Although Antiretroviral Therapy Research Articles

Incidence and risk factors of anaemia among people on antiretroviral therapy in Harare.

Anaemia is associated with reduced quality of life and increased mortality risk among people living with HIV (PLHIV). Although antiretroviral therapy (ART) reduces the prevalence of anaemia, some patients remain at risk after commencing ART. We estimated the incidence of anaemia after ART commencement and identified associated risk factors. We analysed outpatient records at Newlands Clinic, Harare, Zimbabwe. Patients (≥ 5 years old) who were commenced on ART between January 2016 and December 2020 were included and were followed up for up to 2 years. Patients with anaemia at ART commencement and women who were pregnant at any time during follow-up were excluded. Cox proportional hazards regression was used to assess independent risk factors for anaemia. During the study, 1110 patients ≥ 5 years old were commenced on ART with a prevalence of anaemia of 40.0%. Five hundred and twenty-nine patients met the inclusion criteria and were followed up for 823.7 person-years. The median age was 36.1 years and 290 (58.4%) were female. The incidence rate of anaemia after ART commencement was 176.1 per 1000 person-years (95% confidence interval [CI]: 149.6-207.2). Females (aHR: 2.09; 95% CI: 1.46-3.00, P < 0.001), zidovudine use (aHR: 3.50 96% CI: 2.14-5.71, P < 0.001), age 5-12 years or > 50 years, and the presence of World Health Organization stage III/IV disease (aHR: 2.19; 95% CI: 1.14-5.71, P = 0.019) had higher odds of developing anaemia. The incidence of anaemia after ART commencement was high. Female sex, zidovudine use, age and the presence of stage III/IV disease were independent risk factors for anaemia. Clinicians should screen PLHIV on ART regularly for anaemia.

The Use of Broadly Neutralizing Antibodies (bNAbs) in HIV-1 Treatment and Prevention.

Although antiretroviral therapy (ART) effectively halts disease progression in HIV infection, the complete eradication of the virus remains elusive. Additionally, challenges such as long-term ART toxicity, drug resistance, and the demanding regimen of daily and lifelong adherence required by ART highlight the imperative need for alternative therapeutic and preventative approaches. In recent years, broadly neutralizing antibodies (bNAbs) have emerged as promising candidates, offering potential for therapeutic, preventative, and possibly curative interventions against HIV infection. This review aims to provide a comprehensive overview of the current state of knowledge regarding the passive immunization of bNAbs in HIV-1-infected individuals. Recent findings from clinical trials have highlighted the potential of bNAbs in the treatment, prevention, and quest for an HIV-1 cure. While monotherapy with a single bNAb is insufficient in maintaining viral suppression and preventing viral escape, ultimately leading to viral rebound, combination therapy with potent, non-overlapping epitope-targeting bNAbs have demonstrated prolonged viral suppression and delayed time to rebound by effectively restricting the emergence of escape mutations, albeit largely in individuals with bNAb-sensitive strains. Additionally, passive immunization with bNAb has provided a "proof of concept" for antibody-mediated prevention against HIV-1 acquisition, although complete prevention has not been obtained. Therefore, further research on the use of bNAbs in HIV-1 treatment and prevention remains imperative.

Simultaneous quantification of five antiretrovirals in human tissues using ultra-high performance liquid chromatography-tandem mass spectrometry methods for therapeutic drug monitoring at the sites of action

Although antiretroviral therapy (ART) is highly effective for the treatment of HIV-1 infection to suppress virus in the blood, HIV persists in tissues. HIV persistence in the tissues is due to numerous factors, and one of those factors are antiretroviral (ARV) concentrations. ARV concentrations in tissues must be adequate to suppress HIV at the sites of action. While therapeutic drug monitoring in the plasma is well-known, drug monitoring in the tissues provides local assessments of adequate ARV exposure to prevent localized HIV resistance formation. Towards these efforts, we validated an ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) method in human tissues (cervical, rectal, and vaginal tissues) for the simultaneous quantification of five ARVs: bictegravir, cabotegravir, dolutegravir, doravirine, and raltegravir. For this assay, protein precipitation with acetonitrile with stable, isotopically-labeled internal standards followed by supernatant pre-concentration was performed. Analyte separation was accomplished using a multistep UPLC gradient mixture of 0.1 % formic acid in water (A) and acetonitrile (B) with a Waters Cortecs T3 (2.1x100 mm) column. The assay was extensively validated as per the United States Food and Drug Administration Bioanalytical Method Validation Guidance over a clinically observed range (0.05–50 ng/mL) with superb linearity (R2 > 0.99 across all ARVs). The assay run time was 8.5 min. This analytical method achieves appropriate performance of trueness (85.5–107.4 %), repeatability, and precision (CV < 15 %). Our method will be employed for the therapeutic monitoring of guideline-recommended ARVs in human tissues for monitoring therapeutic efficacy in HIV treatment and prevention research efforts.

Tat-dependent conditionally replicating adenoviruses expressing diphtheria toxin A for specifically killing HIV-1-infected cells

HIV-1 infection remains a public health problem with no cure. Although antiretroviral therapy (ART) is effective for suppressing HIV-1 replication, it requires lifelong drug administration due to a stable reservoir of latent proviruses and may cause serious side effects and drive the emergence of drug-resistant HIV-1 variants. Gene therapy represents an alternative approach to overcome the limitations of conventional treatments against HIV-1 infection. In this study, we constructed and investigated the antiviral effects of an HIV-1 Tat-dependent conditionally replicating adenovirus, which selectively replicates and expresses the diphtheria toxin A chain (Tat-CRAds-DTA) in HIV-1-infected cells both invitro and invivo. We found that Tat-CRAds-DTA could specifically induce cell death and inhibit virus replication in HIV-1-infected cells mediated by adenovirus proliferation and DTA expression. A low titer of progeny Tat-CRAds-DTA was also detected in HIV-1-infected cells. In addition, Tat-CRAds-DTA showed no apparent cytotoxicity to HIV-1-negative cells and demonstrated significant therapeutic efficacy against HIV-1 infection in a humanized mouse model. The findings in this study highlight the potential of Tat-CRAds-DTA as a new gene therapy for the treatment of HIV-1 infection.

Darunavir Nanoformulation Suppresses HIV Pathogenesis in Macrophages and Improves Drug Delivery to the Brain in Mice.

Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using an intranasal route that can overcome the limitation of drug metabolic stability and blood-brain barrier (BBB) permeability. The physicochemical properties of PLGA-DRV were characterized. The results indicated that PLGA-DRV formulation inhibits HIV replication in U1 macrophages directly and in the presence of the BBB without inducing cytotoxicity. However, the PLGA-DRV did not inhibit HIV replication more than DRV alone. Notably, the total antioxidant capacity remained unchanged upon treatment with both DRV or PLGA-DRV in U1 cells. Compared to DRV alone, PLGA-DRV further decreased reactive oxygen species, suggesting a decrease in oxidative stress by the formulation. Oxidative stress is generally increased by HIV infection, leading to increased inflammation. Although the PLGA-DRV formulation did not further reduce the inflammatory response, the formulation did not provoke an inflammatory response in HIV-infected U1 macrophages. As expected, in vitro experiments showed higher DRV permeability by PLGA-DRV than DRV alone to U1 macrophages. Importantly, in vivo experiments, especially using intranasal administration of PLGA-DRV in wild-type mice, demonstrated a significant increase in the brain-to-plasma ratio of DRV compared to the free DRV. Overall, findings from this study attest to the potential of the PLGA-DRV nanoformulation in reducing HIV pathogenesis in macrophages and enhancing drug delivery to the brain, offering a promising avenue for treating HIV-related neurological disorders.

A novel high-throughput microwell outgrowth assay for HIV-infected cells.

Although antiretroviral therapy (ART) is effective at suppressing HIV replication, a viral reservoir persists that can reseed infection if ART is interrupted. Curing HIV will require elimination or containment of this reservoir, but the size of the HIV reservoir is highly variable between individuals. To evaluate the size of the HIV reservoir, several assays have been developed, including PCR-based assays for viral DNA, the intact proviral DNA assay, and the quantitative viral outgrowth assay (QVOA). QVOA is the gold standard assay for measuring inducible replication-competent proviruses, but this assay is technically challenging and time-consuming. To begin progress toward a more rapid and less laborious tool for quantifying cells infected with replication-competent HIV, we developed the Microwell Outgrowth Assay, in which infected CD4 T cells are co-cultured with an HIV-detecting reporter cell line in a polydimethylsiloxane (PDMS)/polystyrene array of nanoliter-sized wells. Transmission of HIV from infected cells to the reporter cell line induces fluorescent reporter protein expression that is detected by automated scanning across the array. Using this approach, we were able to detect HIV-infected cells from ART-naïve people with HIV (PWH) and from PWH on ART with large reservoirs. Furthermore, we demonstrate that infected cells can be recovered from individual rafts and used to analyze the diversity of viral sequences. Although additional development and optimization will be required for quantifying the reservoir in PWH with small latent reservoirs, this assay may be a useful prototype for microwell assays of infected cells.IMPORTANCEMeasuring the size of the HIV reservoir in people with HIV (PWH) will be important for determining the impact of HIV cure strategies. However, measuring this reservoir is challenging. We report a new method for quantifying HIV-infected cells that involves culturing cells from PWH in an array of microwells with a cell line that detects HIV infection. We show that this approach can detect rare HIV-infected cells and derive detailed virus sequence information for each infected cell.

γδ T cells mediate robust anti-HIV functions during antiretroviral therapy regardless of immune checkpoint expression.

Although antiretroviral therapy (ART) efficiently suppresses HIV viral load, immune dysregulation and dysfunction persist in people living with HIV (PLWH). γδ T cells are functionally impaired during untreated HIV infection, but the extent to which they are reconstituted upon ART is currently unclear. Utilising a cohort of ART-treated PLWH, we assessed the frequency and phenotype, characterised in vitro functional responses and defined the impact of immune checkpoint marker expression on effector functions of both Vδ1 and Vδ2 T cells. We additionally explore the in vitro expansion of Vδ2 T cells from PLWH on ART and the mechanisms by which such expanded cells may sense and kill HIV-infected targets. A matured NK cell-like phenotype was observed for Vδ1 T cells among 25 ART-treated individuals (PLWH/ART) studied compared to 17 HIV-uninfected controls, with heightened expression of 2B4, CD160, TIGIT and Tim-3. Despite persistent phenotypic perturbations, Vδ1 T cells from PLWH/ART exhibited strong CD16-mediated activation and degranulation, which were suppressed upon Tim-3 and TIGIT crosslinking. Vδ2 T cell degranulation responses to the phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate at concentrations up to 2 ng mL-1 were significantly impaired in an immune checkpoint-independent manner among ART-treated participants. Nonetheless, expanded Vδ2 T cells from PLWH/ART retained potent anti-HIV effector functions, with the NKG2D receptor contributing substantially to the elimination of infected cells. Our findings highlight that although significant perturbations remain within the γδ T cell compartment throughout ART-treated HIV, both subsets retain the capacity for robust anti-HIV effector functions.

Barriers and facilitators for interventions to improve ART adherence in Sub-Saharan African countries: A systematic review and meta-analysis.

The HIV/AIDS pandemic remains a significant public health issue, with sub-Saharan Africa (SSA) at its epicentre. Although antiretroviral therapy (ART) has been introduced to decrease new infections and deaths, SSA reports the highest incidence of HIV/AIDS, constituting two-thirds of the global new infections. This review aimed to elucidate the predominant barriers and facilitators influencing ART adherence and to identify effective strategies to enhance ART adherence across SSA. A comprehensive review was conducted on studies examining barriers to ART adherence and interventions to boost adherence among HIV-positive adults aged 15 and above in SSA, published from January 2010 onwards. The research utilized databases like Medline Ovid, CINAHL, Embase, and Scopus. Included were experimental and quasi-experimental studies, randomized and non-randomized controlled trials, comparative before and after studies, and observational studies such as cross-sectional, cohort, prospective and retrospective studies. Two independent reviewers screened the articles, extracted pertinent data, and evaluated the studies' methodological integrity using Joanna Briggs Institute's standardized appraisal tools. The compiled data underwent both meta-analysis and narrative synthesis. From an initial pool of 12,538 papers, 45 were selected (30 for narrative synthesis and 15 for meta-analysis). The identified barriers and facilitators to ART adherence were categorized into seven principal factors: patient-related, health system-related, medication-related, stigma, poor mental health, socioeconomic and socio-cultural-related factors. Noteworthy interventions enhancing ART adherence encompassed counselling, incentives, mobile phone short message service (SMS), peer delivered behavioural intervention, community ART delivery intervention, electronic adherence service monitoring device, lay health worker lead group intervention and food assistance. The meta-analysis revealed a statistically significant difference in ART adherence between the intervention and control groups (pooled OR = 1.56, 95%CI:1.35-1.80, p = <0.01), with evidence of low none statistically significant heterogeneity between studies (I2 = 0%, p = 0.49). ART adherence in SSA is influenced by seven key factors. Multiple interventions, either standalone or combined, have shown effectiveness in enhancing ART adherence. To optimize ART's impact and mitigate HIV's prevalence in SSA, stakeholders must consider these barriers, facilitators, and interventions when formulating policies or treatment modalities. For sustained positive ART outcomes, future research should target specific underrepresented groups like HIV-infected children, adolescents, and pregnant women in SSA to further delve into the barriers, facilitators and interventions promoting ART adherence.

IRAK1 inhibition blocks the HIV-1 RNA mediated pro-inflammatory cytokine response from microglia.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are a common source of morbidity in people living with HIV (PLWH). Although antiretroviral therapy (ART) has lessened the severity of neurocognitive disorders, cognitive impairment still occurs in PLWH receiving ART. The pathogenesis of HAND is likely multifaceted, but common factors include the persistence of HIV transcription within the central nervous system, higher levels of pro-inflammatory cytokines in the cerebrospinal fluid, and the presence of activated microglia. Toll-like receptor (TLR) 7 and TLR8 are innate pathogen recognition receptors located in microglia and other immune and non-immune cells that can recognise HIV RNA and trigger pro-inflammatory responses. IL-1 receptor-associated kinase (IRAK) 1 is key to these signalling pathways. Here, we show that IRAK1 inhibition inhibits the TLR7 and TLR8-dependent pro-inflammatory response to HIV RNA. Using genetic and pharmacological inhibition, we demonstrate that inhibition of IRAK1 prevents IRAK1 phosphorylation and ubiquitination, and the subsequent recruitment of TRAF6 and the TAK1 complex to IRAK1, resulting in the inhibition of downstream signalling and the suppression of pro-inflammatory cytokine and chemokine release.

Ponatinib Represses Latent HIV-1 by Inhibiting AKT-mTOR.

Although antiretroviral therapy (ART) is effective in suppressing viral replication, it does not cure HIV-1 infection due to the presence of the viral latent reservoir. Rather than reactivating the latent viruses, the "block and lock" strategy aims to shift the viral reservoir to a deeper state of transcriptional silencing, thus preventing viral rebound after ART interruption. Although some latency-promoting agents (LPAs) have been reported, none of them have been approved for clinical application due to cytotoxicity and limited efficacy; therefore, it is important to search for novel and effective LPAs. Here, we report an FDA-approved drug, ponatinib, that can broadly repress latent HIV-1 reactivation in different cell models of HIV-1 latency and in primary CD4+ T cells from ART-suppressed individuals ex vivo. Ponatinib does not change the expression of activation or exhaustion markers on primary CD4+ T cells and does not induce severe cytotoxicity and cell dysfunction. Mechanistically, ponatinib suppresses proviral HIV-1 transcription by inhibiting the activation of the AKT-mTOR pathway, which subsequently blocks the interaction between key transcriptional factors and the HIV-1 long terminal repeat (LTR). In summary, we discovered a novel latency-promoting agent, ponatinib, which could have promising significance for future applications of HIV-1 functional cure.

A Systematic Review and Meta-Analysis on the Impact of Statin Treatment in HIV Patients on Antiretroviral Therapy

The rate of new human immunodeficiency virus (HIV) infections globally is alarming. Although antiretroviral therapy (ART) improves the quality of life among this group of patients, ARTs are associated with risk of cardiovascular diseases (CVD). Moreover, virally suppressed patients still experience immune activation associated with HIV migration from reservoir sites. Statins are widely recommended as therapeutic agents to control ART-related CVD; however, their impacts on the cluster of differentiation (CD)4 count and viral load are inconsistent. To assess the effect of statins on markers of HIV infections, immune activation and cholesterol, we thoroughly reviewed evidence from randomised controlled trials. We found 20 relevant trials from three databases with 1802 people living with HIV (PLHIV) on statin-placebo treatment. Our evidence showed no significant effect on CD4 T-cell count standardised mean difference (SMD): (-0.59, 95% confidence intervals (CI): (-1.38, 0.19), p = 0.14) following statin intervention in PLHIV on ART. We also found no significant difference in baseline CD4 T-cell count (SD: (-0.01, 95%CI: (-0.25, 0.23), p = 0.95). Our findings revealed no significant association between statins and risk of viral rebound in PLHIV with undetectable viral load risk ratio (RR): (1.01, 95% CI: (0.98, 1.04), p = 0.65). Additionally, we found a significant increase in CD8+CD38+HLA-DR+ T-cells (SMD (1.10, 95% CI: (0.93, 1.28), p < 0.00001) and CD4+CD38+HLA-DR+ T-cells (SMD (0.92, 95% CI: (0.32, 1.52), p = 0.003). Finally, compared to placebo, statins significantly reduced total cholesterol (SMD: (-2.87, 95% CI: (-4.08, -1.65), p < 0.0001)). Our results suggest that the statin lipid-lowering effect in PLHIV on ART may elevate immune activation without influencing the viral load and CD4 count. However, due to the limited evidence synthesised in this meta-analysis, we recommend that future powered trials with sufficient sample sizes evaluate statins' effect on CD4 count and viral load, especially in virally suppressed patients.

Human Immunodeficiency Virus: Opportunistic Infections and Beyond.

Human immunodeficiency virus (HIV) infection causes substantial morbidity and mortality worldwide. Although antiretroviral therapy (ART) has changed the epidemiology of HIV in the last 20 years with increased survival and decreasing incidence of opportunistic infections (OI), CNS OI remain a major cause of morbidity. Improved survival has also increased neurological presentations due to co morbid conditions, treatment related side effects and inflammatory syndromes. Being familiar with the imaging findings, the impact of ART and interpretation of imaging in the context of clinical and laboratory findings is important for radiologists as well as clinicians in the management of HIV-infected patients.

ITat transgenic mice exhibit hyper-locomotion in the behavioral pattern monitor after chronic exposure to methamphetamine but are unaffected by Tat expression

Although antiretroviral therapy (ART) has increased the quality of life and lifespan in people living with HIV (PWH), millions continue to suffer from the neurobehavioral effects of the virus. Additionally, the abuse of illicit drugs (methamphetamine in particular) is significantly higher in PWH compared to the general population, which may further impact their neurological functions. The HIV regulatory protein, Tat, has been implicated in the neurobehavioral impacts of HIV and is purported to inhibit dopamine transporter (DAT) function in a way similar to methamphetamine. Thus, we hypothesized that a combination of Tat expression and methamphetamine would exert synergistic deleterious effects on behavior and DAT expression. We examined the impact of chronic methamphetamine exposure on exploration in transgenic mice expressing human Tat (iTat) vs. their wildtype littermates using the behavioral pattern monitor (BPM).During baseline, mice exhibited sex-dependent differences in BPM behavior, which persisted through methamphetamine exposure, and Tat activation with doxycycline. We observed a main effect of methamphetamine, wherein exposure, irrespective of genotype, increased locomotor activity and decreased specific exploration. After doxycycline treatment, mice continued to exhibit drug-dependent alterations in locomotion, with no effect of Tat, or methamphetamine interactions. DAT levels were higher in wildtype, saline-exposed males compared to all other groups.These data support stimulant-induced changes of locomotor activity and exploration, and suggest that viral Tat and methamphetamine do not synergistically interact to alter these behaviors in mice. These findings are important for future studies attempting to disentangle the effect of substances that impact DAT on HAND-relevant behaviors using such transgenic animals.

Immunological and virological findings in a patient with exceptional post-treatment control: a case report

Although antiretroviral therapy (ART) is effective in suppressing viral replication, HIV-1 persists in reservoirs and rebounds after ART has been stopped. However, a very few people (eg, elite and post-treatment controllers) are able to maintain viral loads below detection limits without ART, constituting a realistic model for long-term HIV remission. Here, we describe the HIV control mechanisms of an individual who showed exceptional post-treatment control for longer than 15 years. We report the case of a Hispanic woman aged 59 years with sexually acquired acute HIV infection, who was included in an immune-mediated primary HIV infection trial involving a short course of ciclosporine A, interleukin-2, granulocyte macrophage colony-stimulating factor, and pegylated interferon alfa, followed by analytical treatment interruption. We did the following viral assays: total and integrated HIV-1 DNA in CD4 T cells and rectal tissue, quantitative viral outgrowth assay, HIV-1 infectivity in peripheral blood mononuclear cells and CD4 T-cell cultures and viral inhibitory activity by natural killer (NK) and CD8 T cells. NK and T-cell phenotypes were determined by flow cytometry. HLA, killer cell immunoglobulin-like receptors, Δ32CCR5, and NKG2C alleles were genotyped. After ART and immunomodulatory treatment, the person maintained undetectable plasma viral load for 15 years. HIV-1 subtype was CFR_02AG, CCR5-tropic. We found progressive reductions in viral reservoir during the 15-year treatment interruption: total HIV DNA (from 4573·50 copies per 106 CD4 T cells to 95·33 copies per 106 CD4 T cells) and integrated DNA (from 85·37 copies per 106 CD4 T cells to 5·25 copies per 106 CD4 T cells). Viral inhibition assays showed strong inhibition of in vitro HIV replication in co-cultures of CD4 T cells with autologous NK or CD8 T cells at 1:2 ratio (75% and 62%, respectively). Co-cultures with NK and CD8 T cells resulted in 93% inhibition. We detected higher-than-reference levels of both NKG2C-memory-like NK cells (46·2%) and NKG2C γδ T cells (64·9%) associated with HIV-1 control. We described long-term remission in a woman aged 59 years who was treated during primary HIV infection and has maintained undetectable viral load for 15 years without ART. Replication-competent HIV-1 was isolated. NKG2C-memory-like NK cells and γδ T cells were associated with the control viral replication. Strategies promoting these cells could bring about long-term HIV remission. Fondo Europeo para el Desarrollo Regional (FEDER), SPANISH AIDS Research Network (RIS), Fondo de Investigación Sanitaria (FIS), HIVACAT, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CERCA Programme/Generalitat de Catalunya, la Caixa Foundation, and Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC). For the Spanish translation of the abstract see Supplementary Materials section.

Chimeric Antigen Receptor-Modified Immune Cells for Eradication of HIV Reservoirs

Abstract Host immune surveillance can achieve powerful clearance of infectious pathogens. Acute human immunodeficiency virus type I (HIV-1) infection can establish viral reservoirs in humans, and persistent chronic activation by the virus exhausts the immune system and ultimately causes acquired immunodeficiency syndrome. Although antiretroviral therapy (ART) can reduce the viral load and viremia in patients, latent HIV-1 reservoirs are still the biggest challenge that needs to be overcome to eradicate the virus. However, the low or absent viral antigen expression and epitope mutation caused during durable ART result in host immune escape and reservoir cell inaccessibility. In addition, durable ART accompanied by inflammation and persistent activation of immune cells, especially dysfunction and/or exhaustion of T cells. With the development of immunology, genetics, and genetic engineering technology, researchers can construct chimeric antigen receptors (CARs) to modify immune cells to enhance HIV clearance. The important research goals of creating CARs to modify natural killer (NK) and T cells are an attempt to enhance the functional effects of immune cells and restore the function of the immune system. This article reviews the latent characteristics of HIV, the development of CAR molecules, and the strategies for reprogramming T cells and NK cells with CARs, and aims to clear the HIV reservoirs and related potential problems.

Learning to Be Elite: Lessons From HIV-1 Controllers and Animal Models on Trained Innate Immunity and Virus Suppression.

Although antiretroviral therapy (ART) has drastically changed the lives of people living with human immunodeficiency virus-1 (HIV-1), long-term treatment has been associated with a vast array of comorbidities. Therefore, a cure for HIV-1 remains the best option to globally eradicate HIV-1/acquired immunodeficiency syndrome (AIDS). However, development of strategies to achieve complete eradication of HIV-1 has been extremely challenging. Thus, the control of HIV-1 replication by the host immune system, namely functional cure, has long been studied as an alternative approach for HIV-1 cure. HIV-1 elite controllers (ECs) are rare individuals who naturally maintain undetectable HIV-1 replication levels in the absence of ART and whose immune repertoire might be a desirable blueprint for a functional cure. While the role(s) played by distinct human leukocyte antigen (HLA) expression and CD8+ T cell responses expressing cognate ligands in controlling HIV-1 has been widely characterized in ECs, the innate immune phenotype has been decidedly understudied. Comparably, in animal models such as HIV-1-infected humanized mice and simian Immunodeficiency Virus (SIV)-infected non-human primates (NHP), viremic control is known to be associated with specific major histocompatibility complex (MHC) alleles and CD8+ T cell activity, but the innate immune response remains incompletely characterized. Notably, recent work demonstrating the existence of trained innate immunity may provide new complementary approaches to achieve an HIV-1 cure. Herein, we review the known characteristics of innate immune responses in ECs and available animal models, identify gaps of knowledge regarding responses by adaptive or trained innate immune cells, and speculate on potential strategies to induce EC-like responses in HIV-1 non-controllers.

The Impact of Different Parental Figures of Adolescents Living With HIV: An Evaluation of Family Structures, Perceived HIV Related Stigma, and Opportunities for Social Support.

Although antiretroviral therapy (ART) has changed the expected health outcomes for HIV, there are still issues related to stigma, how people living with HIV are perceived, and the availability of social support. The purpose of this study was to explore the associations between family structure and psychosocial wellbeing reflected by perceived HIV stigma and social support among adolescents living with HIV in Kumasi, Ghana. This article used baseline data from two mixed methods studies that evaluated the safety and preliminary efficacy of group-based support programs for ART adherence improvement among adolescents living in Kumasi, Ghana (N = 70, aged 12–18 years). A multivariate linear regression analysis was employed to examine the associations between family structure and the outcomes of stigma and social support. The main variables for family structure were single mothers and female caregivers. We found that single motherhood was a significant determinant of stigma. When compared to other categories of caregiver types, adolescents being raised by their single mothers was associated with a 0.259 decrease in the mean internal HIV stigma score (p = 0.029). Also, for female adolescents, being raised by a female guardian (e.g., mother, aunt, grandmother, and sister) was associated with a 20.92 point increase in the overall support index (p = 0.005). This study shows that the type of parent or guardian, and their gender, influences the perceived stigma and available social support among adolescents living with HIV in Ghana. Vulnerable subgroups of adolescents living with HIV, particularly those raised up by male caregivers, should be provided with additional support.

Mucosal-associated invariant T cells: A cryptic coordinator in HIV-infected immune reconstitution.

Human immunodeficiency virus type 1 (HIV-1) infection causes considerable morbidity and mortality worldwide. Although antiretroviral therapy (ART) has largely transformed HIV infection from a fatal disease to a chronic condition, approximately 10%-40% of HIV-infected individuals who receive effective ART and sustain long-term viral suppression still cannot achieve optimal immune reconstitution. These patients are called immunological nonresponders, a state associated with poor clinical prognosis. Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved unconventional T-cell subset defined by expression of semi-invariant αβ T-cell receptor (TCR), which recognizes metabolites derived from the riboflavin biosynthetic pathway presented on major histocompatibility complex-related protein-1. MAIT cells, which are considered to act as a bridge between innate and adaptive immunity, produce a wide range of cytokines and cytotoxic molecules upon activation through TCR-dependent and TCR-independent mechanisms, which is of major importance in defense against a variety of pathogens. In addition, MAIT cells are involved in autoimmune and immune-mediated diseases. The number of MAIT cells is dramatically and irreversibly decreased in the early stage of HIV infection and is not fully restored even after long-term suppressive ART. In light of the important role of MAIT cells in mucosal immunity and because microbial translocation is inversely associated with CD4+ T-cell counts, we propose that MAIT cells participate in the maintenance of intestinal barrier integrity and microbial homeostasis, thus further affecting immune reconstitution in HIV-infected individuals.

HIV co-infection augments EBV-induced tumorigenesis in vivo.

In most individuals, EBV maintains a life-long asymptomatic latent infection. However, EBV can induce the formation of B cell lymphomas in immune suppressed individuals including people living with HIV (PLWH). Most individuals who acquire HIV are already infected with EBV as EBV infection is primarily acquired during childhood and adolescence. Although antiretroviral therapy (ART) has substantially reduced the incidence of AIDS-associated malignancies, EBV positive PLWH are at an increased risk of developing lymphomas compared to the general population. The direct effect of HIV co-infection on EBV replication and EBV-induced tumorigenesis has not been experimentally examined. Using a humanized mouse model of EBV infection, we demonstrate that HIV co-infection enhances systemic EBV replication and immune activation. Importantly, EBV-induced tumorigenesis was augmented in EBV/HIV co-infected mice. Collectively, these results demonstrate a direct effect of HIV co-infection on EBV pathogenesis and disease progression and will facilitate future studies to address why the incidence of certain types of EBV-associated malignancies are stable or increasing in ART treated PLWH.

Comparison of HIV DNA decay and immune recovery between early and chronic HIV-infected individuals 96 weeks after ART.

Although antiretroviral therapy (ART) has prolonged the lives of HIV-infected individuals, HIV reservoir remains the main stumbling block to HIV cure. Presently, early ART initiation is one of the effective measures to reduce the HIV reservoir. The effects of ART in Chinese individuals with acute and early HIV infection (AEHI) and chronic HIV infection (CHI) were analyzed in this study. We performed virological and immunological parameter analysis in 29 AEHI and 19 CHI individuals who were initiated into ART in Beijing, China. The HIV DNA, CD4+ T-cell and CD8+ T-cell counts, and CD4/CD8 ratios between the two groups were compared using statistical analyses. At weeks 48 and 96, the total HIV DNA was significantly lower in the AEHI group than that the CHI group (2.48 [2.26-2.66] vs. 3.06 [2.79-3.33] log10 copies/106 peripheral blood mononuclear cells (PBMCs), p<0.01 at week 48 and 2.17 [1.85-2.45] vs. 2.92 [2.73-3.24] log10 copies/106 PBMCs, p<0.01 at week 96, respectively). The CD4/CD8T-cell ratio in the AHI group at week 24 was significantly higher than that in the CHI group (0.71 [0.50-0.99] vs. 0.45 [0.34-0.65], p=0.08). After 48weeks of ART, there was still a negative correlation between the CD4/CD8 ratio and the HIV DNA level in the CHI group rather than the AEHI group. Early ART initiation could enhance an earlier immunological recovery in AEHI. Immunological normalization after ART initiation could provide important protection against the viral reservoir seeded in AEHI individuals.