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HIV infection induces age-related changes to monocytes and innate immune activation in young males which persist despite cART
 
 
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AIDS: POST ACCEPTANCE, 4 February 2012

Hearps, Anna C.; Maisa, Anna; Cheng, Wan-Jung; Angelovich, Thomas A.; Lichtfuss, Gregor F.; Palmer, Clovis S.; Landay, Alan L.; Jaworowski, Anthony; Crowe, Suzanne M.

"Here we directly compared monocytes from young HIV+ males
with young and elderly healthy controls and found that young HIV+ individuals show changes to monocyte phenotype, function and telomere length that closely resemble those observed in elderly controls aged approximately 30 years older.

.........Future longitudinal studies are required to investigate the impact of time of viral suppression on innate ageing biomarkers and determine whether the rate of ageing is increased by HIV. Elucidating the mechanisms driving age-related changes in the absence of overt viremia is required to prevent comorbidities in this population. This study has identified biomarkers which may be useful for monitoring immune activation and disease risk in HIV+ individuals and may also represent new targets for interventional strategies."

Abstract


Objectives: To compare the impact of HIV infection and healthy ageing on monocyte phenotype and function and determine whether age-related changes induced by HIV are reversed in antiretroviral treated individuals.

Design: A cross sectional study of monocyte ageing markers in viremic and virologically suppressed HIV+ males aged <=45 years and age-matched and elderly (>=65 years) HIV-uninfected individuals.

Methods: Age-related changes to monocyte phenotype and function were measured in whole blood assays ex vivo on both CD14++CD16- (CD14+) and CD14variableCD16+(CD16+) subsets. Plasma markers relevant to innate immune activation were measured by ELISA.

Results: Monocytes from young viremic HIV+ males resemble those from elderly controls and show increased expression of CD11b (p < 0.0001 on CD14+ and CD16+subsets), and decreased expression of CD62L and CD115 (p = 0.04 and 0.001 respectively on CD14+ monocytes) when compared to young uninfected controls. These changes were also present in young virologically suppressed HIV+ males. Innate immune activation markers neopterin, sCD163 and CXCL10 were elevated in both young viremic (p < 0.0001 for all) and virologically suppressed (p = 0.0005, 0.003 and 0.002 respectively) HIV+ males with levels in suppressed individuals resembling those observed in elderly controls. Like the elderly, CD14+ monocytes from young HIV+ males exhibited impaired phagocytic function (p = 0.007) and telomere shortening (p = 0.03) as compared to young uninfected controls.

Conclusions: HIV infection induces changes to monocyte phenotype and function in young HIV+ males that mimic those observed in elderly uninfected individuals, suggesting HIV may accelerate age-related changes to monocytes. Importantly, these defects persist in virologically suppressed HIV+ individuals.

Discussion

Increasing evidence suggests HIV infection induces premature ageing of the adaptive immune system. Ageing also hastens the development of age-related diseases with inflammatory aetiologies, yet the impact of HIV on agerelated changes to innate cells critical for regulating inflammation (eg. monocytes) is unknown. Here we directly compared monocytes from young HIV+ males with young and elderly healthy controls and found that young HIV+ individuals show changes to monocyte phenotype, function and telomere length that closely resemble those observed in elderly controls aged approximately 30 years older. Furthermore, our data suggest these immune defects are not fully restored by cART.

We found that similar to elderly controls, the proportion of CD16+ monocytes (considered inflammatory due to their high production of TNF [36]) was increased in young viremic HIV+ individuals. An increase in this subset has been reported in other inflammatory conditions [3739], in association with ageing [40] and in patients with HIV-related dementia [28]............

.................In summary, we have shown that young HIV+ men exhibit age-related changes to monocyte phenotype and levels of innate immune activation that resemble those observed in elderly HIV-uninfected individuals. Importantly, age-related changes to plasma and phenotypic markers of monocyte activation (eg. neopterin, CXCL10, sCD163 and CD11b expression) are not normalised by cART, which may have implications for the development of co-morbidities involving activated monocytes (e.g. atherosclerosis) in VS HIV+ individuals. Given the strong links between chronic inflammation and

age-related co-morbidities, our findings have important clinical implications. Future longitudinal studies are required to investigate the impact of time of viral suppression on innate ageing biomarkers and determine whether the rate of ageing is increased by HIV. Elucidating the mechanisms driving age-related changes in the absence of overt viremia is required to prevent comorbidities in this population. This study has identified biomarkers which may be useful for monitoring immune activation and disease risk in HIV+ individuals and may also represent new targets for interventional strategies.

 
 
 
 
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