HIV Immune Reconstitution Research Articles

Recent advances in poor HIV immune reconstitution: what will the future look like?

Combination antiretroviral therapy has demonstrated proved effectiveness in suppressing viral replication and significantly recovering CD4+ T cell count in HIV type-1 (HIV-1)-infected patients, contributing to a dramatic reduction in AIDS morbidity and mortality. However, the factors affecting immune reconstitution are extremely complex. Demographic factors, co-infection, baseline CD4 cell level, abnormal immune activation, and cytokine dysregulation may all affect immune reconstitution. According to report, 10-40% of HIV-1-infected patients fail to restore the normalization of CD4+ T cell count and function. They are referred to as immunological non-responders (INRs) who fail to achieve complete immune reconstitution and have a higher mortality rate and higher risk of developing other non-AIDS diseases compared with those who achieve complete immune reconstitution. Heretofore, the mechanisms underlying incomplete immune reconstitution in HIV remain elusive, and INRs are not effectively treated or mitigated. This review discusses the recent progress of mechanisms and factors responsible for incomplete immune reconstitution in AIDS and summarizes the corresponding therapeutic strategies according to different mechanisms to improve the individual therapy.

Anti‐GM2 antibodies‐associated meningoradiculitis in the context of HIV immune reconstitution inflammatory syndrome

AbstractBackgroundAutoimmune manifestations can occur in the context of HIV immune reconstitution inflammatory syndrome (IRIS). Previous studies have shown that GM2 is overexpressed on HIV‐1 infected T lymphocytes.Case presentationA 71‐year‐old patient diagnosed with HIV‐1 infection developed neurological symptoms congruent with meningoradiculitis 1 month after initiation of antiretroviral therapy. Concurrent syphilitic seroconversion raised the hypothesis of neurosyphilis, which was later infirmed. Serum antiganglioside immunoglobulin M antibodies were highly positive. Treatment with intravenous immunoglobulins was effective.ConclusionWe postulate that meningoradiculitis in this patient was a consequence of anti‐GM2 antibodies produced as part of an anti‐HIV‐1 immune response, and that this case falls within the scope of autoimmune manifestations linked to HIV IRIS.

Association of intestinal and systemic inflammatory biomarkers with immune reconstitution in HIV+ patients on ART

BackgroundHIV infection is characterized by CD4+ T-cells depletion related to gut damage, microbial translocation, immune activation and intestinal and systemic low-grade inflammation. With the use of antiretroviral treatment, these alterations in HIV+ patients reach similar levels to HIV- controls. However, almost 20% patients have deficient immune reconstitution of CD4+ T-cells, which make them more susceptible to develop non-AIDS and AIDS comorbidities.MethodsHIV+ patients on ART, with sustained virologic control were grouped according to their immune reconstitution as: immunological responders (n = 18) and immunological non-responders (n = 18); also, HIV- controls were enrolled (n = 14). CD4+ and CD8+ T-cell activation (HLA-DR+ and CD38+ single and co-expression) were measured by flow cytometry. Serum levels of sCD14, sCD163, lipopolysaccharide, I-FABP, sST2, as well as fecal levels of calprotectin, lactoferrin and secretory IgA were evaluated by ELISA. Levels of C-reactive protein were determined by a high sensibility singleplex bead-based immunoassay. Serum and fecal concentrations of proinflammatory cytokines were quantified by multiplex bead-based immunoassay.ResultsHLA-DR+ and CD38+ co-expression, as well as median fluorescence intensity in CD4+ and CD8+ T-cells subpopulations was greater in immunological non-responders group, after normalization and fold change calculation. Similarly, this group presented higher levels of sCD14, C-reactive protein, as well as fecal calprotectin and lactoferrin. Furthermore, both HIV+ groups showed elevated levels of proinflammatory cytokines in stool.ConclusionsOur data suggests that despite the virologic control, HIV+ patients under treatment with deficient immune reconstitution showed elevation of both innate and T-cells immune activation, as well as intestinal and systemic inflammation. However, some patients with CD4+ T-cells count above 350 cells/μL also presented these alterations. Future studies are necessary to evaluate the dynamics of multiple systemic and intestinal biomarkers in diverse types of HIV+ patients, as such as their clinical impact.

EFFECT OF MATERNAL HIV IMMUNE RECONSTITUTION INFLAMMATORY RESPONSE SYNDROME ON THE RISK OF ADVERSE PREGNANCY-FETAL OUTCOMES IN HIV-1 POSITIVE, ART NAIVE PREGNANT WOMEN OF REPRODUCTIVE AGE IN SELECTED HOSPITALS, NAIROBI, KENYA

Background: Immune reconstitution inflammatory response syndrome (IRIS) is a recovery disease that may be triggered after starting ARV therapy in some individuals. The incidence of adverse pregnancy-fetal outcomes with IRIS has not been studied in Kenya among pregnant women, with focus only, on improved immune response and PMTCT after ART initiation. The indirect effect of ART, the maternal HIV - IRIS on pregnancy outcome has not been elucidated. More than 10% of the global burden of disease is due to pregnancy complications and adverse pregnancy and related birth outcomes and despite recent advances in obstetric medicine, pregnancy complications and adverse birth outcomes are a growing public health concern and economic burden on the health-care system. This has substantial burden of adverse pregnancy-fetal outcomes with prevalence of preterm birth, low birth weight, and small gestational age infants of 19.8%, 14.2%, and 12.6%, respectively, and of still birth and neonatal mortalityat1.9% and 0.4%, respectively. The aim of this study was to evaluate the effect of maternal HIV immune reconstitution inflammatory response syndrome on the risk of adverse pregnancy-fetal outcomes in HIV-1 positive; ART initiated pregnant women of reproductive age in selected hospitals, Nairobi, Kenya. Methodology: The study was conducted among 204 HIV-1 positive, ART initiated pregnant women of reproductive age in selected hospitals, Nairobi, Kenya. A prospective cohort study design was used where the subjects were recruited and followed from the end of first trimester for six and half months after they were confirmed to be HIV positive, and put on ARV treatment using a pretested data collection tool. Bivariate analyses with chi-square test to establish the association between the variables at p-value < 0.05. Logistic regression analysis was performed to identify independent outcome predictors. Adjusted relative risk at 95% confidence interval was determined. Results: The study indicated that, adverse pregnancy-fetal outcome cumulative incidence was 26.47% among women diagnosed with IRIS compared to 10.78% among women not diagnosed with IRIS. The incidence rate estimate was 0.012 and 0.0045 per person’s week respectively with a rate ratio of 012/.0045=2.7. Women with IRIS had 2.46 times the risk of experiencing an adverse pregnancy-fetal outcome compared to those who did not [OR=3; 95%CI: 1.4-6.4; P=.004]. LBW cumulative incidence was the highest with 11 (10.8%) among IRIS exposed women and 3 (2.9%) among non-IRIS exposed women and same case with PTB 8 (7.8%) and 3 (2.9%) respectively. Conclusion: There was a significant relationship of maternal HIV-immune reconstitution inflammatory response syndrome diagnosis with adverse pregnancy-fetal outcomes as a result of ART initiation among HIV-1 positive, pregnant women of reproductive age. This study observes that, being diagnosed with maternal HIV-IRIS following ART initiation during pregnancy among ART naive women is associated with experiencing an adverse pregnancy outcome. This should be a concern in clinical practice as IRIS has self-resolution, it may on the other hand affect pregnancy outcome negatively. PMTCT should integrate monitoring of suspected IRIS cases using the latest defined criteria for its diagnosis in pregnant women starting ant-retroviral therapy especially in resource limited areas.
 
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SUN-518 Graves’ Disease Newly Diagnosed in the Setting of Hypokalemic Periodic Paralysis in an HIV+ Patient

Relevance: A rare yet distinct cause of sudden onset paralysis is severe hypokalemia associated with thyrotoxicosis. This is thought to be associated with mutations in genes encoding cellular potassium channels. We report a case of acute onset paralysis with profound hypokalemia and a new diagnosis of Graves’ thyrotoxicosis in a previously asymptomatic African American, HIV+ man on highly active antiretroviral therapy (HAART) for over 8 years. Clinical case: A 49-year-old man with hypertension and HIV presented with acute paralysis of his bilateral upper and lower extremities. His initial potassium was 1.8 mEq/L (3.5-5.0). Prior to sudden onset loss of motor strength, he denied any preceding palpitations, tremor, anxiety, diaphoresis, hyper-defecation, weight loss, heat or cold intolerance, neck pain, increase in neck girth or difficulty swallowing, proptosis or other ocular symptoms. He has no family history of thyroid disease. He had an enlarged palpable thyroid without nodules and no audible bruit. There was no periorbital edema or proptosis, and no signs of dermopathy. A thyroid ultrasound showed a hyperemic and diffusely enlarged thyroid gland without nodules. Labs included a TSH of 0.007 mCU/mL (0.43-3.8), Free T4 2.1 ng/dL (0.71-1.85), Total T3 229.6 ng/dL (58-194), and thyrotropin receptor antibody 2.6 IU/L (0-1.75). The CD4+ count was 146 in 2010 with a slow gradual rise to 673 in 2019, and HIV viral load was undetectable. There were no offending medications or supplements identified. With aggressive potassium repletion, the serum potassium improved to 4.6 mEq/L and he regained normal strength within several hours. He was started on Methimazole 10mg daily and propranolol 10mg TID. At one month, the thyroid function tests normalized. Methimazole 10mg daily was continued and propranolol was tapered off. He remains euthyroid. Genetic testing is pending. Conclusions: Graves’ disease is the most common thyroid disease triggered by immune reconstitution in HIV + individuals on HAART. The incidence of thyroid disease in HIV patients on HAART is higher in women and Africans with a 1.5-2 fold increase compared with the general population [Muller et. al, Eur Thyroid J 2019;8:173-185]. Despite a higher incidence of hyperthyroidism in women, over 95% of cases of hypokalemic periodic paralysis have been reported in men, with a 10-fold higher incidence among Asians compared to Westerners. There has been one prior case report of Thyrotoxic Periodic Paralysis in an HIV + patient and this was in a Polynesian male (Brown JD et al. Hawaii Med J 2007). To our knowledge, this is the first case report of an African American HIV+ patient with this disorder. An association with mutations in the Kir2.6 gene (encodes a potassium channel, is expressed in skeletal muscle, and is transcriptionally regulated by thyroid hormone) has been proposed [Ryan et. al, Cell 2010 January 8; 140(1):88-98].

Comparative Analysis of Immune Reconstitution in HIV-Positive Recipients of Allogeneic and Autologous Stem Cell Transplant on the BMT-CTN-0903/AMC-080 and BMT-CTN-0803/AMC-071 Trials

Introduction We report the results of a phenotypic and functional analysis of immune reconstitution in HIV(+) patients treated with allogeneic hematopoietic stem cell transplant (allo-HSCT), in comparison with HIV(+) autologous transplant (auto-HSCT) recipients, HIV(-) auto-HSCT recipients and healthy controls (HCs). Methods Blood samples were collected at days 56, 180 and 365 post-transplant from HIV(+) allo-ASCT recipients (n=17, BMT-CTN-0903/AMC-080 trial), HIV(+) auto-SCT recipients (n=36, BMT-CTN-0803/AMC-071 trial) and HIV(-) auto-SCT recipients (n=30, NCT00569309/OSU-07044 trial), and at 1 time point from 71 HCs. Five-color flow cytometry was performed on whole blood. Principal component analysis (PCA) examined global differences across 18 immune cell subsets between all subject cohorts. Wilcoxon rank-sum tests compared median absolute and proportionate cell counts. Feature importance score analysis (FIS) identified contributions of 100 immune cell populations to differences between HIV(+) cohorts and HCs. Functional responsiveness of HIV(+) allo-HSCT recipients' T cells to stimulation with CD3- and CD28-directed antibodies, NK cells to stimulation with IL-12+IL-18 and monocytes to stimulation with lipopolysaccharide (LPS) was assessed by mass cytometry on peripheral blood mononuclear cells (n=2) and compared to HCs (n=2). Results PCA showed that immunomes of HIV(+) allo-HSCT recipients and HIV(+) auto-HSCT recipients clustered together at all time points. HIV(-) auto-SCT recipients and HCs clustered together and away from the HIV(+) cohorts. FIS identified 13 cell subsets that defined the difference between HIV(+) allo-HSCT recipients (all visits) and HCs and 11 immune cell subsets that defined the difference between HIV(+) auto-HSCT recipients (all visits) and HCs; in each comparison, activated CD3+/HLA-DR+ T cells had the greatest impact on the difference between composite HIV(+) and HC immunomes. At 1 year, both HIV(+) transplant recipient cohorts had higher absolute numbers of activated T cells, effector T cells and CD8+ T cells than HCs and lower numbers of CD4+ T cells, naive T cells, and activated NK cells compared to HCs (p Conclusion Chronic HIV infection confers pro-inflammatory immune characteristics on phenotypic and functional profiling of the cellular immunome of stem cell transplant recipients, irrespective of allogeneic or autologous stem cell donor source.

Comparative Analysis of Immune Reconstitution in HIV-Positive Recipients of Allogeneic and Autologous Stem Cell Transplant on the BMT CTN 0903/AMC-080 and BMT CTN 0803/AMC-071 Trials

Introduction. Our previous flow cytometry-based comparison of HIV(+) and HIV(-) autologous hematopoietic stem cell transplant (auto-HSCT) recipient immunomes at 56, 180 and 365 days post-transplant to each other and to healthy controls (HCs) showed that both sets of auto-HSCT recipient immunomes approached HCs over time, but retained significant differences. HIV(+), but not HIV(-), auto-AHCT recipients retained pro-inflammatory features consistent with chronic HIV infection. Here, we report the results of a quantitative and functional analysis of immune reconstitution in HIV(+) patients treated with allogeneic hematopoietic stem cell transplant (allo-HSCT), in comparison with HIV(+) auto-HSCT recipients and HCs. Methods. Blood samples were collected for analysis at days 56, 180 and 365 post-transplant from HIV(+) transplant recipients and at 1 time point from HCs. Whole blood analysis was performed by five-color flow cytometry across 100 immune marker combinations. Comparisons were made between HIV(+) allo-HSCT recipients (n=17, acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, Hodgkin and non-Hodgkin lymphoma that received myeloablative or reduced intensity conditioning on the BMT-CTN-0903/AMC-080 trial), HIV(+) auto-HSCT recipients (n=36, aggressive B cell non-Hodgkin lymphoma or Hodgkin lymphoma that received myeloablative conditioning on the BMT-CTN-0803/AMC-071 trial) and 71 HCs. Unsupervised principal component analysis (PCA) examined differences in immune cell proportions, identified by flow cytometry across 100 cell subsets at each time point. Wilcoxon rank-sum tests compared median absolute counts and median proportions of cell subsets. An independent feature importance score analysis (FIS) identified contributions of immune cell populations expressing specific immune marker combinations to the differences between HIV(+) auto-HSCT recipients, HIV(+) allo-HSCT recipients and HCs. Functional responsiveness of HIV(+) allo-HSCT recipients' T cells to stimulation with CD3- and CD28-directed antibodies, NK cells to stimulation with IL-12 and IL-18 and monocytes to stimulation with lipopolysaccharide (LPS) was assessed in a preliminary mass cytometry on peripheral blood mononuclear cells isolated at the same time points (n=2) and compared to HCs (n=2). Results. PCA showed that immunomes of HIV(+) allo-HSCT recipients and HIV(+) auto-HSCT recipients clustered together with each other, but away from HCs at all time points throughout the post-transplant year. FIS identified: 1) 13 cell subsets that defined the difference between HIV(+) allo-HSCT recipients (all visits) and HCs, and 2) 11 immune cell subsets that defined the difference between HIV(+) auto-HSCT recipients (all visits) and HCs; in both of these comparisons, activated CD3+/HLA-DR+ T cells had the greatest impact on the difference between HIV(+) and HC immunomes. At 1 year, both HIV(+) transplant recipient cohorts had higher absolute numbers of activated T cells, effector T cells and CD8+ T cells than HCs (Wilcoxon rank-sum test, p<0.0031). HIV(+) autologous and allogeneic HSCT recipients also had lower numbers of CD4+ T cells, naïve T cells and activated NK cells compared to HCs (p<0.0031). FIS also identified 20 immune cell subsets that defined the difference between HIV(+) autologous and allogeneic HSCT recipients immunomes at 1 year, with CD8+/CD27- effector T cell subset exerting the highest impact on the difference. Preliminary functional mass cytometry analysis of 2 HIV(+) allo-HSCT recipients and 2 HCs showed that: 1) IFNʏ production by CD8+ T cells was increased above that of HCs at all time points. 2) Expanded populations of CD4+/T-bet+ cytotoxic cells expressing granzyme B and perforin, and CD8+ cytotoxic T cells expressing granzyme B and perforin, persisted in HIV(+) allo-HSCT recipients at all time points, but not in HCs. 3) NK cells retained an ability to produce IFNʏ in response to stimulation with IL-12 and IL-18 in HIV(+) allo-SCT recipients. 4) Monocytes showed an enhanced production of TNFα in response to stimulation with LPS in HIV(+) allo-HSCT recipients compared to HCs at 1 year post-HSCT. Conclusion. Chronic HIV infection confers the pro-inflammatory immune features on the phenotypic and functional profiling of the T lymphocyte immunome of stem cell transplant recipients, irrespective of allogeneic or autologous stem cell donor source. Disclosures Devine: Bristol Myers: Other: Grant for monitoring support & travel support; Kiadis Pharma: Other: Protocol development (via institution); Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Hofmeister:Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Navarro:Atara Biotherapeutics: Employment, Equity Ownership. Behbehani:Fluidigm corporation: Other: Travel funding. Lozanski:Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Baiocchi:Prelude: Consultancy.

Research of Chinese herbal compound on promoting HIV immune reconstitution

This article reviews the research reports of Chinese herbal compound on AIDS immune reconstitution for nearly 20 years, found that Chinese herbal compound has exact clinical efficacy for AIDS immune reconstitution. Therefore, we should give full play to the unique advantages of Chinese herbal compound in improving immunity, thus improving symptoms and improve quality of life, to achieve optimal clinical treatment of AIDS.

Immune Reconstitution in HIV+ Subjects on Lopinavir/Ritonavir-Based HAART According to the Severity of Pre-Therapy CD4+

We aimed to assess the impact of TDF/FTC +LPV/r-based HAART on the quality of immune reconstitution and on microbial translocation (MT) in HIV-infected antiretroviral-na�ve late presenting patients. 40 HIV+ antiretroviral-naive patients starting a first TDF/FTC+LPV/r HAART with CD4+≤350 cell/μL (20 "severe immune depression" patients -SID CD4+≤100/μL; 20 "moderate immune depression" patients -MID, CD4+ 200- 350/μL) were followed for 12 months (T12). CD38+CD8+, CD45R0+CD38+CD8+, CD95+CD4+/CD8+, CD127+CD4+/CD8+, pStat5 signalling (flow cytometry), plasma IL-7, sCD14 (ELISA), LPS (LAL) were tested at T0 and T12. By T12, both study groups displayed significant CD4+ increase and HIV-RNA reduction (p < .01). Despite similar CD38+CD8+ reduction in both SID (p=.039) and MID (p=.007), SID displayed a significant rise in CD45R0+CD38+CD8+ (p=.039). MID displayed significant increase of CD95+CD4+ (p=.002), with higher baseline and T12 levels (p=.024; p=.002), suggesting reduced commitment to apoptosis. At T12, different IL-7/IL-7R profile was shown according to pre-therapy immune depression. As compared to SID, MID increased circulating IL-7 (p=.049) displaying higher baseline and T12 CD127+CD4+ (p=.0001; p=.004) and CD127+CD8+ (p=.006; p=.009). By T12, only MID displayed significant reduction in LPS (p=.020) and sCD14 (p=.005). In antiretroviral-naive late presenters, we show different immune reconstitution quality and MT upon 12 months TDF/FTC+LPV/r-containing HAART according to the severity of pre-therapy immune depression. Despite equal T-cell activation decline, only MID patients tend to reduce pro-apoptotic T-lymphocytes, with a gain in circulating IL-7 and higher CD127+ central-memory T-cells, and a possible control over MT.

Clinical Features and Serum Biomarkers in HIV Immune Reconstitution Inflammatory Syndrome after Cryptococcal Meningitis: A Prospective Cohort Study

Although antiretroviral therapy (ART) improves survival in persons with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune reconstitution inflammatory syndrome (IRIS), an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency. The pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible. We prospectively followed 101 ART-naïve Ugandans with AIDS and recent CM for one year after initiating ART, and used Luminex multiplex assays to compare serum cytokine levels in participants who did or did not develop IRIS. IRIS occurred in 45% of participants with recent CM on ART, including 30% with central nervous system (CNS) manifestations. The median time to CM-IRIS was 8.8 wk on ART. Overall mortality on ART was 36% with IRIS and 21% without IRIS. CM-IRIS was independently associated with death (HR = 2.3, 95% CI 1.1-5.1, p = 0.04). Patients experiencing subsequent CM-IRIS had 4-fold higher median serum cryptococcal antigen (CRAG) levels pre-ART (p = 0.006). Higher pre-ART levels of interleukin (IL)-4 and IL-17 as well as lower tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) predicted future IRIS in multivariate analyses (area under the curve [AUC] = 0.82). An algorithm based on seven pre-ART serum biomarkers was a robust tool for stratifying high (83%), moderate (48%), and low risk (23%) for IRIS in the cohort. After ART was initiated, increasing levels of C-reactive protein (CRP), D-dimer, IL-6, IL-7, IL-13, G-CSF, or IL-1RA were associated with increasing hazard of IRIS by time-to-event analysis (each p≤0.001). At the time of IRIS onset, multiple proinflammatory cytokine responses were present, including CRP and IL-6. Mortality was predicted by pre-ART increasing IL-17, decreasing GM-CSF, and CRP level >32 mg/l (highest quartile). Pre-ART CRP level >32 mg/l alone was associated with future death (OR = 8.3, 95% CI 2.7-25.6, p<0.001). Pre-ART increases in Th(17) and Th(2) responses (e.g., IL-17, IL-4) and lack of proinflammatory cytokine responses (e.g., TNF-α, G-CSF, GM-CSF, VEGF) predispose individuals to subsequent IRIS, perhaps as biomarkers of immune dysfunction and poor initial clearance of CRAG. Although requiring validation, these biomarkers might be an objective tool to stratify the risk of CM-IRIS and death, and could be used clinically to guide when to start ART or use prophylactic interventions.

Efficient immune reconstitution in HIV+ naïve patients (pts) starting a first lopinavir/ritonavir‐containing regimen with low CD4 counts

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Measurement of Naive CD4 Cells Reliably Predicts Potential for Immune Reconstitution in HIV

Pathogenesis studies show that naive CD4 cells are preferentially depleted in lymphoid tissues during HIV infection, and studies of advanced patients suggest levels of naive CD4 cells in blood correlate to total CD4 cells after starting antiretroviral therapy (ARV). We hypothesized that measuring naive CD4 cells in blood in people at earlier stages of disease would identify those at highest risk for poor CD4 reconstitution who may benefit from earlier initiation of ARV. We identified 348 patients from multiple AIDS Clinical Trials Group studies who were ARV naive, had a CD4 count between 200 and 500 cells per microliter, a measure of pretreatment-naive CD4 percent, and serial follow-up measures of CD4 count and plasma HIV RNA after starting ARV. We used logistic regression to model the ability of naive CD4 percent to predict 100 and 200 CD4 cell increases after 24 months of therapy. After controlling for baseline viral load and demographic variables, baseline naive but not total CD4 cell count strongly predicted CD4 cell increases. Lower baseline naive CD4 percent was associated with greater time spent at lower CD4 T-cell counts after initiating ARV. Measurement of naive CD4 percent in patients can identify those least likely to reconstitute immunity, who may benefit from earlier ARV treatment.

Pericardial Large B-Cell Lymphoma as a Manifestation of HIV Immune Reconstitution Inflammatory Syndrome

Pericardial Large B-Cell Lymphoma as a Manifestation of HIV Immune Reconstitution Inflammatory Syndrome

HIV immune reconstitution syndrome in sub-Saharan Africa

We wish to respond to the editorial comment HIV immune reconstitution syndrome in sub-Saharan Africa by Dr Easterbrook. Although our prospective study suggested that the immune reconstitution inflammatory syndrome (IRIS) may have less impact on antiretroviral treatment (ART) programmes in resource-limited settings than previously suggested by retrospective studies Dr Easterbrook questions whether our experience from Johannesburg is representative for sub-Saharan Africa and whether our study has underestimated the IRIS burden. In order to accurately draw conclusions from our study we wish to clarify a few of our findings. (excerpt)

Biomarkers of HIV Immune Reconstitution Inflammatory Syndrome

Dysregulation of the immune system drives HIV pathogenesis. As we develop new ways to treat HIV and AIDS, we encounter new clinical ramifications of our treatment on regulatory components of the immune system. HIV-associated Immune Reconstitution Inflammatory Syndrome (IRIS) occurs after initiation of anti-retroviral therapy (ART) with inappropriate and dysbalanced restoration of the immune system resulting in pathologic inflammatory reactions with significant morbidity. IRIS is most commonly associated with latent, occult, or past infections, including tuberculosis, Cryptococcus neoformans, and Mycobacterium avium-complex. We discuss common clinical presentations, new diagnostic modalities, current hypotheses of IRIS pathogenesis, and future directions of IRIS-related research, focusing on the identification of biomarkers that can be used to predict and diagnose IRIS.

Pediatric HIV immune reconstitution inflammatory syndrome

Little is known regarding HIV immune reconstitution inflammatory syndrome in children. As the antiretroviral therapy roll out has gathered pace since 2004 in resource-limited settings, pediatric immune reconstitution inflammatory syndrome has emerged as a clinical challenge. The incidence of immune reconstitution inflammatory syndrome appears to be between 10 and 20%. The commonest causes are mostly mycobacterial, including tuberculosis, atypical mycobacteria and bacillus Calmette-Guérin related. In many pediatric cohorts, however, a marked early mortality within the first 90 days of antiretroviral therapy occurs. This mortality is poorly understood, and the contribution of immune reconstitution inflammatory syndrome to this mortality is unknown. Children after starting antiretroviral therapy may have paradoxical worsening of previously treated opportunistic infections. Due to the differences, however, in children's immunology with vertical HIV transmission, children are probably at greater risk of unmasking occult, subclinical infections during immune reconstitution.

HIV immune reconstitution syndrome in sub-Saharan Africa

We wish to respond to the editorial comment HIV immune reconstitution syndrome in sub-Saharan Africa by Dr Easterbrook. Although our prospective study suggested that the immune reconstitution inflammatory syndrome (IRIS) may have less impact on antiretroviral treatment (ART) programmes in resource-limited settings than previously suggested by retrospective studies Dr Easterbrook questions whether our experience from Johannesburg is representative for sub-Saharan Africa and whether our study has underestimated the IRIS burden. In order to accurately draw conclusions from our study we wish to clarify a few of our findings. (excerpt)

CD8 apoptosis may be a predictor of T cell number normalization after immune reconstitution in HIV

BackgroundAs part of the Houston Vanguard study, a subset of 10 patients randomized to receive IL-2 therapy were compared to 4 patients randomized to not receive IL-2, for markers of T cell activation and death during the first three cycles of IL-2. All patients were treated with combination antiretroviral therapy (ART) and were virally suppressed. The purpose of the study was to examine the role of CD8+ T cell death in responses to ART and IL-2 therapy.MethodsLymphocytes were examined at Day 0, 5 and 30 days during three cycles of IL-2 therapy. CD25, CD38, HLA-DR expression and annexin (cell death) were examined on CD4 and CD8 subpopulations. Follow up studies examined CD4 levels and CD4:CD8 reconstitution after 6 years using both univariant and multivariate analyses.ResultsHuman lymphocytes responded to IL-2 therapy by upregulation of CD25 on CD4+ T cells, leading to an increase in CD4 cell counts. CD8+ T cells did not increase CD25 expression, but upregulated activation antigens (CD38 and DR) and had increased death. At baseline, 7 of the 14 patients had high CD8+ T cell apoptosis (mean 17.0% ± 6.0). We did an exploratory analysis of immune status after six years, and found that baseline CD8+ T cell apoptosis was correlated with CD4 cell count gain beginning two years post enrollment. Patients with low levels of CD8+ T cell apoptosis at baseline (mean 2.2% ± 2.1) had significantly higher CD4 cell counts and more normalized CD4:CD8 ratios than patients with high CD8+ T cell apoptosis (mean CD4 cell counts 1,209 ± 164 vs 754 ± 320 cells/mm3; CD4:CD8 ratios 1.55 vs. 0.70, respectively).ConclusionWe postulate that CD8+ T cell apoptosis may reflect inherent activation status, which continues in some patients even though viral replication is suppressed which influences the ability of CD4+ T cells to rebound. Levels of CD8+ T cell apoptosis may therefore be an independent predictor of immune status, which should be shown in a prospective study.