Impact of HLA selection pressure on HIV fitness at a population level in Mexico and Barbados.

UNLABELLED: Previous studies have demonstrated that effective cytotoxic T lymphocyte (CTL) responses drive the selection of escape mutations that reduce viral replication capacity (VRC). Escape mutations, including those with reduced VRC, can be transmitted and accumulate in a population. Here we compared two antiretroviral therapy (ART)-naive HIV clade B-infected cohorts, in Mexico and Barbados, in which the most protective HLA alleles (HLA-B*27/57/58:01/81:01) are differentially expressed, at 8% and 34%, respectively. Viral loads were significantly higher in Mexico than in Barbados (median, 40,774 versus 14,200; P < 0.0001), and absolute CD4(+) T-cell counts were somewhat lower (median, 380/mm(3) versus 403/mm(3); P = 0.007). We tested the hypothesis that the disparate frequencies of these protective HLA alleles would be associated with a higher VRC at the population level in Mexico. Analysis of VRC in subjects in each cohort, matched for CD4(+) T-cell count, revealed that the VRC was indeed higher in the Mexican cohort (mean, 1.13 versus 1.03; P = 0.0025). Although CD4 counts were matched, viral loads remained significantly higher in the Mexican subjects (P = 0.04). This VRC difference was reflected by a significantly higher frequency in the Barbados cohort of HLA-B*27/57/58:01/81:01-associated Gag escape mutations previously shown to incur a fitness cost on the virus (P = 0.004), a difference between the two cohorts that remained statistically significant even in subjects not expressing these protective alleles (P = 0.01). These data suggest that viral set points and disease progression rates at the population level may be significantly influenced by the prevalence of protective HLA alleles such as HLA-B*27/57/58:01/81:01 and that CD4 count-based guidelines to initiate antiretroviral therapy may need to be modified accordingly, to optimize the effectiveness of treatment-for-prevention strategies and reduce HIV transmission rates to the absolute minimum. IMPORTANCE: Immune control of HIV at an individual level is strongly influenced by the HLA class I genotype. HLA class I molecules mediating effective immune control, such as HLA-B*27 and HLA-B*57, are associated with the selection of escape mutants that reduce viral replicative capacity. The escape mutants selected in infected patients can be transmitted and affect the viral load and CD4 count in the recipient. These findings prompt the hypothesis that the frequency of protective alleles in a population may affect viral set points and rates of disease progression in that population. These studies in Mexico and Barbados, where the prevalence rates of protective HLA alleles are 8% and 34%, respectively, support this hypothesis. These data suggest that antiretroviral therapy (ART) treatment-for-prevention strategies will be less successful in populations such as those in Mexico, where viral loads are higher for a given CD4 count. Consideration may therefore usefully be given to ART initiation at higher absolute CD4 counts in such populations to optimize the impact of ART for prevention.

Why the inflammatory response is important to the cardiac surgical patient.

Although the systemic inflammatory response is recognized to contribute to patient morbidity and mortality after cardiopulmonary bypass, specific mechanisms linking cause and effect--linking a specific mediator with a defined adverse outcome--are lacking. The problem is partly because of the rarity of hard endpoints (stroke, myocardial injury, renal failure requiring dialysis), which studies are not always powered to measure, and partly one of definition; "systemic inflammatory response" wrongly suggests that the problem is confined to inflammation, whereas, in fact, it is characterized by systemic disturbances to a number of the body's natural defenses against injury and infection: fibrinolysis, coagulation, complement activation, immune cell activation, and oxidative stress in addition to inflammation. A better definition would be to think in terms of a "systemic host response" to surgery. End-organ injury results from the interplay of activated host defense systems with regional vessel wall injury, either because of physical trauma to the vein graft or ischemia/ reperfusion injury to susceptible vascular beds. Improved patient outcomes are going to take a concerted team effort to achieve, from the point of atraumatic vein harvest, to improved biocompatibility and shear resistance of circuits, monitoring, and minimizing of ischemia to organs, minimal cross-clamping trauma, optimized blood management, and combinatorial drug strategies. Surrogate endpoints for major organ dysfunction will play an important role to make sense of multiple interventions by the cardiac surgical team and to monitor continuous improvement to patient outcomes.

Pharmacologic strategies for combating the inflammatory response.

The "systemic inflammatory response" is a multifaceted defensive reaction of the body to surgical trauma and cardiopulmonary bypass (CPB), characterized by systemic activation of fibrinolysis, coagulation, complement, immune cells, platelets, and oxidative pathways, all overlaid onto localized trauma to the grafted vessel or vascular beds susceptible to ischemia/reperfusion. There is going to be no single magic bullet to diminish such a broad host defense response to surgery. The best chance lies with combinatorial--or promiscuous--pharmacotherapy. Combinations of anti-fibrinolytics, anti-coagulants targeted higher up the coagulation cascade, anti-thrombin receptor therapy, improved coated circuits, anti-complement, anti-leukocyte, and antioxidant therapies may blunt sufficient arms of the systemic inflammatory response to be clinically effective. The alternative is a promiscuous drug like aprotinin, which targets plasmin in the fibrinolytic pathway, kallikrein in the coagulation pathway, thrombin receptors on platelets and endothelium, and leukocytes at the extravasation step. Because of the overriding safety concerns relating to the use of anti-fibrinolytics in cardiothoracic surgery, any future combinatorial or promiscuous pharmacotherapy involving anti-fibrinolytics will require solid underpinning with a known mechanism of action and clinical safety data powered to detect well-defined adverse events (stroke, myocardial injury, renal failure requiring dialysis), preferably in isolation and not as a composite endpoint.

Why thrombin PAR1 receptors are important to the cardiac surgical patient.

Targeting of the high-affinity thrombin receptor protease-activated receptor-1 (PAR1) on platelets represents an exciting strategy to curb the pro-thrombotic complications of cardiac surgery without interfering with the hemostatic benefits of thrombin in the coagulation cascade. The first dedicated PAR1 antagonist to complete safety trials this year has justified expectations, showing no increased risk of bleeding when added to standard anti-platelet therapy but halving major adverse cardiovascular events after percutaneous coronary intervention. In the setting of cardiothoracic surgery with cardiopulmonary bypass, an FDA-approved drug already exists with anti-PAR1 properties: aprotinin has been shown to inhibit thrombin-induced platelet activation in vitro and clinically, through sparing of PAR1 receptor cleavage and activation. Because aprotinin also exerts anti-fibrinolytic effects through blockade of plasmin, this indicates a subtle clinical mechanism of action that is simultaneously anti-thrombotic yet hemostatic. PAR1 antagonists would also be expected to exert anti-inflammatory properties through targeting of PAR1 on endothelium, and this principle has been validated in vitro for aprotinin and newer peptidomimetric antagonists. PAR1 antagonism is likely to remain an active and exciting area of research in cardiac surgery, with newer generations of PAR1 antagonists and recombinant aprotinin variants entering clinical development.

Blood viscosity and the expression of inflammatory and adhesion markers in homozygous sickle cell disease subjects with chronic leg ulcers.

OBJECTIVE: To determine differences in TNF-α, IL-1ß, IL-10, sICAM-1 concentrations, leg hypoxia and whole blood viscosity (WBV) at shear rates of 46 sec(-1) and 230 sec(-1) in persons with homozygous S sickle cell disease (SCD) with and without chronic leg ulceration and in AA genotype controls. DESIGN: & METHODS: fifty-five age-matched participants were recruited into the study: 31 SS subjects without leg ulcers (SSn), 24 SS subjects with leg ulcers (SSu) and 18 AA controls. Haematological indices were measured using an AC.Tron Coulter Counter. Quantification of inflammatory, anti-inflammatory and adhesion molecules was performed by ELISA. Measurement of whole blood viscosity was done using a Wells Brookfield cone-plate viscometer. Quantification of microvascular tissue oxygenation was done by Visible Lightguide spectrophotometry. RESULTS: TNF-α and whole blood viscosity at 46 sec(-1) and 230 sec(-1) (1.75, 2.02 vs. 0.83, 1.26, p<0.05) were significantly greater in sickle cell disease subjects than in controls. There were no differences in plasma concentration of sICAM-1, IL-1ß and IL-10 between SCD subjects and controls. IL-1ß (median, IQR: 0.96, 1.7 vs. 0, 0.87; p<0.01) and sICAM-1 (226.5, 156.48 vs. 107.63, 121.5, p<0.005) were significantly greater in SSu group compared with SSn. However there were no differences in TNF-α (2, 3.98 vs. 0, 2.66) and IL-10 (13.34, 5.95 vs. 11.92, 2.99) concentrations between SSu and SSn. WBV in the SSu group at 46 sec(-1) and at 230 Sec 1 were 1.9 (95%CI; 1.2, 3.1) and 2.3 (1.2, 4.4) times greater than in the SSn group. There were no differences in the degree of tissue hypoxia as determined by lightguide spectrophotometry. CONCLUSION: Inflammatory, adhesion markers and WBV may be associated with leg ulceration in sickle cell disease by way of inflammation-mediated vasoocclusion/vasoconstriction. Impaired skin oxygenation does not appear to be associated with chronic ulcers in these subjects with sickle cell disease.