Derek C. Macallan

Bone Mineral Density in Patients with Human Immunodeficiency Virus Infection

Abstract. The Object of this study was to determine whether HIV infection is associated with decreased bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry at total body, lumbar spine, and hip in 45 men with HIV infection and compared with sex, age, and weight-matched controls. Repeat scans were performed after a mean interval of 15 months in 21 patients to determine whether there were detectable losses of BMD. Compared with controls, the HIV patients had marginally lower BMD at the lumbar spine (P= 0.04) but there was no significant difference in total body or hip BMD. None of the patients had reduced BMD to levels associated with a diagnosis of osteoporosis. On longitudinal follow-up, a small decrease in total body BMD (−1.6%; P= 0.02) was observed but there was no significant change in spine and hip BMD. In spite of the many features of HIV infection that might be expected to cause a reduction in BMD such as cytokine activation, decreased physical activity, small bowel disease, hypogonadism, and direct infection of osteogenic cells by HIV, we found only minimal differences in BMD between HIV patients and controls. Furthermore, the HIV patients studied did not appear to show excessive loss in bone mineral over time.

Measurement and modeling of human T cell kinetics

The ability to measure, describe and interpret T cell kinetics is pivotal in understanding normal lymphocyte homeostasis and diseases that affect T cell numbers. Following in vivo labeling of dividing cells with 6,6‐D2‐glucose in eight healthy volunteers, peripheral blood T cells were sorted by CD4, CD8 and CD45 phenotype. Enrichment of deuterium in DNA was measured by gas chromatography‐mass spectrometry. A novel model of T cell kinetics, allowing for heterogeneity within T cell pools, was used to analyze data on acquisition and loss of label and calculate proliferation and disappearance rates for each subpopulation. Proliferation rates for CD45RO+CD8+ cells and CD45RO+CD4+ cells were 5.1% and 2.7% /day, respectively (equivalent doubling times: 14 and 26 days). CD45RA+CD8+ lymphocytes and CD45RA+CD4+ lymphocytes had slower proliferation rates, 0.5% and 0.6% / day, respectively (doubling time about 4 months). Disappearance rates of labeled cells were similar for all cell types (7%–12% / day) and exceeded corresponding proliferation rates. This disparity may be understood conceptually in terms of either phenotypic heterogeneity (rapid versus slow turnover pools), or history (recently divided cells are more likely to die). The new kinetic model fits the data closely and avoids the need to postulate a large external source of lymphocytes to maintain equilibrium.

Direct Measurement of T Cell Subset Kinetics In Vivo in Elderly Men and Women

The age-associated decline in immunocompetence is paralleled by changes in the proportions of PBL subpopulations. In turn, the size and composition of the peripheral lymphocyte pool is determined by input from the thymus and bone marrow and by the balance of proliferation and death in each lymphocyte subpopulation. We compared the kinetics of lymphocyte subtypes in young (seven of eight CMV seronegative) and healthy elderly human subjects (six of seven CMV seropositive), using deuterated glucose DNA labeling in vivo to measure rates of T cell proliferation and disappearance. For CD45RO+ cells of both CD4+ and CD8+ subtypes and for CD4+CD45RA+ cells the kinetics of proliferation and disappearance were remarkably similar between elderly and young subjects. In the young, the kinetics of CD8+CD45RA+ cells with a naive phenotype resembled those of CD4+CD45RA+ cells. However, CD8+CD45RA+ T cells from the elderly exhibited a predominantly primed phenotype, and for this subset, although the proliferation rate was similar to that of other CD45RA+ cells, the disappearance rate of labeled cells was greatly decreased compared with that of all other T cell subsets. Our data provide a direct demonstration that there are no substantial changes in in vivo kinetics for most T cell populations in healthy elderly compared with young subjects. However, primed CD8+CD45RA+ cells show unusual kinetic properties, indicating the persistence of these cells in the blood and dissociation of proliferation from disappearance.

Lymphocyte kinetics: the interpretation of labelling data

DNA labelling provides an exciting tool for elucidating the in vivo dynamics of lymphocytes. However, the kinetics of label incorporation and loss are complex and results can depend on the method of interpretation. Here we describe two approaches to interpreting labelling data. Both seek to explain the common observation that the estimated death rate of lymphocytes is higher than their estimated proliferation rate. In the first approach, an additional source of lymphocytes is postulated. In the second, it is maintained that lymphocyte heterogeneity is sufficient to account for the observation. We explain why we favour the second approach, arguing that the addition of a large source of lymphocytes is unnecessary and difficult to reconcile with what is currently known about lymphocyte physiology. We discuss how the choice of model can affect data interpretation.

Predictors of Renal Outcome in HIV-Associated Nephropathy

BACKGROUND Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is an important cause of end-stage renal disease among African American patients. This study was performed to study the epidemiology of HIVAN in a predominantly black African population and the impact of highly active antiretroviral therapy and other factors on the development of end-stage renal disease. METHODS We retrospectively identified all patients with HIVAN, defined by biopsy or strict clinical criteria, in 8 clinics in the United Kingdom. Baseline renal function, HIV parameters, renal pathological index of chronic damage, and responses to highly active antiretroviral therapy were analyzed, and factors associated with adverse renal outcome were identified. RESULTS From 1998 through 2004, we studied 16,834 patients, 61 of whom had HIVAN. HIVAN prevalence in black patients was 0.93%, and HIVAN incidence in those without renal disease at baseline was 0.61 per 1000 person-years. After a median of 4.2 years, 34 patients (56%) had developed end-stage renal disease. There were no significant differences in renal function and HIV parameters at baseline, time to initiation of highly active antiretroviral therapy, and rates of HIV RNA suppression between the 20 patients who developed end-stage renal disease >3 months after receiving the HIVAN diagnosis and the 23 patients who maintained stable renal function. However, the index of chronic damage score was significantly higher in those who developed end-stage renal disease (P < .001), and an index of chronic damage score >75 was associated with shorter renal survival (P < .001). CONCLUSIONS Whereas overall patient survival suggested an important benefit of highly active antiretroviral therapy, no additional renal benefit of early initiation of highly active antiretroviral therapy or viral suppression could be demonstrated in this large cohort of patients with established HIVAN. Severity of chronic kidney damage, as quantified by biopsy, was the strongest predictor of renal outcome.

The fate and lifespan of human monocyte subsets in steady state and systemic inflammation

In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition. Intermediate and nonclassical monocytes have longer circulating lifespans (∼4 and ∼7 d, respectively). In a human experimental endotoxemia model, a transient but profound monocytopenia was observed; restoration of circulating monocytes was achieved by the early release of classical monocytes from bone marrow. The sequence of repopulation recapitulated the order of maturation in healthy homeostasis. This developmental relationship between monocyte subsets was verified by fate mapping grafted human classical monocytes into humanized mice, which were able to differentiate sequentially into intermediate and nonclassical cells.

Rapid turnover of T cells in acute infectious mononucleosis

During acute infectious mononucleosis (AIM), large clones of Epstein‐Barr virus‐specific T lymphocytes are produced. To investigate the dynamics of clonal expansion, we measured cell proliferation during AIM using deuterated glucose to label DNA of dividing cells in vivo, analyzing cells according to CD4, CD8 and CD45 phenotype. The proportion of labeled CD8+CD45R0+ T lymphocytes was dramatically increased in AIM subjects compared to controls (mean 17.5 versus 2.8%/day; p<0.005), indicating very rapid proliferation. Labeling was also increased in CD4+CD45R0+ cells (7.1 versus 2.1%/day; p<0.01), but less so in CD45RA+ cells. Mathematical modeling, accounting for death of labeled cells and changing pool sizes, gave estimated proliferation rates in CD8+CD45R0+ cells of 11–130% of cells proliferating per day (mean 47%/day), equivalent to a doubling time of 1.5 days and an appearance rate in blood of about 5×109 cells/day (versus 7×107 cells/day in controls). Very rapid death rates were also observed amongst labeled cells (range 28–124, mean 57%/day),indicating very short survival times in the circulation. Thus, we have shown direct evidence for massive proliferation of CD8+CD45R0+ T lymphocytes in AIM and demonstrated that rapid cell division continues concurrently with greatly accelerated rates of cell disappearance.

Case reports: pernicious complications of benign tertian malaria

We describe 2 patients with complications of Plasmodium vivax malaria. Both patients developed marked intravascular haemolysis and haemoglobinuria despite normal levels of glucose-6-phosphate dehydrogenase activity in blood. One required mechanical ventilation because of life-threatening hypoxia due to acute respiratory distress syndrome.

Nutrition and immune function in human immunodeficiency virus infection.

The triad of human immunodeficiency virus (HIV) infection, nutritional status and immune function are intimately related, each factor having effects on the others. The dominant effect in this three-way relationship is the effect of HIV infection on nutritional status, an effect which, until the advent of potent anti-retroviral drugs, has been manifest primarily as wasting. Recently, more complex metabolic abnormalities have become apparent, particularly fat redistribution syndromes, hyperlipidaemia and hypercholesterolaemia. For the converse effect, the effect of nutritional state on HIV disease progression, there is good evidence that clinical outcome is poorer in individuals with compromised nutrition. However, the beneficial effects of nutritional support have been more difficult to demonstrate. For macronutrients, effective macronutrient supply improves survival in severely-malnourished individuals and may have beneficial effects in less-severely-affected individuals. Micronutrient deficiencies appear to be involved in modifying clinical HIV disease and may also be associated with enhanced mother-to-child transmission of virus, particularly in developing countries. Intervention trials in this setting are currently under way. In conclusion, the interaction of HIV infection and nutrition is of great importance not just because of the major impact that HIV infection has on nutritional state, but also because strategies to improve nutritional status, both quantitatively and qualitatively, may have a beneficial effect on the clinical and immunological course of the disease.

Determinants of energy intake and energy expenditure in HIV and AIDS.

To determine the relative importance of various factors in the causation of wasting related to human immunodeficiency virus (HIV), quantitative analysis and linear structural modeling was performed on energy metabolism data collected longitudinally and prospectively from 33 men positive for the human immunodeficiency virus at 105 time points over a 3-y period before the era of highly active antiretroviral therapy. Measured variables included energy intake, total energy expenditure, resting energy expenditure, rate of change in weight, CD4 count, clinical status, appetite, and mood. Derived variables included energy balance, activity-related energy expenditure, and physical activity level. Relative contributions were assessed by linear structural modeling based on multiple regression expressing results as path coefficients for individual relationships. The primary determinant of energy balance was energy intake (r = 0.80). Total energy expenditure made a very minor contribution to energy balance (r = -0.04). Total energy expenditure was primarily determined by activity level (r = 0.91), which itself was negatively related to the presence of opportunistic infection and CD4 count. Energy intake was related to activity level (r = 0.28) and appetite (r = 0.30), which were closely interrelated (r = 0.59). Such linear structural models allow quantitative importance to be apportioned to factors determining weight change in those infected with HIV and represent a powerful tool for future metabolic studies.