Samantha MaWhinney

Influence of Plasma Viremia on Defects in Number and Immunophenotype of Blood Dendritic Cell Subsets in Human Immunodeficiency Virus 1–Infected Individuals

Dendritic cells (DCs) are postulated to be involved in transmission of human immunodeficiency virus (HIV) type 1 to T cells and in stimulation of HIV-1-specific cell-mediated immunity. Blood DCs have been categorized as myeloid (mDC) and plasmacytoid (pDC) subsets, on the basis of differences in phenotype and function. Blood DC subset numbers and expression of costimulatory molecules and HIV-1 coreceptors on DCs were measured in the blood of treated and untreated HIV-1-infected subjects and uninfected control subjects. Absolute numbers of mDCs and pDCs were lower in HIV-1-infected subjects than in control subjects, most significantly in those with active HIV-1 replication. Increased surface expression of costimulatory molecules was observed on both DC subsets in subjects with HIV-1 viremia. Highly active antiretroviral therapy suppression of plasma viremia resulted in increases in blood DC numbers and decreases in DC costimulatory molecule expression. These findings further define the impact of HIV-1 replication on blood DC subsets in vivo.

Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi's sarcoma clinical stage.

ObjectiveTo determine the relationship between human herpesvirus 8 (HHV-8 or Kaposis sarcoma-associated herpesvirus) peripheral blood virus load and Kaposis sarcoma (KS) clinical stage. DesignBlinded, cross-sectional analysis of peripheral blood HHV-8 DNA levels in persons with AIDS-related KS in Harare, Zimbabwe. MethodsSubjects were stratified by KS clinical stage. The amount of HHV-8 DNA in plasma and peripheral blood mononuclear cells (PBMC) was determined by quantitative real-time PCR amplification of the HHV-8 open reading frame 26. ResultsThirty-one HIV-1/HHV-8-coinfected persons were studied: 26 subjects had histologically confirmed KS (one stage II, 11 stage III and 14 stage IV) and five subjects had antibodies to HHV-8 but did not have KS. The age, CD4 lymphocyte count and plasma HIV-1 RNA levels were similar in all groups. HHV-8 DNA was detected in the plasma of all HHV-8-infected subjects (range < 2.4 to 5.2 log10 copies/ml), but plasma HHV-8 DNA levels were not associated with KS disease stage. In contrast, the amount of HHV-8 DNA in PBMC (range < 0.7 to 4.5 log10 copies/μg) was strongly associated with KS clinical stage (P = 0.005). Among stage IV KS cases, there was a linear relationship between plasma and PBMC HHV-8 DNA levels (r2 = 0.42;P = 0.01). ConclusionThe strong association observed between the extent of KS disease and the levels of HHV-8 DNA in PBMC provides further evidence for a relationship between HHV-8 virus load and KS pathogenesis.

Changes in health-related quality of life following coronary artery bypass graft surgery☆

BACKGROUND There are limited data to help clinicians identify patients likely to have an improvement in quality of life following CABG surgery. We evaluated the relationship between preoperative health status and changes in quality of life following CABG surgery. METHODS We evaluated 1,744 patients enrolled in the VA Cooperative Processes, Structures, and Outcomes in Cardiac Surgery study who completed preoperative and 6-month postoperative Short Form-36 (SF-36) surveys. The primary outcome was change in the Mental Component Summary (MCS) and Physical Component Summary (PCS) scores from the SF-36. RESULTS On average, physical and mental health status improved following the operation. Preoperative health status was the major determinant of change in quality of life following surgery, independent of anginal burden and other clinical characteristics. Patients with MCS scores less than 44 or PCS scores less than 38 were most likely to have an improvement in quality of life. Patients with higher preoperative scores were unlikely to have an improvement in quality of life. CONCLUSIONS Patients with preoperative health status deficits are likely to have an improvement in their quality of life following CABG surgery. Alternatively, patients with relatively good preoperative health status are unlikely to have a quality of life benefit from surgery and the operation should primarily be performed to improve survival.

Plasmacytoid and myeloid dendritic cells with a partial activation phenotype accumulate in lymphoid tissue during asymptomatic chronic HIV-1 infection.

Dendritic cells (DCs) from HIV-1-infected individuals display numeric and functional defects, and recent evidence suggests that HIV-1 can directly and indirectly activate DCs in vitro. The in vivo activation state and compartmentalization of DC subsets during HIV-1 infection remain poorly understood, however. We evaluated phenotypic and functional characteristics of myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) directly ex vivo in peripheral blood and lymphoid tissue from HIV-1-infected and HIV-seronegative individuals. Analysis of a wide range of chemokine receptors and activation/maturation markers on circulating DCs from viremic HIV-1-infected donors revealed a phenotype indicative of partial activation. Yet, blood DCs from viremic subjects still achieved full maturation when stimulated in vitro. In addition, blood pDCs from viremic individuals had a reduced capacity to migrate to CXCL12 in vitro. Total numbers of both DC subsets were increased in lymph nodes of asymptomatic untreated HIV-1-infected subjects, consistent with DC accumulation in the lymphoid compartment. Lymph node DCs also expressed high levels of CD40 in the absence of increases of other typical activation/maturation markers. Activation and depletion of DCs in blood with accumulation in lymphoid tissue may contribute to HIV-associated chronic immune activation and T-cell dysfunction.

Development of a DNA vaccine designed to induce cytotoxic T lymphocyte responses to multiple conserved epitopes in HIV-1.

Epitope-based vaccines designed to induce CTL responses specific for HIV-1 are being developed as a means for addressing vaccine potency and viral heterogeneity. We identified a set of 21 HLA-A2, HLA-A3, and HLA-B7 restricted supertype epitopes from conserved regions of HIV-1 to develop such a vaccine. Based on peptide-binding studies and phenotypic frequencies of HLA-A2, HLA-A3, and HLA-B7 allelic variants, these epitopes are predicted to be immunogenic in greater than 85% of individuals. Immunological recognition of all but one of the vaccine candidate epitopes was demonstrated by IFN-γ ELISPOT assays in PBMC from HIV-1-infected subjects. The HLA supertypes of the subjects was a very strong predictor of epitope-specific responses, but some subjects responded to epitopes outside of the predicted HLA type. A DNA plasmid vaccine, EP HIV-1090, was designed to express the 21 CTL epitopes as a single Ag and tested for immunogenicity using HLA transgenic mice. Immunization of HLA transgenic mice with this vaccine was sufficient to induce CTL responses to multiple HIV-1 epitopes, comparable in magnitude to those induced by immunization with peptides. The CTL induced by the vaccine recognized target cells pulsed with peptide or cells transfected with HIV-1 env or gag genes. There was no indication of immunodominance, as the vaccine induced CTL responses specific for multiple epitopes in individual mice. These data indicate that the EP HIV-1090 DNA vaccine may be suitable for inducing relevant HIV-1-specific CTL responses in humans.

Mild renal failure is associated with adverse outcome after cardiac valve surgery

The present study was performed to ascertain whether the presence of mild renal failure (defined as a serum creatinine concentration of 1. 5 to 3.0 mg/dL) is an independent risk factor for adverse outcome after cardiac valve surgery. An extensive set of preoperative and postoperative data was collected in 834 prospectively evaluated patients undergoing cardiac valve surgery at 14 Veterans Affairs Medical Centers. Univariate and multivariable analyses were performed to determine whether an independent association of mild renal dysfunction with adverse outcomes was present. Patients with mild renal failure had significantly greater 30-day mortality rates (P = 0.001; 16% versus 6%) and frequency of postoperative bleeding (P = 0.023; 16% versus 8%), respiratory complications (P = 0.02, 29% versus 16%), and cardiac complications (P = 0.002; 18% versus 7%) than patients with normal renal function (serum creatinine <1.5 mg/dL) when controlling for multiple other variables. The presence of a serum creatinine concentration of 1.5 to 3.0 mg/dL is significantly and independently associated with adverse outcomes after cardiac valve surgery.

Risk factors for falls in HIV-infected persons

Background:The incidence of and risk factors for falls in HIV-1–infected persons are unknown. Methods:Fall history during the prior 12 months, medical diagnoses, and functional assessments were collected on HIV-infected persons 45–65 years of age receiving effective antiretroviral therapy. Fall risk was evaluated using univariate and multivariate regression analyses. Results:Of 359 subjects, 250 persons (70%) reported no falls, 109 (30%) had ≥1 fall; and 66 (18%) were recurrent fallers. Females, whites, and smokers were more likely to be recurrent fallers (P ⩽ 0.05). HIV-related characteristics including current and nadir CD4 T-cell count, estimated HIV duration, and Veterans Aging Cohort Study Index scores were not predictors of falls (all P ≥ 0.09); didanosine recipients were more likely to be recurrent fallers (P = 0.04). The odds of falling increased 1.7 for each comorbidity and 1.4 for each medication (P < 0.001) and were higher in persons with cardiovascular disease, hypertension, dementia, neuropathy, arthritis, chronic pain, psychiatric disease, frailty, or disability [all odds ratio (OR) ≥ 1.8; P ⩽ 0.05]. Beta-blockers, antidepressants, antipsychotics, sedatives, and opiates were independently associated with falling (all OR ≥ 2.7; P ⩽ 0.01). Female gender, diabetes, antidepressants, sedatives, opiates, didanosine, exhaustion, weight loss, and difficulty with balance were the most significant predictors of falls in logistic regression (all OR ≥ 2.5; P ⩽ 0.05). Conclusions:Middle-aged HIV-infected adults have high fall risk. Multiple comorbidities, medications, and functional impairment were predictive of falls, but surrogate markers of HIV infection or an HIV-specific multimorbidity index were not. Fall risk should be assessed routinely as part of the care of HIV-infected persons.

Human Prion Disease and Relative Risk Associated with Chronic Wasting Disease

Colorado death certificate data from 1979 through 2001 show that the risk for Creutzfeldt-Jakob disease did not increase for residents of counties where chronic wasting disease is endemic among deer and elk.

Functional impairment is associated with low bone and muscle mass among persons aging with HIV infection.

Background:Disability and frailty are associated with osteoporosis, obesity, and sarcopenia. HIV-infected persons have early functional impairment, but the association between body composition and functional impairment is unknown. Methods:HIV-1–infected participants on combination antiretroviral therapy with virologic suppression, aged 45–65 years, had standardized physical function measures. In a nested analysis, 30 low- and 48 high-functioning cases and controls were matched by age, gender, and time since HIV diagnosis. Bone mineral density, fat mass, and lean body mass were assessed by dual-energy x-ray absorptiometry. Odds ratios (ORs) with 95% confidence intervals were obtained from conditional logistic regression. Results:Mean age was 53 years, mean CD4+ lymphocytes 598 cells per microliter, and 96% had plasma HIV-1 RNA <50 copies per milliliter. Low- and high-function subjects had similar CD4+ lymphocyte count and duration and type of antiretroviral therapy. Lower T scores at the hip [OR: 3.8 (1.1 to 12.5)] and lumbar spine [OR: 2.3 (1.1 to 4.5)] and lower lean body mass [OR: 1.1 (1.0 to 1.2)] were associated with significantly greater odds of low function (P ⩽ 0.03). Lower insulin-like growth hormone [IGF-1; OR: 5.0 (1.4 to 20.0)] and IGF-1 binding protein-3 [OR: 3.3 (1.7 to 9.9)] increased the odds of low functional status (P ⩽ 0.02). Fat mass and lower 25-OH vitamin D did not increase the odds of low functional status (P > 0.05). Conclusions:Functional impairment in HIV-1–infected persons on successful antiretroviral therapy is associated with low muscle mass, low bone mineral density, and low IGF-1 and IGF-1 binding protein-3. These characteristics may be a manifestation of early “somatopause” in middle-aged HIV-infected adults.

Comparison of Functional Status Instruments in HIV-Infected Adults on Effective Antiretroviral Therapy

Abstract Background: The best method for assessment of functional status in human immunodeficiency virus type 1 (HIV-1) infected persons is unknown. Objective: We hypothesized that 3 instruments to assess frailty or disability in elderly populations would perform similarly in HIV-1–infected persons. Methods: HIV-infected subjects 45 to 65 years old with plasma HIV-1 RNA <48 copies/mL were classified prospectively as low, moderate, or high function by Frieds frailty phenotype (FFP), the Short Physical Performance Battery (SPPB), and 400-m walk test. Functional instrument agreement was evaluated by weighted kappa statistic, and relationships with demographic or clinical factors were evaluated by odds ratios (OR). Results: There were 359 participants (85% male, mean age 52 years, mean CD4+ lymphocyte count 551 cells/µL) who were evaluated. Three percent to 8% were low, 31% to 51% were moderate, and 42% to 62% were high function. FFP, SPPB, and 400-m walk test had moderate agreement for functional classification (61%-64%; κ = 0.34-0.41). Across instruments, lower reported physical activity (OR ≯ 5.5; P ≤ .005), no current employment (OR ≯ 4.2; P < .02), arthritis (OR ≯ 6.5; P < .02), neurologic disease (OR ≯ 2.6; P < .05), debilitating pain (OR ≯ 5.4; P < .008), psychiatric disease (OR ≯3.1; P < .03), more comorbidities (OR ≯ 3.6; P ≤ .005), and more non-antiretroviral therapy medications (OR ≯ 3.5; P ≤ .01) were associated with lower function. Current CD4 <200 cells/µL was more likely among low-function (11%) than high-function (2%) persons on FFP (P = .04); other HIV-related characteristics were not significantly different (P > .05) between functional categories on any instrument. Conclusions: Moderate functional impairment is common among middle-aged HIV-infected persons, with similar frequencies of impairment detected by 3 instruments. Reduction in comorbid disease, increased physical activity, and improved pain symptom management could reduce functional impairment among persons aging with HIV-infection.