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Background. Intermittent interleukin (IL)-2 administration to human immunodeficiency virus (HIV)-infected patients leads to CD4(+) T cell expansions. The factors potentially affecting these expansions were investigated in the present study.Methods. A matched (for baseline CD4(+) T cell count) case-control study was designed. Nonresponders (NRs) were defined as patients with a /=50% increase in CD4(+) T cell count at week 24. Immunophenotype, Ki67 and forkhead box protein P3 (FoxP3) expression, and T cell receptor excision circle (TREC) measurements in T cells were evaluated at weeks 0 and 24 in both groups.Results. Control subjects and NRs did not differ significantly at baseline in age, viral load, CD4(+) T cell count, nadir CD4(+) T cell count, or CD8(+) T cell count. At week 0, NRs had lower TREC levels per 1x106 T cells and higher levels of T cell proliferation and activation than did control subjects. At week 24, both groups experienced decreases in T cell proliferation and increases in CD25 and FoxP3 expression on CD4(+) T cells, with TREC levels per 1x106 CD4(+) T cells decreasing significantly only in control subjects.Conclusions. Increased immune activation can adversely affect CD4(+) T cell expansions after IL-2 administration. Despite the lack of expansion, other evidence of IL-2-induced biological activity was observed. This article is in the public domain, and no copyright is claimed. [ABSTRACT FROM AUTHOR]

The Accelerating COVID-19 Therapeutic Interventions and Vaccines Therapeutic-Clinical Working Group members gathered critical recommendations in follow-up to lessons learned manuscripts released earlier in the COVID-19 pandemic. Lessons around agent prioritization, preclinical therapeutics testing, master protocol design and implementation, drug manufacturing and supply, data sharing, and public-private partnership value are shared to inform responses to future pandemics., (© The Author(s) 2024.)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) was an extraordinary example of a public-private partnership (PPP) that brought together over thirty organizations and hundreds of individuals to address one of the most pressing global health needs in recent decades. In particular, ACTIV provided a key avenue for testing numerous therapeutics for their potential benefit in treating the SARS-CoV-2 virus or the resulting symptoms of acute COVID-19 infection. Given the speed and scale at which ACTIV designed and implemented master protocols across global networks that it was simultaneously working to create, the PPP can provide valuable lessons for best practices and avoiding pitfalls the next time the world is faced with a global pandemic of a novel pathogen. This report provides a general overview of the ACTIV partnership to set the stage and context for the subsequent articles in this issue that will relay these lessons learned., Competing Interests: None., (© The Author(s) 2024.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

New tuberculosis vaccine candidates that are in the development pipeline need to be studied in people with HIV, who are at high risk of acquiring Mycobacterium tuberculosis infection and tuberculosis disease and tend to develop less robust vaccine-induced immune responses. To address the gaps in developing tuberculosis vaccines for people with HIV, a series of symposia was held that posed six framing questions to a panel of international experts: What is the use case or rationale for developing tuberculosis vaccines? What is the landscape of tuberculosis vaccines? Which vaccine candidates should be prioritised? What are the tuberculosis vaccine trial design considerations? What is the role of immunological correlates of protection? What are the gaps in preclinical models for studying tuberculosis vaccines? The international expert panel formulated consensus statements to each of the framing questions, with the intention of informing tuberculosis vaccine development and the prioritisation of clinical trials for inclusion of people with HIV., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The rapid development of COVID-19 vaccines and their deployment in less than a year is an unprecedented scientific, medical, and public health achievement. This rapid development leveraged knowledge from decades of HIV/AIDS research and advances. However, the search for an HIV vaccine that would contribute to a durable end to the HIV pandemic remains elusive. Here, we draw from the US government experience and highlight lessons learned from COVID-19 vaccine development, which include the importance of public-private partnerships, equitable inclusion of populations impacted by the infectious pathogen, and continued investment in basic research. We summarize key considerations for an accelerated and re-energized framework for developing a safe and efficacious HIV vaccine., Competing Interests: Competing interestsThe authors declare no competing interests., (© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022.)

Given the urgent need for coronavirus disease 2019 therapeutics, early in the pandemic the Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership rapidly designed a unique therapeutic agent intake and assessment process for candidate treatments of coronavirus disease 2019. These treatments included antivirals, immune modulators, severe acute respiratory syndrome coronavirus 2 neutralizing antibodies, and organ-supportive treatments at both the preclinical and clinical stages of development. The ACTIV Therapeutics-Clinical Working Group Agent Prioritization subgroup established a uniform data collection process required to perform an assessment of any agent type using review criteria that were identified and differentially weighted for each agent class. The ACTIV Therapeutics-Clinical Working Group evaluated over 750 therapeutic agents with potential application for coronavirus disease 2019 and prioritized promising candidates for testing within the master protocols conducted by ACTIV. In addition, promising agents among preclinical candidates were selected by ACTIV to be matched with laboratories that could assist in executing rigorous preclinical studies. Between April 14, 2020, and May 31, 2021, the Agent Prioritization subgroup advanced 20 agents into the Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines master protocols and matched 25 agents with laboratories to assist with preclinical testing., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Working in an unprecedented time frame, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership developed and launched 9 master protocols between 14 April 2020 and 31 May 2021 to allow for the coordinated and efficient evaluation of multiple investigational therapeutic agents for COVID-19. The ACTIV master protocols were designed with a portfolio approach to serve the following patient populations with COVID-19: mild to moderately ill outpatients, moderately ill inpatients, and critically ill inpatients. To facilitate the execution of these studies and minimize start-up time, ACTIV selected several existing networks to launch the master protocols. The master protocols were also designed to test several agent classes prioritized by ACTIV that covered the spectrum of the disease pathophysiology. Each protocol, either adaptive or pragmatic, was designed to efficiently select those treatments that provide benefit to patients while rapidly eliminating those that were either ineffective or unsafe. The ACTIV Therapeutics-Clinical Working Group members describe the process by which these master protocols were designed, developed, and launched. Lessons learned that may be useful in meeting the challenges of a future pandemic are also described.

This article outlines the significant scientific progress reported in 2019 that has led to the development of new drugs and therapeutic regimens, vaccine candidates, and diagnostics for the prevention and treatment of tuberculosis. In 2020, it will be important to build on this momentum and continue to advance basic and clinical research to develop improved tools and interventions, simultaneously optimizing their implementation in national control programs. To successfully achieve the goal to end tuberculosis within a generation, a concerted, collective, and collaborative effort is required, involving government, academia, industry and civil society at all levels., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Background: Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART)., Methods: HIV-positive adults receiving ART for ≥96 weeks with undetectable viremia for ≥48 weeks and CD4(+) T-cell counts <350 cells/mm(3) were randomized 2:1 to rifaximin versus no study treatment for 4 weeks. T-cell activation, LPS, and soluble CD14 were measured at baseline and at weeks 2, 4, and 8. Wilcoxon rank sum tests compared changes between arms., Results: Compared with no study treatment (n = 22), rifaximin (n = 43) use was associated with a significant difference between study arms in the change from baseline to week 4 for CD8(+)T-cell activation (median change, 0.0% with rifaximin vs +0.6% with no treatment; P = .03). This difference was driven by an increase in the no-study-treatment arm because there was no significant change within the rifaximin arm. Similarly, although there were significant differences between study arms in change from baseline to week 2 for LPS and soluble CD14, there were no significant changes within the rifaximin arm., Conclusions: In immune nonresponders to ART, rifaximin minimally affected microbial translocation and CD8(+)T-cell activation. Trial registration number. NCT01466595., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Combination antiretroviral therapy can suppress human immunodeficiency virus (HIV) infection but cannot completely eradicate the virus. A major obstacle in the quest for a cure is the difficulty in targeting and measuring latently infected cells. To date, a single person seems to have been cured of HIV. Hematopoietic stem cell transplantation (HSCT) preceded this cancer patient's long-term sustained HIV remission, but researchers have been unable to replicate this cure, and the mechanisms that led to HIV remission remain to be established. In February 2014, the National Institute of Allergy and Infectious Diseases sponsored a workshop that provided a venue for in-depth discussion of whether HSCT could be exploited to cure HIV in cancer patients requiring such procedures. Participants also discussed how HSCT might be applied to a broader community of HIV-infected persons in whom the risks of HSCT currently outweigh the likelihood and benefits of HIV cure., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Unlabelled: Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits., Clinical Trials Registration: NCT 01543958., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: The impact of raltegravir-resistant HIV-1 minority variants (MVs) on raltegravir treatment failure is unknown. Illumina sequencing offers greater throughput than 454, but sequence analysis tools for viral sequencing are needed. We evaluated Illumina and 454 for the detection of HIV-1 raltegravir-resistant MVs., Methods: A5262 was a single-arm study of raltegravir and darunavir/ritonavir in treatment-naïve patients. Pre-treatment plasma was obtained from 5 participants with raltegravir resistance at the time of virologic failure. A control library was created by pooling integrase clones at predefined proportions. Multiplexed sequencing was performed with Illumina and 454 platforms at comparable costs. Illumina sequence analysis was performed with the novel snp-assess tool and 454 sequencing was analyzed with V-Phaser., Results: Illumina sequencing resulted in significantly higher sequence coverage and a 0.095% limit of detection. Illumina accurately detected all MVs in the control library at ≥0.5% and 7/10 MVs expected at 0.1%. 454 sequencing failed to detect any MVs at 0.1% with 5 false positive calls. For MVs detected in the patient samples by both 454 and Illumina, the correlation in the detected variant frequencies was high (R2 = 0.92, P<0.001). Illumina sequencing detected 2.4-fold greater nucleotide MVs and 2.9-fold greater amino acid MVs compared to 454. The only raltegravir-resistant MV detected was an E138K mutation in one participant by Illumina sequencing, but not by 454., Conclusions: In participants of A5262 with raltegravir resistance at virologic failure, baseline raltegravir-resistant MVs were rarely detected. At comparable costs to 454 sequencing, Illumina demonstrated greater depth of coverage, increased sensitivity for detecting HIV MVs, and fewer false positive variant calls.

IL-7 is essential for T-cell homeostasis. Elevated serum IL-7 levels in lymphopenic states, including HIV infection, are thought to be due to increased production by homeostatic feedback, decreased receptor-mediated clearance, or both. The goal of this study was to understand how immune reconstitution through antiretroviral therapy (ART) in HIV(+) patients affects IL-7 serum levels, expression of the IL-7 receptor (CD127), and T-cell cycling. Immunophenotypic analysis of T cells from 29 HIV(-) controls and 43 untreated HIV(+) patients (30 of whom were followed longitudinally for ≤ 24 months on ART) was performed. Restoration of both CD4(+) and CD8(+) T cells was driven by increases in CD127(+) naive and central memory T cells. CD4(+) T-cell subsets were not fully restored after 2 years of ART, whereas serum IL-7 levels normalized by 1 year of ART. Mathematical modeling indicated that changes in serum IL-7 levels could be accounted for by changes in the receptor concentration. These data suggest that T-cell restoration after ART in HIV infection is driven predominantly by CD127(+) cells and that decreases of serum IL-7 can be largely explained by improved CD127-mediated clearance.

During acute human immunodeficiency virus (HIV) infection, there is a massive depletion of CD4(+) T cells in the gut mucosa that can be reversed to various degrees with antiretroviral therapy. Th17 cells have been implicated in mucosal immunity to extracellular bacteria, and preservation of this subset may support gut mucosal immune recovery. However, this possibility has not yet been evaluated in HIV-1-infected long-term nonprogressors (LTNPs), who maintain high CD4(+) T cell counts and suppress viral replication in the absence of antiretroviral therapy. In this study, we evaluated the immunophenotype and function of CD4(+) T cells in peripheral blood and gut mucosa of HIV-uninfected controls, LTNPs, and HIV-1-infected individuals treated with prolonged antiretroviral therapy (ART) (VL [viral load]<50). We found that LTNPs have intact CD4(+) T cell populations, including Th17 and cycling subsets, in the gut mucosa and a preserved T cell population expressing gut homing molecules in the peripheral blood. In addition, we observed no evidence of higher monocyte activation in LTNPs than in HIV-infected (HIV(-)) controls. These data suggest that, similar to nonpathogenic simian immunodeficiency virus (SIV) infection, LTNPs preserve the balance of CD4(+) T cell populations in blood and gut mucosa, which may contribute to the lack of disease progression observed in these patients.

We sought to determine the effects of interleukin-2 administered in combination with antiretroviral therapy (ART) on CD4+ T cells in the gut. Lymphocytes from whole blood, colon, and terminal ileum of HIV-infected adults treated with interleukin-2 and ART or ART alone were examined. There were no differences between groups in the proportion of CD4+ T cells or in expression of CD25 or Ki67 by CD4+ T cells in the gut. Although IL-2 administration leads to expansion of peripheral blood CD4+ T cells, there is no alteration in the proportion or activation of CD4+ T cells in the gut mucosa.

HIV/AIDS is a global pandemic and is the leading infectious cause of death among adults. Although antiretroviral (ARV) therapy has dramatically improved the quality of life and increased the life expectancy of those infected with HIV, life-long suppressive treatment is required and a cure for HIV infection remains elusive; frequency of dosing and drug toxicity as well as the development of viral resistance pose additional limitations. Furthermore, preventative measures such as a vaccine or microbicide are urgently needed to curb the rate of new infections. The capabilities inherent to nanotechnology hold much potential for impact in the field of HIV treatment and prevention. This article reviews the potential for the multidisciplinary field of nanotechnology to advance the fields of HIV treatment and prevention., (© 2010 John Wiley & Sons, Inc.)

Background: The pathogenesis of immunodeficiency due to human immunodeficiency virus (HIV)-1 is incompletely understood, but immune activation is believed to play a central role. Immunomodulatory agents that decrease immune activation may be useful in the treatment of HIV-1 infection., Methodology: A randomized, double blind, placebo-controlled pilot study of leflunomide for 28 days was performed in participants with HIV-1 infection who were not receiving antiretroviral therapy. Participants randomized to leflunomide were subsequently treated with cholestyramine until leflunomide levels were below detection limit., Findings: Treatment with leflunomide was well tolerated with mostly low-grade adverse events. Leflunomide administration reduced cycling of CD4 T cells (by ex vivo bromodeoxyuridine uptake and Ki67 expression) and decreased expression of activation markers (HLA-DR/CD38 co-expression) on CD8 T cells in peripheral blood. In addition, decreased expression of HIV-1 co-receptors was observed in both CD4 and CD8 T cells in the leflunomide group. There were no significant changes in naïve and memory T cell subsets, apoptosis of T cells or markers of microbial translocation., Conclusions: Leflunomide was effective in reducing immune activation in the setting of chronic HIV-1 infection suggesting that targeting immune activation with immunomodulatory agents may be a feasible strategy., Trial Registration: ClinicalTrials.gov NCT00101374.

The gut mucosa is an important site of HIV immunopathogenesis with severe depletion of CD4+ T cells occurring during acute infection. The effect of prolonged anti-retroviral therapy (ART) on cycling and restoration of T lymphocytes in the gut remains unclear. Colon and terminal ileal biopsies and peripheral blood samples were collected from viremic, untreated, HIV-infected participants, patients treated with prolonged ART (>5 years), and uninfected controls and analyzed by flow cytometry. In the gut, the proportion of cycling T cells decreased and the number of CD4+ T cells normalized in treated patients in parallel with beta 7 expression on CD4+ T cells in blood. Cycling of gut T cells in viremic patients was associated with increased plasma LPS levels, but not colonic HIV-RNA. These data suggest that gut T-cell activation and microbial translocation may be interconnected whereas prolonged ART may decrease activation and restore gut CD4+ T cells.

Translocation of microbial products has been described in chronic human immunodeficiency virus (HIV) infection and correlates with activation of the immune system. We investigated the potential translocation of microbial products in idiopathic CD4 lymphocytopenia (ICL), a rare disorder characterized by low CD4 T cell counts in the absence of HIV infection. Plasma lipopolysaccharide (LPS) levels and T cell activation were measured in a cross-sectional cohort study of patients with ICL and HIV infection and healthy control subjects. Increases in CD4 T cell proliferation but not CD8 T cell proliferation were observed in patients with ICL. LPS levels were significantly elevated both in patients with ICL and in patients with HIV infection, and they were strongly correlated with the proportion of proliferating CD4 T cells in the cohort of patients with ICL (r = 0.88; P= .003). The proportions of T helper (Th) 17 and Th1 CD4 cells in peripheral blood were similar between patients with ICL, patients with HIV infection, and control subjects. These findings suggest a potential association of translocation of microbial products with perturbed CD4 T cell homeostasis in individuals with CD4 lymphopenic states other than HIV infection.

Administration of interleukin (IL)-2 to human immunodeficiency virus (HIV)-infected patients leads to significant increases in CD4 T cell counts. We previously have shown that IL-2 induces increased proliferation and survival of CD4 T cells. Deuterium labeling studies were undertaken to study the relationship between IL-2-induced increases in the CD4 T cell count and the effects of IL-2 on cell proliferation and survival. A strong inverse correlation was noted between the rate of decay of the label in CD4 cells and increases in CD4 cell counts (R =or- 0.67; P<.001). This correlation was not seen with the level of proliferating cells. Although the CD4 cell count at baseline and the number of CD4 cells expressing CD25 were also predictive of increases in the CD4 cell count, the rate of decay remained the most statistically significant predictor in multivariate regression models. Thus, an increase in the survival of CD4 T cells appears to be the critical mechanism leading to sustained increases in the CD4 cell counts of HIV-infected patients receiving intermittent IL-2 therapy.

Background: The interleukin-7 (IL-7)/IL-7 receptor alpha (IL-7Ralpha) system is an important regulator of T-cell homeostasis. We evaluated the IL-7/IL-7Ralpha system in a large cohort of HIV-infected patients, including a subset treated with intermittent IL-2., Methods: IL-7 serum levels and CD127 (IL-7Ralpha) expression on T cells were evaluated in a cross-sectional study of 36 healthy volunteers, 151 HIV-infected patients, and 83 HIV-infected patients who had received IL-2 therapy. Multivariate regression models were used to determine predictors of CD127 expression., Results: HIV-infected patients had higher IL-7 levels compared with healthy volunteers (P = 0.022) and IL-2-treated patients (P = 0.012). CD127 expression was significantly lower on CD4 and CD8 T cells of HIV-infected patients compared with healthy volunteers (P = 0.008 and P < 0.001, respectively), and CD127 median fluorescence intensity was lowest on CD4 T cells in IL-2-treated patients (P < 0.001 compared with HIV-infected patients). The proportion of naive and effector memory/effector T cells were significant predictors of CD127 expression on T cells. IL-2 immunotherapy led to the expansion of a CD25/CD127-low subset of CD4 T cells., Conclusions: CD127 expression on T cells remains low in HIV-infected patients despite antiretroviral therapy, reflecting persistent aberration in the subset composition of the T-cell pool.