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Inflammation, Activation and Lipodystrophy & Comorbidities....
4 relevant studies below
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Download the PDF here
CROI 2015
Reported by Jules Levin, NATAP
One of the key focuses at CROI were that there were many studies finding links between inflammation/immune activation & peripheral fat loss, neurocognitive impairment, bone disease & heart disease. Related to this is the affect by HIV on the immune system, it disrupts the overall system of immunity including that numerous studies report it exhausts the immune system & it exacerbates cellular aging markers and accelerates the aging process or senescence (see reports at CROI 2015 below); this is not new the concerns regarding accelerated aging & senescence have been the focus of a major concern for several years now. Below are just 3 studies of interest, there are more. Of note Grace McComsey MD, an ACTG metabolics researcher for many years in her study comparing 3 ARTs - raltegravir, DRV/r & ATV/r reported finding high viral load (>100,000) associated with big gains in central fat after starting ART in the 1st 2 years (30%) and baseline inflammation makers associated with developing peripheral fat loss, suggesting that HIV itself & inflammation are as well likely playing a role in developing body fat changes. We have spent 20 yrs & millions of dollars on lipodystryphy without getting too many answers. Many older HIV+ are left with the legacy of peripheral/limb fat less without any research answers & solutions. This may be a complex problem but now perhaps it is realized that inflammation & activation may play a crucial or causatory role in these body changes, as we are spending the past several years looking closely at inflammation, Dr McComsey's study acutely brings to attention this issue with her finding that peripheral fat loss was associated with baseline inflammation markers. And in her talk she said we should look at this in future research, I agree.
Most of the comorbidities - kidney, CVD, cognitive/neurologic, perhaps some cancers, now lipodystrophy too, bone are all found to be associated with impaired immunity & inflammation/activation. All together highlighting the interconnectedness of all the metabolic issues (the vascular system), immunity, inflammation & activation, HIV appears to cause the entire system to go awry, its the virus! HIV even in small amounts in individuals with undetectable viral load in the blood (<50 c/ml) still have HIV present in low levels, this is enough to throw things into disorder, and in patients with detectable viral load of course the system is in worse shape.
A recent published research paper (pdf attached for download) found "We report here that HIV-infected patients have increased plasma levels of oxLDL
confirming a previous report37.......OxLDL may contribute to monocyte activation and further study in the context of HIV disease is warranted.....Markers of monocyte activation2, inflammation, and coagulation1 are predictive of all cause mortality in HIV-infected patients.....A relationship between plasma levels of oxLDL and carotid intima-media thickness (CIMT) has also been reported in HIV disease38. Increased levels of oxLDL have also been observed in HIV-uninfected patients with acute coronary syndromes (ACS) or with stable coronary artery disease (CAD).......The underlying mechanism(s) that may contribute to monocyte activation, inflammation, and coagulation in this setting have been incompletely described3. Recently, Piconi et al demonstrated that low-density LDL and apolipoprotein A were better correlated with cardiovascular risk in ART-treated, HIV+ patients than were inflammatory markers36. We propose that oxidized low-density lipoprotein may play a role in monocyte activation in HIV disease."....."Plasma levels of oxLDL were significantly increased in HIV-infection compared to controls (60.1 units vs 32.1 units, p<0.001). Monocyte expression of the oxLDL receptors, CD36 and Toll-like receptor 4, were also increased in HIV. OxLDL levels correlated with markers of monocyte activation, including soluble CD14, TF expression on inflammatory monocytes, and CD36. In vitro, stimulation with oxLDL, but not to LDL, resulted in expansion of inflammatory monocytes and increased monocyte expression of TF, recapitulating the monocyte profile we find in HIV disease.......We have shown that HIV is associated with a prothrombotic monocyte phenotype, which can be partially mitigated by statin therapy. We therefore explored the relationship between oxidized LDL particles and monocyte activation......Immune activation and inflammation are hallmarks of chronic HIV infection, and even in the setting of combination antiretroviral therapy (ART) and well-controlled viremia, markers of inflammation and immune activation often remain elevated. Numerous studies have demonstrated that markers of inflammation1,5,6, coagulation1,7,8 and indices of T cell and monocyte activation2,9 are independently associated with morbidity and mortality in HIV-infected. Inflammation and leukocyte activation are important contributors to cardiovascular disease (CVD) and thrombotic risk in the general population10-12. Increased inflammation may contribute to greater risk for both venous13,14 and arterial15 thromboembolic events in HIV-infection......A number of potential drivers of immune activation have been suggested in treated HIV infection, including low level HIV replication, systemic translocation of bacterial products from the damaged gastrointestinal tract, the presence of copathogens, and homeostatic responses to cytopenia3. As many HIV-infected patients also have altered lipid and metabolic profiles.
CROI: Early ART, Acute HIV & Chronic HIV & Inflammation/Activation, the Gut (Microbial Translocation): "Inflammatory Biomarkers Decline but Do Not Normalize after 10 Years of cART "....."Inflammation Persists Despite Early Initiation of ART in Acute HIV Infection"...... Inflammation in Acute HIV Infection Correlates with Blood and Gut CD4 T-cell Loss and HIV Viral Burden" - (03/13/15)
CROI: Confirmed kidney deficit tied to rising cardiovascular disease incidence in D:A:D......."need intensified monitoring for all types of emerging cardiovascular disease, in particular in older individuals with continuously low eGFR levels, and cincreased focus on applying different renal and cardiovascular preventive measures in HIV-positive persons" - (03/11/15)
CROI: Impaired Cardiac Strain and Biomarkers of Immune Activation in HIV - (03/11/15).......HIV-infected subjects demonstrate subclinical impairment in systolic function and this is associated with markers of chronic immune activation, inflammation and tissue remodeling.......Our findings indicate that subclinical impairment in cardiac strain tracks with markers of chronic inflammation and immune activation, which may serve as targets for future therapeutic strategies to optimize long-term cardiovascular health in persons living with HIV.
CROI: Kidney Dysfunction and Markers of Inflammation in the Multicenter AIDS Cohort Study - (03/06/15)
CROI: Immunologic Predictors of Bone Loss in a Contemporary HIV Cohort - (03/11/15)
CROI: Asymptomatic genital CMV replication in MSM linked to T-cell exhaustion
CROI: Chronic HIV Infection Exacerbates Cellular Aging Markers in Isolated T cell Subsets - (03/06/15)
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