HLA-mismatched allogeneic adoptive immune therapy in patients with severely immunosuppressed AIDS: a multicenter, open-label, controlled, phase 2a study.

Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (P = 0.048) and 96 (P = 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; P = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770).Trial registration: ClinicalTrials.gov identifier: NCT04098770.Trial registration: ClinicalTrials.gov identifier: NCT02651376.

HIV immunological non-responders are characterized by extensive immunosenescence and impaired lymphocyte cytokine production capacity.

Introduction: Immunological non-responders (INR) are people living with HIV (PLHIV) who fail to fully restore CD4+ T-cell counts despite complete viral suppression with antiretroviral therapy (ART). INR are at higher risk for non-HIV related morbidity and mortality. Previous research suggest persistent qualitative defects. Methods: The 2000HIV study (clinical trials NTC03994835) enrolled 1895 PLHIV, divided in a discovery and validation cohort. PLHIV with CD4 T-cell count <350 cells/mm3 after ≥2 years of suppressive ART were defined as INR and were compared to immunological responders (IR) with CD4 T-cell count >500 cells/mm3. Logistic and rank based regression were used to analyze clinical data, extensive innate and adaptive immunophenotyping, and ex vivo monocyte and lymphocyte cytokine production after stimulation with various stimuli. Results: The discovery cohort consisted of 62 INR and 1224 IR, the validation cohort of 26 INR and 243 IR. INR were older, had more advanced HIV disease before starting ART and had more frequently a history of non-AIDS related malignancy. INR had lower absolute CD4+ T-cell numbers in all subsets. Activated (HLA-DR+, CD38+) and exhausted (PD1+) subpopulations were proportionally increased in CD4 T-cells. Monocyte and granulocyte immunophenotypes were comparable. INR lymphocytes produced less IL-22, IFN-γ, IL-10 and IL-17 to stimuli. In contrast, monocyte cytokine production did not differ. The proportions of CD4+CD38+HLA-DR+ and CD4+PD1+ subpopulations showed an inversed correlation to lymphocyte cytokine production. Conclusions: INR compared to IR have hyperactivated and exhausted CD4+ T-cells in combination with lymphocyte functional impairment, while innate immune responses were comparable. Our data provide a rationale to consider the use of anti-PD1 therapy in INR.

A Dual-domain Engineered Antibody for Efficient HBV Suppression and Immune Responses Restoration.

Chronic hepatitis B (CHB) remains a major public health concern because of the inefficiency of currently approved therapies in clearing the hepatitis B surface antigen (HBsAg). Antibody-based regimens have demonstrated potency regarding virus neutralization and HBsAg clearance. However, high dosages or frequent dosing are required for virologic control. In this study, a dual-domain-engineered anti-hepatitis B virus (HBV) therapeutic antibody 73-DY is developed that exhibits significantly improved efficacy regarding both serum and intrahepatic viral clearance. In HBV-tolerant mice, administration of a single dose of 73-DY at 2 mg kg-1 is sufficient to reduce serum HBsAg by over 3 log10 IU mL-1 and suppress HBsAg to < 100 IU mL-1 for two weeks, demonstrating a dose-lowering advantage of at least tenfold. Furthermore, 10 mg kg-1 of 73-DY sustainably suppressed serum viral levels to undetectable levels for ≈ 2 weeks. Molecular analyses indicate that the improved efficacy exhibited by 73-DY is attributable to the synergy between fragment antigen binding (Fab) and fragment crystallizable (Fc) engineering, which conferred sustained viral suppression and robust viral eradication, respectively. Long-term immunotherapy with reverse chimeric 73-DY facilitated the restoration of anti-HBV immune responses. This study provides a foundation for the development of next-generation antibody-based CHB therapies.

Primary and secondary defects of the thymus.

The thymus is the primary site of T-cell development, enabling generation, and selection of a diverse repertoire of T cells that recognize non-self, whilst remaining tolerant to self- antigens. Severe congenital disorders of thymic development (athymia) can be fatal if left untreated due to infections, and thymic tissue implantation is the only cure. While newborn screening for severe combined immune deficiency has allowed improved detection at birth of congenital athymia, thymic disorders acquired later in life are still underrecognized and assessing the quality of thymic function in such conditions remains a challenge. The thymus is sensitive to injury elicited from a variety of endogenous and exogenous factors, and its self-renewal capacity decreases with age. Secondary and age-related forms of thymic dysfunction may lead to an increased risk of infections, malignancy, and autoimmunity. Promising results have been obtained in preclinical models and clinical trials upon administration of soluble factors promoting thymic regeneration, but to date no therapy is approved for clinical use. In this review we provide a background on thymus development, function, and age-related involution. We discuss disease mechanisms, diagnostic, and therapeutic approaches for primary and secondary thymic defects.

Intravenously administered interleukin-7 to reverse lymphopenia in patients with septic shock: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Profound lymphopenia is an independent predictor of adverse clinical outcomes in sepsis. Interleukin-7 (IL-7) is essential for lymphocyte proliferation and survival. A previous phase II study showed that CYT107, a glycosylated recombinant human IL-7, administered intramuscularly reversed sepsis-induced lymphopenia and improved lymphocyte function. Thepresent study evaluated intravenous administration of CYT107. This prospective, double-blinded, placebo-controlled trial was designed to enroll 40 sepsis patients, randomized 3:1 to CYT107 (10 µg/kg) or placebo, for up to 90 days. RESULTS: Twenty-one patients were enrolled (fifteen CYT107 group, six placebo group) at eight French and two US sites. The study was halted early because three of fifteen patients receiving intravenous CYT107 developed fever and respiratory distress approximately 5-8 h after drug administration. Intravenous administration of CYT107 resulted in a two-threefold increase in absolute lymphocyte counts (including in both CD4+ and CD8+ T cells (all p < 0.05)) compared to placebo. This increase was similar to that seen with intramuscular administration of CYT107, was maintained throughout follow-up, reversed severe lymphopenia and was associated with increase in organ support free days (OSFD). However, intravenous CYT107 produced an approximately 100-fold increase in CYT107 blood concentration compared with intramuscular CYT107. No cytokine storm and no formation of antibodies to CYT107 were observed. CONCLUSION: Intravenous CYT107 reversed sepsis-induced lymphopenia. However, compared to intramuscular CYT107 administration, it was associated with transient respiratory distress without long-term sequelae. Because of equivalent positive laboratory and clinical responses, more favorable pharmacokinetics, and better patient tolerability, intramuscular administration of CYT107 is preferable. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03821038. Registered 29 January 2019, https://clinicaltrials.gov/ct2/show/NCT03821038?term=NCT03821038&draw=2&rank=1 .

Hepatitis C virus-specific immune responses following direct-acting antivirals administered during recent hepatitis C virus infection.

Individuals who spontaneously clear hepatitis C virus (HCV) infection have demonstrated evidence of partial protective immunity, whereas treatment-induced clearance provides little or no protection against reinfection. We aimed to investigate whether treatment of acute HCV infection with direct-acting antivirals (DAA) prevents establishment of, or reverses, T-cell exhaustion, leading to a virus-specific T-cell immune profile more similar to that seen in spontaneous clearance. The magnitude and breadth of HCV-specific T-cell responses before and after DAA or interferon-based therapy in acute or chronic HCV were compared to those of participants with spontaneous clearance of infection, using Enzyme-linked Immunospot (ELISPOT). PBMCs were available for 55 patients comprising 4 groups: spontaneous clearance (n = 17), acute interferon (n = 14), acute DAA (n = 13) and chronic DAA (n = 11). After controlling for sex, the magnitude of post-treatment HCV-specific responses after acute DAA treatment was greater than after chronic DAA or acute IFN treatment and similar to those found in spontaneous clearers. However, spontaneous clearers responded to more HCV peptide pools indicating greater breadth of response. In conclusion, early treatment with DAAs may prevent or reverse some degree of immune exhaustion and result in stronger HCV-specific responses post-treatment. However, individuals with spontaneous clearance had broader HCV-specific responses.

Solubilized curcuminoid complex prevents extensive immunosuppression through immune restoration and antioxidant activity: Therapeutic potential against SARS-CoV-2 (COVID-19).

The therapeutic benefits of curcuminoids in various diseases have been extensively reported. However, little is known regarding their preventive effects on extensive immunosuppression. We investigated the immunoregulatory effects of a curcuminoid complex (CS/M), solubilized with stevioside, using a microwave-assisted method in a cyclophosphamide (CTX)-induced immunosuppressive mouse model and identified its new pharmacological benefits. CTX-treated mice showed a decreased number of innate cells, such as dendritic cells (DCs), neutrophils, and natural killer (NK) cells, and adaptive immune cells (CD4 and CD8 T cells) in the spleen. In addition, CTX administration decreased T cell activation, especially that of Th1 and CD8 T cells, whereas it increased Th2 and regulatory T (Treg) cell activations. Pre-exposure of CS/M to CTX-induced immunosuppressed mice restored the number of innate cells (DCs, neutrophils, and NK cells) and increased their activity (including the activity of macrophages). Exposure to CS/M also led to the superior restoration of T cell numbers, including Th1, activated CD8 T cells, and multifunctional T cells, suppressed by CTX, along with a decrease in Th2 and Treg cells. Furthermore,CTX-injected mice pre-exposed to CS/M were accompanied by an increase in the levels of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase), which play an essential role against oxidative stress. Importantly, CS/M treatment significantly reduced viral loads in severe acute respiratory syndrome coronavirus2-infected hamsters and attenuated the gross pathology in the lungs. These results provide new insights into the immunological properties of CS/M in preventing extensive immunosuppression and offer new therapeutic opportunities against various cancers and infectious diseases caused by viruses and intracellular bacteria.

Serum globulin levels are associated with HIV reservoir size and immune restoration during long-term ART.

OBJECTIVES: The objectives of this study were to analyze the relationship between serum globulin levels and immune restoration and HIV reservoir size during long-term antiretroviral therapy (ART). METHODS: We enrolled 13 patients living with HIV who had been receiving ART for 5 years. We measured levels of serum globulin, cell-associated (CA) HIV DNA and RNA, and p24 antibody at 0, 1, 3, and 5 years of ART. CD38 and human leukocyte antigen - DR isotype (HLA-DR) were used as activation markers for T-cell activation. Serum concentrations of the inflammatory cytokines interferon gamma-inducible protein (IP)-10 and soluble CD163 (sCD163) were detected by enzyme-linked immunosorbent assay. We analyzed the relationship between serum globulin levels, HIV reservoir size, immune restoration, T-cell immune activation, and inflammatory levels during long-term ART. RESULTS: Our data showed that serum globulin levels in people living with HIV were higher than in healthy controls and significantly decreased during the first year of ART. Serum globulin levels during long-term ART were positively correlated with CA HIV DNA, CA HIV RNA, p24 antibody levels, and CD8+ T-cell counts and negatively correlated with CD4+ T-cell counts and CD4/CD8 ratios. Moreover, serum globulin levels were positively correlated with CD4+ and CD8+ T-cell activation and the concentrations of inflammatory biomarkers IP-10 and sCD163 during long-term ART. CONCLUSIONS: Our findings suggest that serum globulin levels may be associated with HIV reservoir size and immune restoration during long-term ART.

Immune restoration affects 10-year survival in people living with HIV/AIDS.

INTRODUCTION: In recent years, a reduction in the life expectancy gap between people living with HIV (PLWH) and the general population has been observed, irrespective of CD4 lymphocyte count, due to widespread access to antiretroviral treatment. The increase in the life expectancy of PLWH has increased awareness of both the ageing process and gender discrepancies in immune restoration and survival. MATERIALS AND METHODS: Longitudinal data were collected for 2240 patients followed up at the Hospital for Infectious Diseases in Warsaw, Poland (n = 1482), and the Department of Acquired Immunodeficiency, Pomeranian Medical University, Szczecin, Poland (n = 758). Immune restoration was measured from the time of starting combination antiretroviral therapy until achieving 500 CD4 lymphocytes/µL, 800 CD4 lymphocytes/µL, and CD4/CD8 lymphocyte ratios of > 0.8 and > 1.0. Full recovery was achieved when the patient was restored to both 800 CD4 lymphocytes/µL and a CD4/CD8 lymphocyte ratio > 1.0. RESULTS: For all endpoints, immune restoration had a protective effect by reducing mortality. Patients who achieved immune restoration had a greater chance of reduced mortality than those who did not achieve immune restoration: for CD4 count > 500 cells/µL, HR = 5.4 (interquartile range: 3.09-9.41), p < 0.001; for CD4 > 800 cells/µL, HR = 5.37 (2.52-11.43), p < 0.001; for CD4/CD8 ratio > 0.8, HR = 3.16 (1.81-5.51), p < 0.001; for CD4/CD8 ratio > 1.0, HR = 2.67 (1.49-5.24), p = 0.001, and for full immune recovery, HR = 3.62 (1.63-8.04), p = 0.002. CONCLUSIONS: Immune restoration remains a powerful factor in improving the survival of PLWH, regardless of the speed of recovery.

HIV-1 therapeutic vaccines in clinical development to intensify or replace antiretroviral therapy: the promising results of the Tat vaccine.

INTRODUCTION: Upon the introduction of the combination antiretroviral therapy (cART), HIV infection has become a chronic disease. However, cART is unable to eradicate the virus and fails to restore the CD4 counts in about 30% of the treated individuals. Furthermore, treatment is life-long, and it does not protect from morbidities typically observed in the elderly. Therapeutic vaccines represent the most cost-effective intervention to intensify or replace cART. AREAS COVERED: Here, we briefly discuss the obstacles to the development and evaluation of the efficacy of therapeutic vaccines and review recent approaches evaluated in clinical trials. EXPERT OPINION: Although vaccines were generally safe and immunogenic, evidence of efficacy was negligible or marginal in most trials. A notable exception is the therapeutic Tat vaccine approach showing promising results of cART intensification, with CD4 T-cell increase and proviral load reduction beyond those afforded by cART alone. Rationale and evidence in support of choosing Tat as the vaccine target are thoroughly discussed.

Bispecific Antibodies in Cancer Immunotherapy: A Novel Response to an Old Question.

Immunotherapy has redefined the treatment of cancer patients and it is constantly generating new advances and approaches. Among the multiple options of immunotherapy, bispecific antibodies (bsAbs) represent a novel thoughtful approach. These drugs integrate the action of the immune system in a strategy to redirect the activation of innate and adaptive immunity toward specific antigens and specific tumor locations. Here we discussed some basic aspects of the design and function of bsAbs, their main challenges and the state-of-the-art of these molecules in the treatment of hematological and solid malignancies and future perspectives.

Serial Analysis of the T-Cell Receptor ß-Chain Repertoire in People Living With HIV Reveals Incomplete Recovery After Long-Term Antiretroviral Therapy.

Long-term antiretroviral therapy (ART) in people living with HIV (PLHIV) is associated with sustained increases in CD4+ T-cell count, but its effect on the peripheral blood T-cell repertoire has not been comprehensively evaluated. In this study, we performed serial profiling of the composition and diversity of the T-cell receptor ß-chain (TRB) repertoire in 30 adults with HIV infection before and after the initiation of ART to define its long-term impact on the TRB repertoire. Serially acquired blood samples from 30 adults with HIV infection collected over a mean of 6 years (range, 1-12) years, with 1-4 samples collected before and 2-8 samples collected after the initiation of ART, were available for analysis. TRB repertoires were characterized via high-throughput sequencing of the TRB variable region performed on genomic DNA extracted from unsorted peripheral blood mononuclear cells. Additional laboratory and clinical metadata including serial measurements of HIV viral load and CD4 + T-cell count were available for all individuals in the cohort. A previously published control group of 189 TRB repertoires from peripheral blood samples of adult bone marrow transplant donors was evaluated for comparison. ART initiation in PLHIV was associated with a sustained reduction in viral load and a significant increase in TRB repertoire diversity. However, repertoire diversity in PLHIV remained significantly lower than in the control group even after long-term ART. The composition of TRB repertoires of PLHIV after ART also remained perturbed compared to the control cohort, as evidenced by large persistent private clonal expansions, reduced efficiency in the generation of TRB CDR3 amino acid sequences, and a narrower range of CDR3 lengths. Network analysis revealed an antigen-experienced structure in the TRB repertoire of PLHIV both before and after ART initiation that was quite distinct from the structure of control repertoires, with a slight shift toward a more naïve structure observed after ART initiation. Though we observe significant improvement in TRB repertoire diversity with durable viral suppression in PLHIV on long-term ART, the composition and structure of these repertoires remain significantly perturbed compared to the control cohort of adult bone marrow transplant donors.

Factors Influencing Immune Restoration in People Living with HIV/AIDS.

Introduction: Immune restoration is a key clinical aspect that is pursued in the care of human immunodeficiency virus (HIV)-infected patients. Despite effective antiretroviral treatment and undetectable viremia, immune recovery is often incomplete. Materials and methods: Data from 311 Caucasian patients were collected. SNP in CCR2(rs1799864), CX3CR1(rs3732378), HLAC-35(rs9264942), and CCR5(promoter, rs1799988); a 32bp deletion(Δ32) in CCR5; and HLA-B*5701 genotypes were correlated with clinical data and selected endpoints. Kaplan−Meier and Cox proportional hazards models were used to analyze the effects of genetic factors over time. Results: For HLA-B*5701, the effect on the CD4+/CD8+ >0.8 cell ratio was lost within 48 months (HR = 2.04, 95% CI: 1.04−4.03), and the effect on the CD4+ cell count >500 cells/µL was lost within 12 months (HR = 2.12, CI: 1.11−4.04). The effect of CCR2 GG on the CD4+/CD8+ >0.8 cell ratio was lost within 36 months (HR = 1.7, CI: 1.05−2.75). For CCR5 wt/Δ32, the effect on the CD4+/CD8+ >1.0 cell ratio was lost within 24 months (HR = 2.0, CI: 1.08−3.69), and the effect on the CD4+ >800 cells/µL cell count was lost within 18 months (HR = 1.98, CI: 1.14−4.73). Conclusions: Selected genetic polymorphisms, namely CCR2 GG and CCR5 Δ32, and the presence of the HLA-B*5701 allele positively influenced immune restoration in cART-treated patients with HIV/AIDS.

Phenotypic frailty in people living with HIV is not correlated with age or immunosenescence.

BACKGROUND: It has been hypothesized that HIV-1 infection prematurely "ages" individuals phenotypically and immunologically. We measured phenotypic frailty and immune "aging" markers on T-cells of people living with HIV on long term, suppressive anti-retroviral therapy (ART) to determine if there is an association between frailty and immunosenescence. METHODS: Thirty-seven (37) community-dwelling people living with HIV were measured for frailty using a sensor-based frailty meter that quantifies weakness, slowness, rigidity, and exhaustion. An immunological profile of the patients' CD4+ and CD8+ T-cell expression of cell surface proteins and cytokines was performed (n = 20). RESULTS: Phenotypic frailty prevalence was 19% (7/37) and correlated weakly with the number of past medical events accrued by the patient (r = 0.34, p = .04). There was no correlation of frailty with age, sex, prior AIDS diagnosis or HIV-1 viral load, or IFN-γ expression by CD4+ or CD8+ T-cells. There were more immune competent (CD28+ CD57-) cells than exhausted/senescent (CD28- CD57+) T cells. CONCLUSION: Frailty in people living with HIV on long term, suppressive ART did not correlate with aging or T cell markers of exhaustion or immunosenescence.

Recovery of Innate Immune Cells and Persisting Alterations in Adaptive Immunity in the Peripheral Blood of Convalescent Plasma Donors at Eight Months Post SARS-CoV-2 Infection.

Persisting alterations and unique immune signatures have been previously detected in the peripheral blood of convalescent plasma (CP) donors at approximately two months after initial SARS-CoV-2 infection. This article presents the results on the sequential analysis of 47 CP donors at a median time of eight months (range 7.5-8.5 months) post infection, as assessed by flow cytometry. Interestingly, our results show a significant variation of the relevant immune subset composition among CP donors. Regarding innate immunity, both non-classical monocytes, and CD11b- granulocytes had fully recovered at eight months post COVID-19 infection. Intermediate monocytes and natural killer (NK) cells had already been restored at the two-month evaluation and remained stable. Regarding adaptive immunity, the COVID-19-related skewed Th1 and Th2 cell polarization remained at the same levels as in two months. However, low levels of total B cells were detected even after eight months from infection. A persisting reduction of CD8+ Tregs and changes in the NKT cell compartment were also remarkable. CP donors present with a unique immune landscape at eight months post COVID-19 infection, which is characterized by the notable restoration of the components of innate immunity along with a persisting imprint of SARS-CoV-2 in cells of the adaptive immunity.

CD4/CD8 Ratio Recovery of Children and Adolescents Living With HIV With Virological Suppression: A Prospective Cohort Study.

BACKGROUND: There are limited data on immune restoration of young adults living with virologically suppressed human immunodeficiency virus (HIV). We investigated recovery rates of CD4/CD8 ratio among Thai children and adolescents after they initiated combination antiretroviral therapy (cART). METHODS: Children and adolescents who started cART at age of ≥ 5 years were eligible in this study if they achieved HIV RNA < 50 copies/mL and had a CD4/CD8 ratio < 0.8 at the time of virological suppression. Normalization of CD4/CD8 ratio was defined as 2 consecutive values ≥ 1. Using group-based trajectory analysis, low- and high-recovery groups were identified in terms of CD4/CD8 ratio recovery. RESULTS: One hundred thirty-eight children and adolescents (101 perinatally infected and 37 behaviorally infected) with median age of 10.6 years at cART treatment initiation were included. After 559 person-years of follow-up (PYFU), overall incidence rate of CD4/CD8 ratio normalization was 4.1 (95% confidence interval, 2.7-6.2) per 100 PYFU. The probabilities of normalization at 2, 5, and 10 years after HIV suppression were 5.2%, 22.6%, and 35.6%, respectively. The low-recovery group had lower median pre-cART CD4 count (146 vs 304 cells/µL, P = .01), pre-cART CD4/CD8 ratio (0.15 vs 0.23, P = .03) and at first viral suppression (0.38 vs 0.65, P = .0001), compared to the high-recovery group. CONCLUSIONS: Less than half of children and adolescents living with HIV on cART with viral suppression had CD4/CD8 ratio normalization. Those with older age at cART initiation, lower pre-cART CD4 count, or CD4/CD8 ratio had slower ratio recovery. Long-term prognoses such as ongoing immune activation and clinical outcomes among children and adolescents on suppressive cART without CD4/CD8 ratio normalization need to be further investigated.

Immune restoration in HIV-1-infected patients after 12 years of antiretroviral therapy: a real-world observational study.

Using normalization of CD4 counts as the main evaluation parameter of complete immune restoration for HIV-1 patients under antiretroviral therapy (ART) might be not enough. A comprehensive evaluation system more accurately reflecting immune restoration are urgently needed. Totally, 91,805 HIV-1 patients from 17 tertiary hospitals in China during 2005-2018 were included in this study. Immune restoration and mortality were assessed. Patients initiated ART with baseline CD4 counts <50, 50-199, 200-349, 350-499, and ≥500 cells/µL, and results showed an increase in the median CD4 counts to 445 (12-year), 467 (12-year), 581 (11-year), 644 (7-year), and 768 cells/µL (5-year), as well as the CD4/CD8 ratio to 0.59 (12-year), 0.65 (12-year), 0.79 (11-year), 0.82 (7-year), 0.9 (5-year), respectively. The median CD8 count was relatively high (median range 732-845 cells/µL), regardless of the baseline CD4 counts. Furthermore, the probabilities of death in patients achieving CD4 counts ≥500 cells/µL and CD4/CD8 ratio ≥0.8 simultaneously were significantly lower than those in patients achieving either CD4 counts ≥500 cells/µL (2.77% vs 3.50%, p=0.02) or CD4/CD8 ≥ 0.8 (2.77% vs 4.28%, p<0.001) after 12-year of ART. In this study, a new binary-indicator would accurately assess immune restoration in the era of "treat all."

Natural killer cell counts in primary HIV infection predicts disease progression and immune restoration after treatment.

The relationship between NK cell counts during primary infection and disease progression or immune restoration after antiretroviral treatment (ART) was explored. We followed 462 individuals with HIV infection and measured their NK, CD4+ T, CD8+ T cell counts and viral loads. Our data showed that individuals with high NK cell counts had much lower viral loads and higher CD4+ T cell counts. NK cell counts during primary infection were negatively correlated with viral set-point and viral loads at one-year-infection point, and positively correlated with CD4+ T cell counts at one-year-infection and one-year-ART point. Moreover, the NK cell counts during primary infection can predict HIV disease progression and immune restoration after ART. In conclusion, NK cell counts during primary infection represents a potential predictive biomarker to predict HIV disease prognosis in the clinic.

Management Issues in Myasthenia Gravis Patients Living With HIV: A Case Series and Literature Review.

South Africa is home to more than seven million people living with human immunodeficiency virus (HIV) and a high prevalence of tuberculosis. Human immunodeficiency virus-infected individuals may develop myasthenia gravis (MG), which raises questions regarding their management. An MG database, with 24 years of observational data, was audited for HIV-infected persons. Case reports of MG in HIV-infected persons were reviewed. We identified 17 persons with MG and HIV infection. All had generalized MG with a mean age at onset of 37.8 years. Eleven had acetylcholine receptor antibody-positive MG; one had antibodies against muscle-specific kinase. Six developed MG prior to HIV infection (mean CD4+ 361 cells/mm3); four worsened <6 months of starting antiretrovirals. Eleven developed MG while HIV-infected (mean CD4+ 423 cells/mm3); five presented with mild MG; three in MG crisis requiring rescue therapies (intravenous immune globulin or plasma exchange and/or intravenous cyclophosphamide). Two were diagnosed with HIV infection and MG at the same time. Fifteen required maintenance steroid-sparing immune therapies, predominantly azathioprine, or methotrexate. Plasma HIV viral loads remained below detectable levels on antiretrovirals during immunosuppressant treatment. Over the average follow-up of 6 years, 10 achieved minimal manifestation status, and the remainder improved to mild symptoms. Three cases had tuberculosis before MG, but none developed tuberculosis reactivation on immunosuppressive therapy; one used isoniazid prophylaxis. Herpes zoster reactivation during treatment occurred in one. Conclusions include the following: MG in HIV-infected patients should be managed similarly to individuals without HIV infection; half develop moderate-severe MG; MG symptoms may worsen within 6 months of antiretroviral initiation; safety monitoring must include plasma HIV viral load estimation. Isoniazid prophylaxis may not be indicated in all cases.