUSION: HIV infection induces the activation and proliferation of CD8+T and γδT cells, contributing to the decrease of CD4+T cells, while CD8+T and γδT cells are involved in the immune response and tissue damage after HIV infection.

Rapid Emergence of T Follicular Helper and Germinal Center B Cells Following Antiretroviral Therapy in Advanced HIV Disease.

Low nadir CD4 T-cell counts in HIV+ patients are associated with high morbidity and mortality and lasting immune dysfunction, even after antiretroviral therapy (ART). The early events of immune recovery of T cells and B cells in severely lymphopenic HIV+ patients have not been fully characterized. In a cohort of lymphopenic (CD4 T-cell count < 100/µL) HIV+ patients, we studied mononuclear cells isolated from peripheral blood (PB) and lymph nodes (LN) pre-ART (n = 40) and 6-8 weeks post-ART (n = 30) with evaluation of cellular immunophenotypes; histology on LN sections; functionality of circulating T follicular helper (cTfh) cells; transcriptional and B-cell receptor profile on unfractionated LN and PB samples; and plasma biomarker measurements. A group of 19 healthy controls (HC, n = 19) was used as a comparator. T-cell and B-cell lymphopenia was present in PB pre-ART in HIV+ patients. CD4:CD8 and CD4 T- and B-cell PB subsets partly normalized compared to HC post-ART as viral load decreased. Strikingly in LN, ART led to a rapid decrease in interferon signaling pathways and an increase in Tfh, germinal center and IgD-CD27- B cells, consistent with histological findings of post-ART follicular hyperplasia. However, there was evidence of cTfh cells with decreased helper capacity and of limited B-cell receptor diversification post-ART. In conclusion, we found early signs of immune reconstitution, evidenced by a surge in LN germinal center cells, albeit limited in functionality, in HIV+ patients who initiate ART late in disease.

Dynamics of T-Lymphocyte Activation Related to Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in Persons With Advanced HIV.

Most persons living with HIV (PLWH) experience a significant restoration of their immunity associated with successful inhibition of viral replication after antiretroviral therapy (ART) initiation. Nevertheless, with the robust quantitative and qualitative restoration of CD4+ T-lymphocytes, a fraction of patients co-infected with tuberculosis develop immune reconstitution inflammatory syndrome (TB-IRIS), a dysregulated inflammatory response that can be associated with significant tissue damage. Several studies underscored the role of adaptive immune cells in IRIS pathogenesis, but to what degree T lymphocyte activation contributes to TB-IRIS development remains largely elusive. Here, we sought to dissect the phenotypic landscape of T lymphocyte activation in PLWH coinfected with TB inititating ART, focusing on characterization of the profiles linked to development of TB-IRIS. We confirmed previous observations demonstrating that TB-IRIS individuals display pronounced CD4+ lymphopenia prior to ART initiation. Additionally, we found an ART-induced increase in T lymphocyte activation, proliferation and cytotoxicity among TB-IRIS patients. Importantly, we demonstrate that TB-IRIS subjects display higher frequencies of cytotoxic CD8+ T lymphocytes which is not affected by ART. Moreover, These patients exhibit higher levels of activated (HLA-DR+) and profilerative (Ki-67+) CD4+ T cells after ART commencenment than their Non-IRIS counterparts. Our network analysis reveal significant negative correlations between Total CD4+ T cells counts and the frequencies of Cytotoxic CD8+ T cells in our study population which could suggest the existance of compensatory mechanisms for Mtb-infected cells elimination in the face of severe CD4+ T cell lymphopenia. We also investigated the correlation between T lymphocyte activation profiles and the abundance of several inflammatory molecules in plasma. We applied unsupervised machine learning techniques to predict and diagnose TB-IRIS before and during ART. Our analyses suggest that CD4+ T cell activation markers are good TB-IRIS predictors, whereas the combination of CD4+ and CD8+ T cells markers are better at diagnosing TB-IRIS patients during IRIS events Overall, our findings contribute to a more refined understanding of immunological mechanisms in TB-IRIS pathogenesis that may assist in new diagnostic tools and more targeted patient management.

How Antibodies Recognize Pathogenic Viruses: Structural Correlates of Antibody Neutralization of HIV-1, SARS-CoV-2, and Zika.

The H1N1 pandemic of 2009-2010, MERS epidemic of 2012, Ebola epidemics of 2013-2016 and 2018-2020, Zika epidemic of 2015-2016, and COVID-19 pandemic of 2019-2021, are recent examples in the long history of epidemics that demonstrate the enormous global impact of viral infection. The rapid development of safe and effective vaccines and therapeutics has proven vital to reducing morbidity and mortality from newly emerging viruses. Structural biology methods can be used to determine how antibodies elicited during infection or vaccination target viral proteins and identify viral epitopes that correlate with potent neutralization. Here we review how structural and molecular biology approaches have contributed to our understanding of antibody recognition of pathogenic viruses, specifically HIV-1, SARS-CoV-2, and Zika. Determining structural correlates of neutralization of viruses has guided the design of vaccines, monoclonal antibodies, and small molecule inhibitors in response to the global threat of viral epidemics.

Pharmacokinetics of fluconazole and ganciclovir as combination antimicrobial chemotherapy on ECMO: a case report.

Extracorporeal membrane oxygenation (ECMO) can affect antimicrobial pharmacokinetics. This case report describes a 33-year-old male with newly diagnosed acquired immunodeficiency syndrome presenting in acute severe type 1 respiratory failure. On investigation, the patient had positive cultures for Candida albicans from respiratory specimens and high blood cytomegalovirus titres, and required venovenous ECMO therapy for refractory respiratory failure. Intravenous fluconazole (6 mg/kg, 24-h) and ganciclovir (5 mg/kg, 12-h) was commenced. Pre-oxygenator, post-oxygenator and arterial blood samples were collected after antibiotic administration, and were analysed for total fluconazole and ganciclovir concentrations. Although there was a 40% increase in the volume of distribution for fluconazole relative to healthy volunteers, the pharmacodynamic targets for prophylaxis were still met. The area under the curve exposure of ganciclovir (50.78 mg•h/L) achieved target thresholds. The ECMO circuit had no appreciable effect on achievement of therapeutic exposures of fluconazole and ganciclovir.

COVID-19, Ebola virus disease, and Nipah virus infection reclassification as novel acute immune dysrhythmia syndrome (n-AIDS): potential crucial role for immunomodulators.

In this manuscript, COVID-19, Ebola virus disease, Nipah virus infection, SARS, and MERS are suggested to be considered for a novel immunological reclassification as acute onset immune dysrhythmia syndrome (n-AIDS) due to altered monocytic, Th1/Th2, as well as cytokines and chemokines balances. n-AIDs is postulated to be the cause of the acute respiratory distress and multi-inflammatory syndromes which are described with fatal COVID-19, and immunomodulators are suggested to effectively manage the mentioned diseases as well as for other disorders caused by Th1/Th2 imbalance. Meanwhile, para COVID syndrome is suggested to describe various immune-related complications, whether before or after recovery, and to embrace a potential of a latent infection, that might be discovered later, as occurred with Ebola virus disease. Finally, our hypothesis has evolved out of our real-life practice that uses immunomodulatory drugs to manage COVID-19 safely and effectively.

Recent developments in CCR5 regulation for HIV cure.

Acquired immunodeficiency syndrome (AIDS) has affected millions of people worldwide. The human immunodeficiency virus (HIV) which infects T cells by using CD4 as its main receptor. Currently different treatments are available against HIV infection which can improve life expectancy of the patient but still it remains incurable. CCR5, which is also required as a co-receptor by majority of HIV strains for entry into the target cells, is now being targeted for gene therapy to develop HIV resistance in patients. In this review, we discuss different strategies that are being adapted for CCR5-gene disruption in CD4+ T cells and in hematopoietic stem cells (HSCs) to generate a HIV-resistant immune system in infected individuals. If CCR5 gene that can shape HIV-resistant T cells, it will aim in new approaches in clinical trials. But these techniques have certain weaknesses and disadvantages, and will need to be paired with other strategies to form a full HIV remedy. There is also a need to establish methods to help deter HIV re-emergence following targeted CCR5 therapy. But ultimately, this brought us a better knowledge of the road to HIV treatment.

A preliminary study on the characteristics of Th1/Th2 immune response in cerebrospinal fluid of AIDS patients with cryptococcal meningitis.

BACKGROUND: Cryptococcal Meningitis (CM) is a common opportunistic infection in the late stage of acquired immunodeficiency syndrome (AIDS). Despite the wide use of effective antiretroviral and antifungal therapy in AIDS patients, CM is still a major morbidity and mortality cause. Understanding the immune response in cryptococcal infection may help to improve the treatment strategies. METHODS: We established a prospective cohort of twelve AIDS patients with CM (HIV + CM+) admitted to the hospital from 2019 to 2020. All patients were examined at the baseline, 2 weeks, and 4 weeks thereafter. The level of 19 cytokines in cerebrospinal fluid (CSF) were recorded to analyze the characteristics and dynamic changes of Th1/Th2 immune response. Meanwhile, six AIDS patients without CM (HIV + CM-) and seventeen healthy subjects (HIV-CM-) were included as control groups for CSF assessment. RESULTS: The HIV+ CM+ group had higher CSF IFN-γ, TNF-α, IL-6, IL-7, IL-8, IL-10, IL-12 (P40), IL-15, IL-18, CCL2 levels but lower IL-4 when compared with the HIV-CM- group at baseline. And they also had a higher level of IL-12 (P40) and IL-17A compared with HIV + CM- patients. Except one patient dropped out of the study, eleven HIV + CM+ patients received induction antifungal therapy and regular CSF testing, and the mortality rate was 9.1% (1/11) and 18.2% (2/11) respectively at week 2 and week 4. Compared with baseline CSF cytokines, IL-2, IL-13, IL-17A, and VEGF-A decreased in week 2, and the VEGF-A levels further decreased in week 4. But there was no difference in the levels of all cytokines between survivors and the dead. CONCLUSION: No evidence of Th1/Th2 imbalance was found in AIDS patients with CM. However, the CSF cytokine network may provide new clues for the treatment of AIDS patients with CM. TRIAL REGISTRATION: This trial was prospectively registered in 2019.7.16. The registered number is ChiCTR1900024565 .

Temporal and spatial characterization of negative regulatory T cells in HIV-infected/AIDS patients raises new diagnostic markers and therapeutic strategies.

BACKGROUND: Negative regulatory T cells (Tregs) not only deplete effector T cells but also inhibit the clearance of HIV during infection, which may allow Tregs to be used as informative diagnostic markers. To facilitate both diagnosis and treatment, a thorough understanding of these regulators by characterizing them on temporal and spatial scales is strongly required. METHODS: Hundred HIV-infected/AIDS patients, including 87 males, with an average age of 35.8 years, as well as 20 healthy controls, were enrolled. Flow cytometry was used to analyze CD3+T cells, CD4+T cells, and CD8+T cells to evaluate the immune status of the participants. Then, a group of representative negative regulatory T cells, including CD4+PD-1+T cells, CD4+PD-1high T cells, CD8+PD-1+T cells, and CD4+CD25high Tregs was also analyzed to explore their effects on disease progression and intercorrelation. RESULTS: The percentages of CD4+ PD-1+ T cells and CD4+ CD25high Tregs increased in patients with the same ultrahigh significance. Temporally, the patients with both intermediate-stage and late-stage disease had higher percentages of CD4+ PD-1+ T cells; however, the percentage of CD4+ CD25high Tregs only increased in the patients with late-stage disease. In addition, CD4+ PD-1+ T cells but not CD4+ CD25high Tregs were negatively correlated with the absolute CD4+ T cell count. Spatially, no correlations between CD4+ PD-1+ T cells and CD4+ CD25high Tregs were observed, which suggests these Tregs function differently during immunosuppression. CONCLUSIONS: This study characterized negative regulatory T cells in HIV-infected/AIDS patients at both temporal and spatial scales and found that CD4+ CD25+ Tregs and CD4+ PD-1+ T cells could be used as potential diagnostic markers for identifying different disease stages and monitoring disease progression.

HLA-mismatched allogeneic adoptive immune therapy in severely immunosuppressed AIDS patients.

Severely immunosuppressed AIDS patients with recurrent opportunistic infections (OIs) represent an unmet medical need even in the era of antiretroviral therapy (ART). Here we report the development of a human leukocyte antigen (HLA)-mismatched allogeneic adaptive immune therapy (AAIT) for severely immunosuppressed AIDS patients. Twelve severely immunosuppressed AIDS patients with severe OIs were enrolled in this single-arm study. Qualified donors received subcutaneous recombinant granulocyte-colony-stimulating factor twice daily for 4-5 days to stimulate hematopoiesis. Peripheral blood mononuclear cells were collected from these donors via leukapheresis and transfused into the coupled patients. Clinical, immunological, and virological parameters were monitored during a 12-month follow-up period. We found AAIT combined with ART was safe and well-tolerated at the examined doses and transfusion regimen in all 12 patients. Improvements in clinical symptoms were evident throughout the study period. All patients exhibited a steady increase of peripheral CD4+ T cells from a median 10.5 to 207.5 cells/µl. Rapid increase in peripheral CD8+ T-cell count from a median 416.5 to 1206.5 cells/µl was found in the first 90 days since initiation of AAIT. In addition, their inflammatory cytokine levels and HIV RNA viral load decreased. A short-term microchimerism with donor cells was found. There were no adverse events associated with graft-versus-host disease throughout the study period. Overall, AAIT treatment was safe, and might help severely immunosuppressed AIDS patients to achieve a better immune restoration. A further clinical trial with control is necessary to confirm the efficacy of AAIT medication.

Case Report: Interferon-γ Restores Monocytic Human Leukocyte Antigen Receptor (mHLA-DR) in Severe COVID-19 With Acquired Immunosuppression Syndrome.

Background: The major histocompatibility complex (MHC) class II characterized by monocytes CD14+ expression of human leukocyte antigen receptors (HLA-DR), is essential for the synapse between innate and adaptive immune response in infectious disease. Its reduced expression is associated with a high risk of secondary infections in septic patients and can be safely corrected by Interferon-y (IFNy) injection. Coronavirus disease (COVID-19) induces an alteration of Interferon (IFN) genes expression potentially responsible for the observed low HLA-DR expression in circulating monocytes (mHLA-DR). Methods: We report a case of one-time INFy injection (100 mcg s.c.) in a superinfected 61-year-old man with COVID-19-associated acute respiratory distress syndrome (ARDS), with monitoring of mHLA-DR expression and clinical tolerance. Observations: Low mHLA-DR pretreatment expression (26.7%) was observed. IFNy therapy leading to a rapid increase in mHLA-DR expression (83.1%). Conclusions: Severe ARDS in a COVID-19 patient has a deep reduction in mHLA-DR expression concomitantly with secondary infections. The unique IFNy injection was safe and led to a sharp increase in the expression of mHLA-DR. Based on immune and infection monitoring, more cases of severe COVID-19 patients with low mHLA-DR should be treated by IFNy to test the clinical effectiveness.

Survival, CD4 T lymphocyte count recovery and immune reconstitution pattern during the first-line combination antiretroviral therapy in patients with HIV-1 infection in Mongolia.

Mongolia has a low incidence of human immunodeficiency virus (HIV) infection, with 281 cases reported at the end of 2019 and an estimated incidence rate of <0.01 cases per 1000 population. However, no study has analyzed the association between antiretroviral therapy (ART) outcomes and pretreatment characteristics of patients with HIV/acquired immunodeficiency syndrome (AIDS) in Mongolia. This retrospective study aimed to determine the survival, CD4 T cell recovery, and immune reconstitution pattern during ART in HIV patients and to determine baseline patient characteristics associated with ART outcomes. Based on three different World Health Organization (WHO) guidelines, we analyzed the 3-year observation data of 166 patients with HIV/AIDS who received treatment between 2010 and 2017. An increase of >50 cells/µL indicated CD4 T cell count recovery, and a cell count of ≥500 cells/µL in patients with a baseline cell count of <500 cells/µL indicated immune reconstitution. In this study, the 3- and 1-year mortality rates were 5.4% (survival rate: 94.6%) and 3.6%, respectively. A total of 83% of deaths that occurred in the observation time occurred within the first 3 months. The CD4 T cell count recovery rates at 3, 12, and 36 months were 62.7%, 80.7%, and 89.2%, respectively. The CD4 T cell count increased to >500 cells/µL in 95 of 145 (65.5%) patients with a baseline cell count of <500 cells/µL after 36 months of ART. The baseline CD4 T cell count was found to be a sensitive indicator for immune reconstitution. An advanced pretreatment clinical stage of HIV infection (as classified by the WHO classification), a low CD4 T cell count in the peripheral blood, and a high viral load before the initiation of the first-line ART accurately predicted survival, CD4 T cell count recovery, and immune reconstitution in Mongolian patients with HIV/AIDS.

Cutaneous manifestations of patients with Human Immunodeficiency Virus (HIV) Infection: A retrospective review of a tertiary referral centre with clinicopathological correlation.

INTRODUCTION: The majority of patients with Human Immunodeficiency Virus (HIV) will have cutaneous manifestation during their disease course. We report the spectrum of cutaneous manifestations and clinicopathological concordance in the diagnosis of skin diseases in patients with HIV. METHODS: A retrospective review of all cutaneous manifestations of HIV-infected patients with skin biopsy-proven histopathological confirmation, treated in the University of Malaya Medical Centre, from 2016 till 2018, was performed. Clinical characteristics and histopathological correlation of these patients were reviewed. RESULTS: A total of 38 cases were included where the median age was 40.5 (interquartile range (IQR) 13.3). The median duration of HIV diagnosis to the development of skin disease was 3 years (IQR 7.8). Majority of our patients were male (89.5%, n = 34), and the commonest mode of transmission is men who have sex with men (36.8%, n = 14). Most patients (92.1%, n = 35) had Acquired Immunodeficiency Syndrome when they presented with skin diseases, predominantly non-infectious types (51.4%, n = 19). Commonest skin diseases include eczema (n = 7) and pruritic papular eruption of HIV (n = 6). Papules and plaques were the commonest morphology for both infectious and non-infectious skin diseases. Duration of HIV diagnosis (P = 0.018) and non-compliance to Highly Active Antiretroviral Therapy (HAART) (P = 0.014) were significantly associated with the development of non-infectious skin diseases. Overall, clinicopathological concordance was 84.2% in our centre. CONCLUSION: A wide spectrum of cutaneous diseases can occur in HIV patients depending on the degree of immunosuppression. skin biopsy along with appropriate stains, and microbiological cultures are important in helping clinicians clinch the right diagnosis.