Susanne D. Nielsen

Incomplete immune recovery in HIV infection: mechanisms, relevance for clinical care, and possible solutions.

Treatment of HIV-infected patients with highly active antiretroviral therapy (HAART) usually results in diminished viral replication, increasing CD4+ cell counts, a reversal of most immunological disturbances, and a reduction in risk of morbidity and mortality. However, approximately 20% of all HIV-infected patients do not achieve optimal immune reconstitution despite suppression of viral replication. These patients are referred to as immunological nonresponders (INRs). INRs present with severely altered immunological functions, including malfunction and diminished production of cells within lymphopoetic tissue, perturbed frequencies of immune regulators such as regulatory T cells and Th17 cells, and increased immune activation, immunosenescence, and apoptosis. Importantly, INRs have an increased risk of morbidity and mortality compared to HIV-infected patients with an optimal immune reconstitution. Additional treatment to HAART that may improve immune reconstitution has been investigated, but results thus far have proved disappointing. The reason for immunological nonresponse is incompletely understood. This paper summarizes the known and unknown factors regarding the incomplete immune reconstitution in HIV infection, including mechanisms, relevance for clinical care, and possible solutions.

Microbial translocation in HIV infection is associated with dyslipidemia, insulin resistance, and risk of myocardial infarction.

Objective:Microbial translocation has been suggested to be a driver of immune activation and inflammation. It is hypothesized that microbial translocation may be related to dyslipidemia, insulin resistance, and the risk of coronary heart disease in HIV-infected individuals. Design:Cross-sectional study of 60 HIV-infected patients on combination antiretroviral therapy with viral suppression >2 years and 31 healthy age-matched controls. Methods:Lipopolysaccharide (LPS) was analyzed by limulus amebocyte lysate colorimetric assay. Lipids, including cholesterol, low-density lipoprotein (LDL), and triglycerides, were measured. Glucose metabolism was determined using an oral glucose tolerance test. Body composition was determined using whole-body dual-energy x-ray absorptiometry scans and magnetic resonance imaging. The Framingham risk score was used to assess risk of cardiovascular disease and myocardial infarction. Results:HIV-infected patients had higher level of LPS compared with controls (64 pg/mL vs. 50 pg/mL, P = 0.002). Likewise, HIV-infected patients had higher triglycerides, LDL, and fasting insulin as well as evidence of lower insulin sensitivity compared with controls. Among HIV-infected patients, high LPS was associated with a higher level of triglycerides and LDL and with lower insulin sensitivity. Importantly, among HIV-infected patients, high LPS was associated with a higher Framingham risk score. Conclusions:HIV-infected patients with suppressed viral replication had increased level of microbial translocation as measured by LPS. LPS was associated with cardiometabolic risk factors and increased Framingham risk score. Hence, the gastrointestinal mucosal barrier may be a potential therapeutic target to prevent dyslipidemia and future cardiovascular complications in HIV infection.

Thirty Years with HIV Infection—Nonprogression Is Still Puzzling: Lessons to Be Learned from Controllers and Long-Term Nonprogressors

In the early days of the HIV epidemic, it was observed that a minority of the infected patients did not progress to AIDS or death and maintained stable CD4+ cell counts. As the technique for measuring viral load became available it was evident that some of these nonprogressors in addition to preserved CD4+ cell counts had very low or even undetectable viral replication. They were therefore termed controllers, while those with viral replication were termed long-term nonprogressors (LTNPs). Genetics and virology play a role in nonprogression, but does not provide a full explanation. Therefore, host differences in the immunological response have been proposed. Moreover, the immunological response can be divided into an immune homeostasis resistant to HIV and an immune response leading to viral control. Thus, non-progression in LTNP and controllers may be due to different immunological mechanisms. Understanding the lack of disease progression and the different interactions between HIV and the immune system could ideally teach us how to develop a functional cure for HIV infection. Here we review immunological features of controllers and LTNP, highlighting differences and clinical implications.

Correlation of increases in 1,25-dihydroxyvitamin D during vitamin D therapy with activation of CD4+ T lymphocytes in HIV-1-infected males.

Abstract Background: In HIV-1–infected individuals, levels of CD4+ T lymphocytes are depleted and regulatory T-lymphocytes (Tregs) are elevated. In vitro studies have demonstrated effects of vitamin D on the growth and differentiation of these cells. We speculated whether supplementation with vitamin D could have an effect on CD4+ T lymphocytes or Tregs in HIV-1–infected males. Methods: We conducted a placebo-controlled randomized study that ran for 16 weeks and included 61 HIV-1–infected males, of whom 51 completed the protocol. The participants were randomized to 1 of 3 daily treatments: (1) 0.5-1.0 µg calcitriol and 1200 IU (30 µg) cholecalciferol, (2) 1200 IU cholecalciferol, (3) placebo. Percentages of the following T-lymphocyte subsets were determined: naïve CD4+ and CD8+ cells, activated CD4+ and CD8+ cells, and CD3+CD4+CD25+CD127low Tregs. Furthermore 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and parathyroid hormone were measured. Results: No significant changes of the studied T-lymphocyte subsets occurred in the treatment groups compared to the placebo group. Increases in 1,25-dihydroxyvitamin D were associated with increases in activated CD4+ T lymphocytes (P = .001) and Tregs (P = .01) in adjusted models. Changes in parathyroid hormone correlated inversely with Tregs (P = .02). Smokers had higher levels of naïve CD4+ T lymphocytes (37% vs 25%;P = .01), naïve CD8+ T lymphocytes (28% vs 19%; P = .03), and Tregs (9% vs 7%; P = .03). Conclusion: Cholecalciferol and calcitriol administered during 16 weeks did not change the levels of T-lymphocyte fractions compared to placebo. However, increases in 1,25-dihydroxyvitamin D were associated with an expansion of activated CD4+ cells and Tregs.

Improved thymic index, density and output in HIV-infected patients following low-dose growth hormone therapy: a placebo controlled study.

Objectives:To investigate the effect of low-dose, long-term recombinant human growth hormone (rhGH) therapy on immune reconstitution in human immunodeficiency virus (HIV)-infected patients with focus on thymic index, density and output. Design:Randomized, placebo-controlled, double-blind, single-centre trial. Methods:Forty-six HIV-infected Caucasian men on highly active antiretroviral therapy, 21–60 years of age, were included. Twenty-eight patients were randomized to 0.7mg/day rhGH and 18 patients to placebo, administrated as daily subcutaneous injections between 1300 and 1500 h for 40 weeks. Endpoints were changes from baseline in thymic size and thymic output measured as T-cell receptor rearrangement excision circles (TREC) frequency and total TREC content, and total and naive CD4+ cells. Results:Thymic density and thymic index increased in the GH group, compared with the placebo group (28 versus 4 Hounsfield units, P = 0.006 and 1 versus 0, P = 0.004). TREC frequency and total TREC content increased in the GH group, compared with the placebo group (37 versus −8%, P = 0.049 and 51 versus –14%, P = 0.026). Total CD4+ cells and naive CD4+ cells increased insignificantly more in the GH than the placebo group [11.4%, 95% confidence interval (CI) −6.0 to 28.9; P = 0.19 and 18%, interquartile range (IQR) −4, 40 versus 13%, IQR −12, 39; P = 0.79]. Therapy was well tolerated. Conclusions:Daily treatment with a low dose rhGH of 0.7 mg for 40 weeks stimulated thymopoiesis expressed by thymic index, density and area, TREC frequency and total TREC content in CD4+ cells in HIV-infected patients on highly active antiretroviral therapy.

The naive CD4+ count in HIV-1-infected patients at time of initiation of highly active antiretroviral therapy is strongly associated with the level of immunological recovery.

Current antiretroviral therapy can induce considerable, sustained viral suppression followed by immunological recovery, in which naive CD4+ cells are important. Long-term immunological recovery was investigated during the first 3 y of highly active antiretroviral therapy (HAART) in 210 HIV-1-infected patients. The focus was on the naive CD4+ cell time course and associations between naive CD4+ cell counts and established prognostic markers. Total and naive CD4+ cell counts were measured using flow cytometry. The HIV-RNA detection limit was 20 copies/ml. During 36 months of HAART, the total CD4+ count followed a triphasic pattern, reflecting an initial phase of rapid redistribution from lymphoid tissues, followed by a slow increase, partially due to an increase in naive CD4+ cell count. From Month 18 onwards, both naive and total CD4+ cell counts stabilized, although viral suppression was sustained. There was no association between plasma viral load and the increase in naive CD4+ cell count. Importantly, baseline naive CD4+ cell count was significantly associated with the change in naive CD4+ cell count, suggesting that the naive cell count at baseline does influence the immunological recovery that can be obtained from treatment. Surprisingly, the naive CD4+ cell count tended to stabilize at a subnormal level after 18 months of HAART. This finding merits further investigation.

Microbiota-Dependent Marker TMAO Is Elevated in Silent Ischemia but Is Not Associated With First-Time Myocardial Infarction in HIV Infection.

Objectives:HIV infection is associated with increased risk of coronary heart disease beyond that explained by traditional risk factors, and altered gut microbiota has been proposed as a potential trigger. Trimethylamine-N-oxide (TMAO) is a proatherogenic substance formed in the liver from trimethylamine, exclusively generated by gut microbiota from dietary phosphatidylcholine. We aimed to investigate whether TMAO is associated with subclinical and clinical coronary heart disease in HIV infection. Methods:Two previously described cohorts were examined as follows: (1) cross-sectional cohort of HIV-infected persons and uninfected controls with known atherosclerotic plaque burden as assessed by myocardial perfusion scintigraphy, coronary artery calcium score, and intima-media thickness and (2) nested case–control study of HIV-infected persons with first-time myocardial infarction (MI) compared with HIV-infected persons without MI, assessed at 4 time points from before initiation of antiretroviral therapy (ART) to last sample before the cases MI (median: 51, range: 0–239 days). Results:There was no difference in plasma TMAO when comparing HIV-infected persons and uninfected controls. TMAO was elevated in HIV-infected persons with myocardial perfusion defects but was not associated with coronary artery calcium score, intima media thickness, or Framingham risk score. In the nested case control study, plasma TMAO was not associated with first-time MI. However, TMAO increased after ART introduction and was associated with the use of protease inhibitors in both cohorts. Conclusions:TMAO was elevated in HIV-infected persons with myocardial perfusion defects, but was not associated with first-time MI. Our data question TMAO as a useful biomarker of cardiovascular risk in HIV infection, at least in ART-treated individuals.

Increased Tryptophan Catabolism Is Associated With Increased Frequency of CD161+Tc17/MAIT Cells and Lower CD4+ T-Cell Count in HIV-1 Infected Patients on cART After 2 Years of Follow-Up.

Background:HIV infection is associated with increased ratio between kynurenine and tryptophan (KTR) in plasma, increased microbial translocation, expansion of regulatory T cells (Tregs), and depletion of Tc17/mucosa-associated invariant T (MAIT) cells. The association between these parameters and the impact of KTR on CD4+ T-cell recovery in HIV-infected patients on combination antiretroviral therapy (cART) after 2 years of follow-up was investigated. Methods:Forty-one HIV-infected individuals treated with cART for a minimum of 2 years were included. Tregs, CD161+Tc17/MAIT cells, naive cells, immune activation, senescence, and apoptosis were measured using flow cytometry. Soluble CD14 (sCD14), lipopolysaccharide, and tryptophan metabolites in plasma were measured retrospectively before cART and at inclusion initiation using Limulus Amebocyte Lysate colometric assay, enzyme-linked immunosorbent assay, and tandem mass spectrometry, respectively. KTR was calculated, and patients were divided into 2 groups defined by high vs. low KTR. CD4+ T-cell count was determined at inclusion and after 2 years of follow-up. Results:KTR decreased after cART initiation. Patients on cART with high KTR displayed an immunological profile with high sCD14, high percentage Tregs, low percentage CD161+Tc17/MAIT cells, low percentage naive cells, low CD4/CD8 ratio, and poor immune reconstitution after 2 years of follow-up compared with patients with low KTR. Conclusions:Our results support the hypothesis that tryptophan catabolism, indoleamine 2,3-dioxygenase 1 (IDO1) activation, microbial translocation, and perturbed distribution of Tregs and CD161+Tc17/MAIT cells are part of a vicious circle that perpetuates exhaustion of the immune system and progression of untreated HIV infection and challenge immune reconstitution in patients on cART.

Sex-specific trends in 4-year survival in 37 276 men and women with acute myocardial infarction before the age of 55 years in Sweden, 1987-2006: a register-based cohort study

Objective To examine sex-specific trends in 4-year mortality among young patients with first acute myocardial infarction (AMI), 1987–2006. Design Prospective cohort study. Setting Sweden. Participants We identified 37 276 cases (19.4% women; age, 25–54 years) from the Swedish Inpatient Register, 1987–2006, who had survived 28 days after an AMI. Outcome measures 4-year mortality from all causes and standard mortality ratio (SMR). Results From the first to last 5-year period, the absolute excess risk decreased from 1.38 to 0.50 and 1.53 to 0.59 per 100 person-years among men aged 25–44 and 45–54 years, respectively. Corresponding figures for women were a decrease from 2.26 to 1.17 and from 1.93 to 1.45 per 100 person-years, respectively. Trends for women were non-linear, decreasing to the same extent as those for men until the third period, then increasing. For the last 5-year period, the standardised mortality ratio for young survivors of AMI compared with the general population was 4.34 (95% CI 3.04 to 5.87) and 2.43 (95% CI 2.12 to 2.76) for men aged 25–44 and 45–54 years, respectively, and 13.53 (95% CI 8.36 to 19.93) and 6.42 (95% CI 5.24 to 7.73) for women, respectively. Deaths not associated with cardiovascular causes increased from 21.5% to 44.6% in men and 41.5% to 65.9% in women. Conclusions Young male survivors of AMI have low absolute long-term mortality rates, but these rates remain twofold to fourfold that of the general population. After favourable development until 2001, women now have higher absolute mortality than men and a 6-fold to 14-fold risk of death compared with women in the general population.

Reduced thymic size but no evidence of impaired thymic function in uninfected children born to human immunodeficiency virus-infected mothers.

Background: HIV-exposed, uninfected (HIV-EU) infants present hematologic and immunologic abnormalities at birth, and it remains to be clarified whether these abnormalities persist beyond infancy, for instance, affecting vaccination responses. Methods: Thymic size and thymic output were evaluated in 20 HIV-EU children at 15 months of age and compared with 10 age- and gender-matched controls. Regulatory T-cells (Tregs) and immune activation as well as cytokine profiles were determined, and the antibody response to Haemophilus influenzae Type b (Hib) vaccination was evaluated. Results: Thymic size was significantly lower in HIV-EU children (P = 0.011). However, CD4 and CD8 counts did not differ between HIV-EU and control children. Likewise, thymic output estimated as CD4+ cells expressing naive (CD45RA+CD62L+CD27+, P = 0.31) or recent thymic naive (CD45RA+CD27+CD31+, P = 0.13) phenotype, or CD4+ cells containing T-cell receptor excision circles (P = 0.47) were comparable. HIV-EU children and controls had similar levels of activated cells (CD4+CD38+HLA-DR+, P = 0.87; CD8+CD38+HLA-DR+, P = 0.22), Tregs (CD4+CD25+CD127lowFOXP3+, P = 0.53), and naive Tregs (CD4+CD25+CD127lowFOXP3+CD45RA+CD27+, P = 0.65). Finally, comparable titers of Haemophilus influenzae Type b antibodies in the 2 groups were found (P = 0.43). Conclusion: The study demonstrates reduced thymic size in HIV-EU children compared with children born to HIV-negative mothers, but no evidence of impaired thymic function, immune regulation, or antibody vaccination response was detected, suggesting that no qualitative immune deficits persist in HIV-EU children at 15 months of age.