Soluble biomarkers of HIV transmission, disease progression and comorbidities

Leeansyah, Edwina; Malone, David F.G.a; Anthony, Donald D.b; Sandberg, Johan K.a,c

Current Opinion in HIV & AIDS: March 2013 - Volume 8 - Issue 2 - p 117–124
doi: 10.1097/COH.0b013e32835c7134

Purpose of review: The purpose of this study is to survey and synthesize recent progress in soluble biomarkers relevant to HIV-1 disease stages, progression and comorbidities.

Recent findings: Soluble biomarkers in plasma and other body fluids provide insight into many aspects of HIV-1 disease. Chemokines and defensins in breast milk and cervicovaginal secretions have been associated with HIV-1 susceptibility and transmission. Acute infection plasma cytokine storm components, including serum amyloid A, IFNγ-induced protein 10, interleukin (IL)-12, interferon-gamma (IFNγ), IL-7 and IL-15, may help predict viral load set-point and the subsequent disease progression. During chronic infection, IL-6, soluble (s)CD14, sCD163, high-sensitivity C-reactive protein, D-dimer, fibrin and hyaluronic acid can help predict comorbidities, and to some extent disease progression and mortality, in patients both on and off antiretroviral therapy. Furthermore, recent results suggest that assessment of combinations of soluble biomarkers may prove more powerful than the single factors alone in predicting disease.

Summary: Soluble biomarkers help us understand HIV-1 immunopathogenesis. Integration of many biomarkers derived from a single plasma sample might become a powerful tool to optimize and individualize treatment and care.

aCenter for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

bDepartment of Medicine, Divisions of Infectious and Rheumatic Diseases, Case Western Reserve University, Center for AIDS Research, University Hospitals of Cleveland and VA Medical Center, Cleveland, Ohio, USA

cCenter for HIV Research, Karolinska Institutet, Stockholm, Sweden

Correspondence to Dr Johan K. Sandberg, CIM, Department of Medicine, F59, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden. E-mail:

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Chronic diseases are associated with changes in the expression of various endogenous cell-bound or soluble proteins. Such factors may be directly involved in pathogenic processes or be mere byproducts of such processes. Irrespective of causative relationships, however, proteins that display altered expression during disease can prove useful as biomarkers to facilitate the understanding of pathogenic processes. Ultimately, some of these biomarkers can make their way into the clinical immunology laboratory and help predict a patient's clinical course or response to therapy. Chronic uncontrolled viral infections, such as HIV-1 infection, are associated with persistent ongoing immune responses as well as progressive immunopathology. These processes give rise to soluble markers related to innate and adaptive immune activation, as well as cell death and tissue destruction [1,2]. The goal of the present review is to cover recent progress in our understanding of soluble biomarkers in plasma and other bodily fluids during HIV-1 infection. We will aim to briefly cover recently published data on putative biomarkers during transmission, in acute infection, during chronic progressive infection, as well as biomarkers relevant for comorbidities.

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Soluble markers in plasma and other body fluids reflect the individual's immunological status and may therefore be helpful in assessing risk of HIV-1 transmission, acquisition, as well as early-stage disease progression in those who become infected.

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Breast feeding accounts for a large fraction of mother-to-child transmissions, particularly in sub-Saharan Africa. Bosire et al.[3] reported that HIV-1-infected women in Kenya have elevated levels of the chemokines regulated upon activation normal T cell expressed and presumably secreted (RANTES) and macrophage inflammatory protein-1β (MIP-1β) in breast milk at 10 days postpartum, and that the RANTES levels are significantly higher in milk from mothers who transmit infection to their infant. Together with the recent results indicating that MIP-1β levels, as well as T cell interferon-gamma (IFNγ) responses against HIV-1 Gag, in breast milk are associated with lower odds of transmission [4], we can begin to understand which biomarkers might inform us about the risk for vertical transmission. Amniotic fluid from HIV-negative women was recently found to inhibit HIV-1 replication [5], although the factors involved are yet to be identified. Relationships between factors in cervicovaginal lavage (CVL) and perinatal infection remain to be determined.

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Dezzutti et al.[6▪] identified markers in CVL predictive of sexual transmission in a cohort of high-risk women and found that seroconverters had higher Escherichia coli bactericidal activity in their preseroconversion CVL. Higher levels of human β defensin-2 (HβD-2) were found in the vaginal swabs of seroconverters prior to HIV acquisition [6▪]. In this case, HβD-2 may be a biomarker of environmental stimuli that predisposes to a higher risk of infection, and this might explain the seemingly contradicting results in the study by Ghosh et al.[7] suggesting HβD-2 in CVL having an antiviral activity. Ghosh et al.[7] also found that Elafin and secretory leukocyte protease inhibitor (SLPI) were both positively associated with viral load in the CVL, while MIP-3α correlated with CVL antiviral activity. It would be interesting to investigate these soluble CVL factors in terms of susceptibility to infection. Furthermore, two recent studies [8,9▪] have tracked cytokines and chemokines in the CVL of HIV-1-infected women and link changes in a range of factors to detectable viral load in CVL. These may, however, represent responses to infection rather than innate protective factors. In contrast, Naranbhai et al.[10] recently reported in a nested case–control study of immunological risk factors that the systemic cytokine signature in women who acquired HIV-1 was more pro-inflammatory than in women who did not get infected.

Levels of cytokines and chemokines in semen are difficult to link to susceptibility. However, enrichment of certain cytokines has been observed in semen and this may indicate a constitutive innate activation state, which may be supportive of HIV-1 replication [11]. The cytokine profile in semen was broadened in infected individuals. Whether these soluble components can be used to identify individuals carrying a higher risk of transmission remains to be elucidated.

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Events during acute HIV-1 infection, the period before establishment of the viral load set-point, are likely to be important for the subsequent course of disease. In a proteomics-based screen, an increase in the acute phase protein serum amyloid A (A-SAA) in plasma was the first sign of an immune response [12▪]. A-SAA was demonstrated to have antiviral properties and was detected 5 days prior to the first measurable viral RNA, thus posing as a possible biomarker of hyperacute infection. A-SAA displayed a biphasic response, the first during viral eclipse phase and the second during the viral expansion phase that overlapped with the cytokine storm associated with acute HIV-1 infection [13] (Fig. 1).

During the cytokine storm in acute infection, the immune system produces a milieu of cytokines that may work to help or hinder virus growth and reservoir establishment. Two studies explored a range of cytokines in a cohort from preinfection to 3 weeks postinfection [13], and in follow-up out to 16–24 weeks postinfection [14] (Fig. 1). These soluble factors can be regarded as candidate biomarkers of the subsequent clinical development. Building on these results, Jiao et al.[15] found that higher levels of IFNγ-induced protein 10 (IP-10) during Fiebig stages III, IV and V [16] was strongly associated with low CD4 cell counts 2 years after the initial infection, suggesting that IP-10 might be a useful acute stage biomarker of disease progression. Roberts et al.[17▪] confirmed the elevation of tumour necrosis factor (TNF), IP-10 and interleukin (IL)-10 six weeks after initial infection, and also proposed a model for predicting viral load set-point 12 months after infection from five cytokines measured during acute infection. Plasma concentrations of IL-12p40/70, IFNγ, IL-7 and IL-15 together predicted 66% of viral set-point variation [17▪]. Interrogation of these plasma cytokine networks for prediction of future viral load set-point and disease progression may have great potential [18].

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Chronic untreated HIV-1 infection is characterized by a state of persistent immune activation, and this broad activation is a strong contributor to disease progression (reviewed in [19]). As discussed above, components of the acute stage cytokine storm may be biomarkers to predict the viral load set-point [17▪]. Deeks et al.[20] in 2004 found that the immune activation set-point, defined by the levels of T-cell activation, predicts disease progression independently of viral load. The link between the acute cytokine storm and the T-cell activation set-point and chronic stage activation levels remains to be defined. Studies such as the large Early Capture HIV Cohort Study (ECHO), or RV217, by the US Military HIV Research Program, will be important to ascertain such relationships and define broadly applicable soluble biomarkers.

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HIV-1 infection is associated with severe loss of CD4 T cells and disruption of immune homeostasis at mucosal sites. This in turn leads to impaired mucosal barrier function and enhanced microbial translocation into the tissues and eventually into circulation. This topic has recently been reviewed elsewhere [21,22].

Monocyte and macrophage activation and their dysregulation in HIV disease are partly caused by the high sensitivity of these cells to elevated microbial products in the systemic circulation, and partly due to direct effects of HIV-1 replication. Activated monocytes and macrophages release several measurable biomarkers in the plasma and cerebrospinal fluid, including soluble (s)CD14, sCD163 and IL-6. Perhaps the most widely used biomarkers of microbial translocation are lipopolysaccharide (LPS) and sCD14 [23]. LPS is a direct biomarker of bacterial biomaterial in plasma and probably reflects translocation of Gram-negative bacterial material [24]. Marchetti et al.[25] observed that LPS levels are predictive of disease progression, suggesting that LPS is a functionally relevant biomarker of microbial translocation. Redd et al.[26], however, did not observe such a relationship in a Ugandan cohort. It is possible that environmental and microbiome differences might affect the utility of LPS as a biomarker in different parts of the world. Sandler et al.[27▪] also did not observe a predictive association between plasma LPS and clinical outcome in the Strategies for Management of Anti-Retroviral Therapy (SMART) study. However, this study instead found levels of sCD14 to be significantly associated with all-cause mortality [27▪]. A similar relationship was observed in an HIV-uninfected cohort of patients undergoing haemodialysis, suggesting that sCD14 might reflect health status unrelated to HIV infection [28▪]. Eller et al.[29] observed no significant association between sCD14 levels and HIV-1 disease progression in a Ugandan cohort, whereas a recent study by Thiebaut et al.[30] did observe a significant association between sCD14 and HIV-2 disease progression.

Microbial translocation products from the gut would normally arrive in the liver via the portal circulation. Sandler et al.[31▪] observed that sCD14 is a biomarker of liver cirrhosis in hepatitis C virus (HCV) infected patients. Furthermore, sCD14 was associated with interferon and ribavirin treatment outcome in HCV/HIV-1 coinfected patients [32,33▪]. Thus, systemic sCD14 levels are likely influenced not only by the rate of microbial translocation but perhaps also by the status of the liver (Fig. 2). Furthermore, we have observed that sCD14 levels increased during interferon treatment in the setting of HCV/HIV-1 coinfection, suggesting that the type I interferon response also influences the levels of sCD14 in circulation [33▪]. In addition to LPS and sCD14, recent studies have highlighted the role of IL-6 [34], intestinal fatty acid binding protein (I-FABP) [27▪] and bacterial 16S DNA [35], as possible biomarkers of microbial translocation [21,22].

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Activation and turnover of cells of the macrophage lineage are implicated in HIV-associated comorbidities, including the development of atherosclerosis, cardiovascular disease (CVD) and HIV-associated neurocognitive disorders (HANDs) [36,37]. HIV-1 disease is also associated with persistent inflammation, which is thought to disrupt the homeostatic balance of the coagulation pathway, shifting it to a net procoagulant state [38,39].

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Coagulopathy has been linked to an increased incidence of comorbidities from CVD and all-cause mortality observed among HIV-infected people. Findings from the SMART study show that levels of D-dimer, a fibrin degradation product and a biomarker of coagulation, as well as IL-6 and high-sensitivity (hs)CRP, biomarkers of inflammation, are associated with an increased risk of all-cause mortality in the combination antiretroviral therapy (cART)-untreated group [40]. More recent findings from the SMART cohort show that HIV-infected people with higher levels of IL-6, High-sensitivity C-reactive protein (hsCRP) and D-dimer also have an increased risk of CVD even after adjustment for other traditional risk factors, with similar associations in the untreated and cART-treated groups [41▪]. Higher pre-ART levels of IL-6, hsCRP and D-dimer are linked with an increased risk of AIDS and death among the Flexible Initial Retrovirus Suppression Therapy (FIRST) cohort [42▪], as well as those of hyaluronic acid, a biomarker of tissue fibrosis, although caution should be exercised as hyaluronic acid was more likely to be detectable in hepatitis virus coinfection than in HIV mono-infection alone [42▪]. Indeed, hyaluronic acid levels predict time to a major liver-related event and non-AIDS mortality in the SMART study [43]. Elevated levels of D-dimer have been associated with endothelial dysfunction as measured by brachial artery flow-mediated dilation, despite effective virological suppression [44]. Furthermore, detectable viraemia has been linked with increased levels of IL-6 [27▪,45], and D-dimer in the SMART cohort [27▪], and fibrinogen [27▪,45], a biomarker of coagulation that is associated with excess mortality among HIV-infected people from the Study of Fat and Redistribution and Metabolic Change in HIV infection (FRAM) cohort [46]. Higher plasma levels of IL-6 are also associated with faster progression to AIDS in a Ugandan cohort [29]. Higher levels of hsCRP, D-dimer and IL-6 before and during cART are furthermore associated with the development of immune reconstitution inflammatory syndrome in the FIRST and another Ugandan cohort [42▪,47]. These findings together indicate that IL-6, hsCRP, D-dimer, fibrin and hyaluronic acid can be clinically useful in predicting comorbidities in HIV-1-infected patients both on and off cART.

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Plasma levels of sCD14 are independently associated with all-cause mortality and directly correlate with IL-6, hsCRP and D-dimer levels in the SMART cohort [27▪]. Elevated plasma concentrations of sCD14 are furthermore associated with increased rates of carotid artery intima-media thickening, a surrogate marker for progression of subclinical atherosclerosis [48]. Interestingly, levels of sCD14 in plasma and CSF are also linked with neurocognitive impairment in advanced HIV-1 infection despite suppressive ART [49,50]. Levels of the soluble scavenger receptor for haemoglobin, CD163, are elevated in both early and chronic infection, and parallel to viral load and associated with monocyte expansion [51]. Interestingly, the same investigators discovered that levels of sCD163 are independently associated with noncalcified coronary plaque in HIV-infected people, but not in uninfected controls with similar CVD risk factors [52]. Indeed, another study [53▪] has linked sCD163 levels with arterial inflammation in patients receiving cART as determined by PET.

In nonhuman primates, pathogenic simian immunodeficiency virus (SIV) infection of pig-tailed and rhesus macaques results in elevated levels of D-dimer, sCD14 and sCD163, and evidence of cardiovascular lesions at the histological level, but not in the nonpathogenic SIV infection of African green monkeys and sooty mangabeys [54▪]. Administration of LPS to replicate microbial translocation in the nonpathogenic, chronically SIV-infected African green monkeys led to elevated sCD14 and D-dimer levels [54▪]. Collectively, these studies strengthen the notion that microbial translocation and the concomitant monocyte and macrophage activation in HIV-1 disease may play a direct role in coagulopathy and associated comorbidities. Furthermore, they identify a set of soluble biomarkers that may prove useful in predicting such comorbidities.

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Although many soluble biomarkers that reflect different pathological processes in HIV-1 infection have been identified, it is essential to continue the search for novel useful biomarkers. Asymmetric dimethylarginine, an endogenous inhibitor of the nitric oxide synthase pathway that reflects endothelial dysfunction, may be one such new marker [55]. Furthermore, in the SMART cohort, levels of this factor decrease following therapy [56].

It is possible that assessment of combinations of soluble biomarkers may prove more powerful than the single factors alone in predicting disease. As discussed above, a combination of five cytokines may be predictive of viral set-point variation [17▪]. Another recent example in this direction is the observation that soluble factors from T cells inhibiting C-X-C chemokine receptor type 4-using HIV strains are composed of a mixture of three β-chemokines and two RNases [57].

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A vast array of soluble biomarkers has been shown to be associated with various aspects of HIV-1 disease throughout the duration of infection (Table 1). Correlates between disease stages or manifestations and soluble markers are being very instructive in forming our understanding of this complex disease. New soluble factors that can function as biomarkers in HIV-1 infection will probably be discovered. Looking further into the future, it is tempting to speculate that integration of many biomarkers derived from a single plasma sample might become a powerful tool in clinical practice to optimize and individualize treatment and care.

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Conflicts of interest

The authors declare that no conflicts of interest exist.

This work was supported by the Swedish Research Council, the Swedish Cancer Foundation, the Swedish Physicians Against AIDS Foundation, Karolinska Institutet and the Stockholm County Council. J.K.S. is a Senior Fellow of The Swedish research Council. E.L. is a Swedish Institute Postdoctoral Fellow. D.D.A. is supported by AI100809-+1 and VA Merit funding.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 157–158).

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1. Neaton JD, Neuhaus J, Emery S. Soluble biomarkers and morbidity and mortality among people infected with HIV: summary of published reports from 1997 to 2010. Curr Opin HIV AIDS 2010; 5:480–490.
2. Nixon DE, Landay AL. Biomarkers of immune dysfunction in HIV. Curr Opin HIV AIDS 2010; 5:498–503.
3. Bosire R, Guthrie BL, Lohman-Payne B, et al. Longitudinal comparison of chemokines in breastmilk early postpartum among HIV-1-infected and uninfected Kenyan women. Breastfeed Med 2007; 2:129–138.
4. Lohman-Payne B, Slyker JA, Moore S, et al. Breast milk cellular HIV-specific interferon gamma responses are associated with protection from peripartum HIV transmission. AIDS 2012; 26:2007–2016.
5. Farzin A, Ank B, Boyer P, et al. Amniotic fluid exhibits an innate inhibitory activity against HIV-1 replication in vitro. AIDS Res Hum Retroviruses 2012.
6▪. Dezzutti CS, Richardson BA, Marrazzo JM, et al. Mucosal Escherichia coli bactericidal activity and immune mediators are associated with HIV-1 Seroconversion in women participating in the HPTN 035 Trial. J Infect Dis 2012; 206:1931–1935.

This study identifies biomarkers for HIV-1 acquisition in the vaginal mucosal microenvironment.

7. Ghosh M, Fahey JV, Shen Z, et al. Anti-HIV activity in cervical-vaginal secretions from HIV-positive and -negative women correlate with innate antimicrobial levels and IgG antibodies. PLoS One 2010; 5:e11366.
8. Mukura LR, Ghosh M, Fahey JV, et al. Genital tract viral load in HIV type 1-positive women correlates with specific cytokine levels in cervical-vaginal secretions but is not a determinant of infectious virus or anti-HIV activity. AIDS Res Hum Retroviruses 2012; 28:1533–1539.
9▪. Roberts L, Passmore JA, Mlisana K, et al. Genital tract inflammation during early HIV-1 infection predicts higher plasma viral load set point in women. J Infect Dis 2012; 205:194–203.

This study identifies genital tract biomarkers associated with viral load set-point levels.

10. Naranbhai V, Abdool Karim SS, Altfeld M, et al. Innate immune activation enhances HIV acquisition in women, diminishing the effectiveness of tenofovir microbicide gel. J Infect Dis 2012; 206:993–1001.
11. Anderson JA, Ping LH, Dibben O, et al. HIV-1 populations in semen arise through multiple mechanisms. PLoS Pathog 2010; 6:e1001053.
12▪. Kramer HB, Lavender KJ, Qin L, et al. Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection. PLoS Pathog 2010; 6:e1000893.

This study identifies a biomarker indicative of HIV-1 infection prior to detectable viral replication.

13. Stacey AR, Norris PJ, Qin L, et al. Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J Virol 2009; 83:3719–3733.
14. Gay C, Dibben O, Anderson JA, et al. Cross-sectional detection of acute HIV infection: timing of transmission, inflammation and antiretroviral therapy. PLoS One 2011; 6:e19617.
15. Jiao Y, Zhang T, Wang R, et al. Plasma IP-10 is associated with rapid disease progression in early HIV-1 infection. Viral Immunol 2012; 25:333–337.
16. Fiebig EW, Wright DJ, Rawal BD, et al. Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS 2003; 17:1871–1879.
17▪. Roberts L, Passmore JA, Williamson C, et al. Plasma cytokine levels during acute HIV-1 infection predict HIV disease progression. AIDS 2010; 24:819–831.

This study identifies the plasma concentrations of five cytokines during acute infection as biomarkers of subsequent disease progression.

18. Katsikis PD, Mueller YM, Villinger F. The cytokine network of acute HIV infection: a promising target for vaccines and therapy to reduce viral set-point? PLoS Pathog 2011; 7:e1002055.
19. Douek DC, Roederer M, Koup RA. Emerging concepts in the immunopathogenesis of AIDS. Annu Rev Med 2009; 60:471–484.
20. Deeks SG, Kitchen CM, Liu L, et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 2004; 104:942–947.
21. Sandler NG, Douek DC. Microbial translocation in HIV infection: causes, consequences and treatment opportunities. Nat Rev Microbiol 2012; 10:655–666.
22. Klatt NR, Funderburg NT, Brenchley JM. Microbial translocation, immune activation, and HIV disease. Trends Microbiol 2012.
23. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12:1365–1371.
24. Vassallo M, Mercie P, Cottalorda J, et al. The role of lipopolysaccharide as a marker of immune activation in HIV-1 infected patients: a systematic literature review. Virol J 2012; 9:174.
25. Marchetti G, Cozzi-Lepri A, Merlini E, et al. Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4+ cell count. AIDS 2011; 25:1385–1394.
26. Redd AD, Dabitao D, Bream JH, et al. Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa. Proc Natl Acad Sci U S A 2009; 106:6718–6723.
27▪. Sandler NG, Wand H, Roque A, et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis 2011; 203:780–790.

This study assesses associations between several soluble markers of innate immune activation and microbial translocation, and identifies an association between sCd14 levels and all-cause mortality.

28▪. Raj DS, Shah VO, Rambod M, et al. Association of soluble endotoxin receptor CD14 and mortality among patients undergoing hemodialysis. Am J Kidney Dis 2009; 54:1062–1071.

This study identifies sCD14 as a biomarker of mortality in a HIV-uninfected cohort.

29. Eller MA, Blom KG, Gonzalez VD, et al. Innate and adaptive immune responses both contribute to pathological CD4 T cell activation in HIV-1 infected Ugandans. PLoS One 2011; 6:e18779.
30. Thiebaut R, Charpentier C, Damond F, et al. Association of soluble CD14 and inflammatory biomarkers with HIV-2 disease progression. Clin Infect Dis 2012; 55:1417–1425.
31▪. Sandler NG, Koh C, Roque A, et al. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology 2011; 141:1220–1230.

This study identifies sCD14 as a biomarker of liver fibrosis in HCV-infected patients.

32. Marchetti G, Nasta P, Bai F, et al. Circulating sCD14 is associated with virological response to pegylated-interferon-alpha/ribavirin treatment in HIV/HCV co-infected patients. PLoS One 2012; 7:e32028.
33▪. Anthony DD, Conry SJ, Medvik K, et al. Baseline levels of soluble CD14 and CD16+56- natural killer cells are negatively associated with response to interferon/ribavirin therapy during HCV-HIV-1 coinfection. J Infect Dis 2012; 206:969–973.

This study shows that sCD14 levels are elevated in vivo by interferon treatment in patients coinfected with HCV and HIV-1.

34. Shive CL, Biancotto A, Funderburg NT, et al. HIV-1 is not a major driver of increased plasma IL-6 levels in chronic HIV-1 disease. J Acquir Immune Defic Syndr 2012; 61:145–152.
35. Kramski M, Gaeguta AJ, Lichtfuss GF, et al. Novel sensitive real-time PCR for quantification of bacterial 16S rRNA genes in plasma of HIV-infected patients as a marker for microbial translocation. J Clin Microbiol 2011; 49:3691–3693.
36. Kandanearatchi A, Brew BJ. The kynurenine pathway and quinolinic acid: pivotal roles in HIV associated neurocognitive disorders. FEBS J 2012; 279:1366–1374.
37. Crowe SM, Westhorpe CL, Mukhamedova N, et al. The macrophage: the intersection between HIV infection and atherosclerosis. J Leukoc Biol 2010; 87:589–598.
38. Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med 2011; 62:141–155.
39. van der Poll T, de Boer JD, Levi M. The effect of inflammation on coagulation and vice versa. Curr Opin Infect Dis 2011; 24:273–278.
40. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203.
41▪. Duprez DA, Neuhaus J, Kuller LH, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One 2012; 7:e44454.

This study found that in HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors.

42▪. Boulware DR, Hullsiek KH, Puronen CE, et al. Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death. J Infect Dis 2011; 203:1637–1646.

This study found that CRP, IL-6, D-dimer and hyaluronic acid measured pre-ART and at 1 month are associated with a higher risk of AIDS events, immune reconstitution inflammatory syndrome or death.

43. Peters L, Neuhaus J, Mocroft A, et al. Hyaluronic acid levels predict increased risk of non-AIDS death in hepatitis-coinfected persons interrupting antiretroviral therapy in the SMART Study. Antivir Ther 2011; 16:667–675.
44. Hileman CO, Longenecker CT, Carman TL, et al. Elevated D-dimer is independently associated with endothelial dysfunction: a cross-sectional study in HIV-infected adults on antiretroviral therapy. Antivir Ther 2012; 17:1345–1349.
45. Eastburn A, Scherzer R, Zolopa AR, et al. Association of low level viremia with inflammation and mortality in HIV-infected adults. PLoS One 2011; 6:e26320.
46. Tien PC, Choi AI, Zolopa AR, et al. Inflammation and mortality in HIV-infected adults: analysis of the FRAM study cohort. J Acquir Immune Defic Syndr 2010; 55:316–322.
47. Boulware DR, Meya DB, Bergemann TL, et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med 2011; 7:e1000384.
48. Kelesidis T, Kendall MA, Yang OO, et al. Biomarkers of microbial translocation and macrophage activation: association with progression of subclinical atherosclerosis in HIV-1 infection. J Infect Dis 2012; 206:1558–1567.
49. Lyons JL, Uno H, Ancuta P, et al. Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection. J Acquir Immune Defic Syndr 2011; 57:371–379.
50. Kamat A, Lyons JL, Misra V, et al. Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection. J Acquir Immune Defic Syndr 2012; 60:234–243.
51. Burdo TH, Lentz MR, Autissier P, et al. Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after antiretroviral therapy. J Infect Dis 2011; 204:154–163.
52. Burdo TH, Lo J, Abbara S, et al. Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients. J Infect Dis 2011; 204:1227–1236.
53▪. Subramanian S, Tawakol A, Burdo TH, et al. Arterial inflammation in patients with HIV. JAMA 2012; 308:379–386.

This study found that HIV-1-infected patients had signs of increased arterial inflammation, as compared with noninfected control participants with similar cardiac risk factors. This pattern was associated with a circulating marker of monocyte and macrophage activation.

54▪. Pandrea I, Cornell E, Wilson C, et al. Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates. Blood 2012; 120:1357–1366.

This study found that hypercoagulation biomarkers and cardiovascular disease in SIV infection are at least in part a consequence of excessive immune activation and microbial translocation.

55. Jang JJ, Berkheimer SB, Merchant M, Krishnaswami A. Asymmetric dimethylarginine and coronary artery calcium scores are increased in patients infected with human immunodeficiency virus. Atherosclerosis 2011; 217:514–517.
56. Baker JV, Neuhaus J, Duprez D, et al. HIV replication, inflammation, and the effect of starting antiretroviral therapy on plasma asymmetric dimethylarginine, a novel marker of endothelial dysfunction. J Acquir Immune Defic Syndr 2012; 60:128–134.
57. Cocchi F, DeVico AL, Lu W, et al. Soluble factors from T cells inhibiting X4 strains of HIV are a mixture of beta chemokines and RNases. Proc Natl Acad Sci U S A 2012; 109:5411–5416.

chemokines; cytokines; HIV; microbial translocation; soluble biomarkers

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