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The effect of HAART-induced HIV suppression on circulating markers of inflammation and immune activation
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immune activation
AIDS Dec 3 2014
Wada, Nikolas Itaru; Jacobson, Lisa P.; Margolick, Joseph B.; Breen, Elizabeth Crabb; Macatangay, Bernard; Penugonda, Sudhir; Martinez-Maza, Otoniel; Bream, Jay H.
To investigate the impact of HAART-induced HIV suppression on levels of 24 serological biomarkers of inflammation and immune activation. Design: A prospective cohort study.
Methods: Biomarkers were measured with multiplex assays in centralized laboratories using stored serum samples contributed by 1697 men during 8903 person-visits in the Multicenter AIDS Cohort Study (MACS) from 1984 to 2009. Using generalized gamma models, we compared biomarker values across three groups, adjusting for possible confounders: HIV-uninfected (NEG); HIV-positive, HAART-naive (NAI); and HAART-exposed with HIV RNA suppressed to less than 50 copies/ml plasma (SUP). We also estimated changes in biomarker levels associated with duration of HIV suppression, using splined generalized gamma regression with a knot at 1 year.
Results: Most biomarkers were relatively normalized in the SUP group relative to the NAI group; however, 12 biomarkers in the SUP group were distinct (P < 0.002) from NEG values: CXCL10, C-reactive protein (CRP), sCD14, sTNFR2, tumour necrosis factor-alpha (TNF-[alpha]), sCD27, sGP130, IL-8, CCL13, BAFF, GM-CSF and interleukin (IL)-12p70. Thirteen biomarkers exhibited significant changes in the first year after viral suppression, but none changed significantly after that time.
Conclusion: Biomarkers of inflammation and immune activation moved towards HIV-negative levels within the first year after HAART-induced HIV suppression. Although several markers of T cell activation returned to levels present in HIV-negative men, residual immune activation, particularly monocyte/macrophage activation, was present. This residual immune activation may represent a therapeutic target to improve the prognosis of HIV-infected individuals receiving HAART.
To our knowledge, this is the largest study yet reported to examine the effect of HAART-induced HIV suppression on inflammatory and immune biomarkers, both in sample size and in the number of biomarkers assessed. The MACS was well suited for addressing these questions, because serum samples were available for a long follow-up time, and because the MACS recruited HIV-uninfected men from the same population as the men with untreated HIV infection and with HAART-induced HIV suppression. Moreover, the timing of viral suppression was well characterized, as were values of possible confounding covariates.
These aspects of the study design allowed us to identify a constellation of biomarkers of immune activation and inflammation that were abnormal in untreated HIV infection (17 markers) and showed at least some restoration towards HIV-negative levels with HIV suppression (15 markers). Among those showing restoration towards HIV-negative levels, seven markers were indistinguishable from HIV-negative levels among the HIV-suppressed group: the cytokines IL-10, IL-2 and IFN-g, the cytokine receptors sIL-2Ra and sIL-6R, and the chemokines CCL2 and CXCL13. All of these markers are associated with immune activation. For example, CXCL13 is produced by CD4+ T follicular helper cells and drives B cell migration to germinal centres in secondary lymphoid organs [21]. Therefore, it appears that HAART may be resolving ongoing immune activation, perhaps by removing antigenic stimulation by HIV.
The seven markers that were still abnormally high among the HIV-suppressed were the chemokine CXCL10 (also known as interferon gamma-induced protein 10 or IP-10), the soluble cytokine receptors sCD27 and sTNFR2, the pro inflammatory cytokines TNF-a and BAFF, the soluble scavenger receptor sCD14 and the acute phase reactant CRP. Interestingly, these biomarkers include members of the TNF (TNF-a, BAFF) or the TNF-receptor (sCD27, sTNFR2) superfamilies [22], and a receptor associated with microbial translocation and stimulation by LPS (sCD14) [23]. Meanwhile, several important markers of T-cell activation (IL-2, sIL-2Ra, IFN-g) were essentially normalized among the HIV-suppressed. These data strongly suggest that some of the systemic inflammation that remains after HIV suppression may be related to ongoing monocyte/macrophage activation.
This residual inflammation persisted even after many years of HIV suppression. Nearly all of the (partial or complete) restoration occurred during the first year after HAART-induced viral suppression, and the annual change in the markers after the first year was essentially zero. Identifying the underlying processes that cause this residual inflammation among individuals responding well to HAART may aid in setting therapy targets. For example, in the general population, elevated CRP levels are associated with kidney disease mortality [26], cardiovascular disease [27] and colon cancer [28]. Moreover, residual immune activation itself may promote the persistence of HIV despite HAART [29]. The finding that biomarkers were stable after 1 year of viral suppression suggests that repeated assessments of these biomarkers may not be needed for studies of long-term clinical outcomes in people with stable viral suppression. Further study will be needed to confirm this point.
Using serum markers as a proxy for inflammatory and/or immune hyperactivity states holds real utility, especially as levels of these markers may be ascertained via highly sensitive, reproducible and multiplexed assays. Next steps include identifying associations with morbidity and mortality among these biomarkers, and inferring biological mechanisms for these associations from clusters of biomarkers that behave similarly [31]. Developing reliable surrogates of harmful inflammation or immune activation will facilitate development of effective interventions, and we believe that this study is a useful contribution to that process.

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