The role of HIV-1-specific CD4+ T-cell responses in controlling HIV-1 infection remains unclear. Previous work has suggested that such cells are eliminated in the early stages of infection in most subjects, and thus cannot substantially contribute to host defense against HIV-1. Here, using flow cytometric detection of antigen-induced intracellular cytokines, we show that significant frequencies of gag specific, T-helper-1 CD4+ memory T cells are detectable in most subjects with active/progressive HIV-1 infection (median frequency, 0.12% of memory subset; range, 0-0.66%). Median frequencies of these cells were considerably higher in nonprogressive HIV-1 disease (0.40%), but there was substantial overlap between the two groups (range of nonprogressors, 0.10-1.7%). Continuous HIV-1 suppression with anti-retroviral therapy was associated with a time-dependent reduction in median frequencies of gag-specific CD4+ memory T cells: 0.08% in subjects treated for 4-24 weeks, and 0.03% in subjects treated for 47-112 weeks. Thus, functional HIV-1-specific CD4+ T cells are commonly available for support of anti-HIV-1 effector responses in active disease, but their decline with anti-retroviral therapy indicates that immunologic participation in long-term HIV-1 control will probably require effective vaccination strategies.

The highly regulated secretion of effector cytokines by CD4 ϩ T cells plays a critical role in immune protection against pathogens such as cytomegalovirus. Here, we directly compare the frequency and functional characteristics of cytomegalovirus-specific CD4 ϩ memory/effector T cells in normal and HIV ϩ subjects using a novel, highly efficient multiparameter flow cytometric assay that detects the rapid intracellular accumulation of cytokine(s) after short-term (6 h) in vitro antigen stimulation. Responses in this assay correlate precisely with independent measures of sensitization history (e.g., seroreactivity), and allow the simultaneous assessment of multiple cytokines in single effector T cells. Healthy HIV Ϫ individuals manifested an average of 0.71, 0.72, 0.38, and 0.06% CD4 ϩ T cells responding to cytomegalovirus with ␥ -IFN, TNF-␣ , IL-2, and IL-4 production, respectively, with the simultaneous production of ␥ -IFN, TNF-␣ , and IL-2 being the most common effector phenotype. Significantly, overall cytomegalovirus-specific CD4 ϩ effector frequencies were markedly higher among 40% of HIV ϩ subjects (2.7-8.0%), and demonstrated a predominately polarized ␥ -IFN ϩ /TNF-␣ϩ /IL-2 Ϫ /IL-4 Ϫ phenotype. In contrast, CD4 ϩ effector frequencies for heterologous, nonubiquitous viruses such as the mumps virus were low or absent in the HIV ϩ group. These data suggest the existence of homeostatic mechanisms in HIV disease that selectively preserve memory T cell populations reactive with ubiquitous pathogens such as cytomegalovirus-likely at the expense of T cell memory to more sporadically encountered infectious agents. ( J. Clin. Invest. 1997. 99:1739-1750.)

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Different types of platelets in various types of plasma were subjected to levels of shear stress that produce irreversible platelet aggregation in normal platelet-rich plasma (PRP). At shear stresses of 90 or 180 dyne/cm2 applied for 30 seconds or five minutes, aggregation was either absent or only transient and reversible using severe von Willebrand's disease (vWD) PRP (less than 1% von Willebrand factor, vWF); Bernard-Soulier syndrome (BSS) PRP (platelets deficient in the membrane glycoprotein Ib, GPIb); normal PRP plus monoclonal antibody (MoAb) to GPIb; thrombasthenic PRP (platelets deficient in membrane glycoprotein IIb-IIIa complex, GPIIb-IIIa); and normal PRP plus MoAb to GPIIb-IIIa. Shear-induced aggregation was inhibited under the above conditions, even though the platelets were activated to release their granular contents. Sheared normal platelets in vWD plasma aggregated in response to added vWF. These studies demonstrate that the formation of stable platelet aggregates under conditions of high shear requires vWF and the availability of both GPIb and GPIIb-IIIa on platelet membranes. The experiments demonstrate that vWF-platelet interactions can occur in the absence of artificial agonists or chemical modification of vWF. They suggest a possible mechanism for platelet aggregation in stenosed or partially obstructed arterial vessels in which the platelets are subjected to relatively high levels of shear stress.

Lipodystrophy in HIV-infected (LDHIV) patients receiving protease inhibitors (PIs) is associated with dyslipidaemia. Whether lifestyle factors play a role in dyslipidaemia in LDHIV subjects on PIs is not well characterized. MethodsA total of 45 LDHIV male and six LDHIV female patients on PIs were recruited, and data were collected on smoking, exercise, diet (by 3-day food record), and fasting levels of serum lipids and lipoproteins. The relationships between lifestyle factors and metabolic variables were analysed in male patients by Spearman's correlation test and the significant relationships were further analysed by adjusting for age, PI duration, and waist circumference by Spearman's partial correlation test. ResultsIn men, mean (AE standard deviation) serum concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and non-HDL-C were 212 AE 70, 35 AE 7.3, 325 AE 230 and 169 AE 44 mg/dL, respectively. Sixty-seven percent of the men exercised regularly and 31.1% smoked. The reported diet was high in cholesterol (390 AE 212 mg) and percentage energy from saturated (12.2 AE 3.3%) and trans (2.4 AE 1.2%) fats, and low in soluble fibre (6.9 AE 2.3 g) compared with recent dietary guidelines. Following adjustments for the confounding variables, percentage energy intake from total protein and animal protein was positively related to TC (r 5 0.44, Po0.01 and r 5 0.37, Po0.05, respectively), TG (r 5 0.40, Po0.01 and r 5 0.46, Po0.01, respectively) and non-HDL-C (r 5 0.56, Po0.001 and r 5 0.49, Po0.01, respectively), that from trans fat was positively related to TG (r 5 0.34, Po0.05), and soluble fibre was negatively related to non-HDL-C (r 5 À 0.41, Po0.01). Moderate to heavy aerobic exercise tended to be associated with higher HDL-C (r 5 0.30, P 5 0.07) whereas smoking was not associated with any of the metabolic variables. ConclusionsIncreased intake of total protein, animal protein and trans fat, and reduced soluble fibre consumption contribute to dyslipidaemia in LDHIV subjects on PIs.Keywords: diet, dyslipidaemia, exercise, HIV, lipodystrophy, smoking In subjects not infected with HIV, lifestyle factors such as diet, physical activity and smoking contribute significantly to dyslipidaemia [10]. However, there is a paucity of data regarding the role of lifestyle factors in inducing dyslipidaemia in LDHIV individuals on PI-containing HAART. Previous studies [11][12][13] included not only HIV-infected subjects on PI therapy but also PI-naïve subjects. Also, two of these studies [11,12] did not examine or adjust for the role of exercise and smoking in dyslipidaemia. Furthermore, these studies [11][12][13] did not comprehensively examine the relationship between intakes of macronutrients and levels of lipids and lipoproteins. For example, Batterham et al.[11] evaluated only the role of total and saturated fat in dyslipidaemia. Hadigan et al.[12] did not study the role of unsaturated fats such as polyunsaturated, monounsaturated and trans fats. Gavrila et al. [13] did not ...