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The effect of HIV infection and HAART on inflammatory biomarkers in a population-based cohort of US women
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AIDS: POST ACCEPTANCE, 12 May 2011
"This study showed that serum levels of the innate immune system pro-inflammatory modulators TNF-a and IP-10 were elevated, increased among untreated HIV patients, compared with uninfected comparisons, a finding that is consistent with a broad inflammatory response. Additionally, serum IL-12(p40) and IL-15, important for T cell homeostasis and function, were decreased in chronic, untreated HIV infection compared to otherwise similar HIV-uninfected women. When compared with untreated women the HAART recipients showed fewer detectable differences in cytokines from HIV uninfected persons (2 vs. 5 analytes), though TNF-a and FGF-2 were still different in the HAART compared to NEG group. Finally, while as expected many factors correlated with both plasma viral burden and CD4+ T cell counts, some factors correlated with one or the other. Interestingly, the growth factors VEGF, EGF, and FGF-2 showed a positive correlation with higher CD4+ T cell counts."
Keating, Sheila M; Golub, Elizabeth T; Nowicki, Marek; Young, Mary; Anastos, Kathryn; Crystal, Howard; Cohen, Mardge H; Zhang, Jinbing; Greenblatt, Ruth M; Desai, Seema; Wu, Shiquan; Landay, Alan L; Gange, Stephen J; Norris, Philip J; and the Women's Interagency HIV Study
aBlood Systems Research Institute, San Francisco, California, USA, bDepartments of Laboratory Medicine, cPharmacy, dMedicine, University of California, San Francisco, San Francisco, California, USA, eJohns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA, fKeck School of Medicine of the University of Southern California, Los Angeles, California, USA, gGeorgetown University Medical Center, Washington, DC, USA, hAlbert Einstein College of Medicine, Bronx, New York, USA, iSUNY Downstate Medical Center, Brooklyn, New York, USA, jDepartment of Medicine, Stroger Hospital, and kRush University Medical Center, Chicago, Illinois, USA.
Abstract
Objective: HIV causes inflammation that can be at least partially corrected by HAART. To determine the qualitative and quantitative nature of cytokine perturbation, we compared cytokine patterns in three HIV clinical groups including HAART responders (HAART), untreated HIV non-controllers (NC), and HIV-uninfected (NEG).
Methods: Multiplex assays were used to measure 32 cytokines in a cross-sectional study of participants in the Women's Interagency HIV Study (WIHS). Participants from 3 groups were included: HAART (n = 17), NC (n = 14), and HIV NEG (n = 17).
Results: Several cytokines and chemokines showed significant differences between NC and NEG participants, including elevated IP-10 and TNF-[alpha] and decreased IL-12(p40), IL-15, and FGF-2 in NC participants. Biomarker levels among HAART women more closely resembled the NEG, with the exception of TNF-[alpha] and FGF-2. Secondary analyses of the combined HAART and NC groups revealed that IP-10 showed a strong, positive correlation with viral load and negative correlation with CD4+ T cell counts. The growth factors VEGF, EGF, and FGF-2 all showed a positive correlation with increased CD4+ T cell counts.
Conclusion: Untreated, progress HIV infection was associated with decreased serum levels of cytokines important in T cell homeostasis (IL-15) and T cell phenotype determination (IL-12), and increased levels of innate inflammatory mediators such as IP-10 and TNF-[alpha]. HAART was associated with cytokine profiles that more closely resembled those of HIV uninfected women. The distinctive pattern of cytokine levels in the 3 study groups may provide insights into HIV pathogenesis, and responses to therapy.
Introduction
Infection with HIV leads to immune dysfunction and progression to AIDS within 10 - 11 years in the absence of antiretroviral therapy in the majority of infected persons [1,2]. There is considerable variability in the rate of disease progression, and the factors underlying the pathogenesis of HIV are not entirely understood. Persons with progressive HIV infection on average have higher viral loads [3] and elevated levels of activated T cells [3,4], including HIV-specific T cells [5]. Elevated cytokine levels in HIV infection could have positive or negative effects on viral control or CD4ρ T cell homeostasis. In vitro studies have revealed that a number of factors can contribute to enhanced HIV replication, including TNF- a [6 - 8] and IL-2 [9,10]. In contrast, some cytokines appear to decrease HIV replication in tissue culture, including IFN-a [11,12], IFN-g [6,12,13], and GM-CSF [13].
Prior studies have assessed the associations of soluble markers of inflammation with disease outcome during chronic SIV or HIV infection. An SIV model of infection revealed no differences in cytokine perturbations between animals that progressed rapidly versus slowly to AIDS when studied at the terminal stage of AIDS, though animals with encephalitis had higher IL-2 and IL-6 levels compared to animals without encephalopathy [14]. Recent studies of pathogenic vs. non-pathogenic infection of rhesus macaques and African green monkeys have revealed a host of factors differentially regulated in these disease models [15-18]. In humans, prior work has demonstrated that patients with chronic HIV infection typically show elevations in serum or plasma TNF-a levels [19-21]. In a large cohort of HIV-infected men, the plasma activation markers soluble TNF receptor II (sTNF-RII), neopterin, and sIL-2R correlated well with each other and had some ability to predict progression to AIDS independent of CD4ρ T cell count or plasma HIV viral load [22]. More recent data from the SMART trial showed that elevated levels of C-reactive protein, IL-6, and D-dimer were associated with increased risk of death in a cohort in which most participants received HAART [23].
The above studies suggest that soluble mediators of inflammation are associated with HIV disease progression. Our group and others have identified soluble markers of inflammation that are dysregulated in acute HIV infection [24,25], more recently using newly available multiplex cytokine testing reagents [26,27]. We applied these multiplex cytokine detection tech- niques to study HIV seronegative women and women with chronic HIV infection. Thirty-two soluble immune markers were quantified and correlated with clinical group, viral load, and CD4ρ T cell count. This study furnishes a more complete picture of the degree and importantly the breadth of immune dysfunction associ- ated with uncontrolled viral replication, and reveals the ability and limitations of HAART to correct the systemic inflammation associated with HIV.
Study participants
Subjects were participants in the Women's Interagency HIV Study (WIHS), an ongoing multi-site cohort study of HIVamong US women, which enrolled participants in 1994 - 95 and 2001 - 02 [28,29]. Semiannual visits include interview, clinical exam, and collection of biologic specimens. HIV non-controllers (NC, n =14) were antiretroviral therapy naive and had a viral load >10 000 RNA copies/ml for at least one of two time points separated by 6 months. HAART responders (n 1/4 17) had undetectable viral load (<80 RNA copies/ml) for at least 12 months while on a potent combination antiretroviral regimen. HIV uninfected women (NEG, n = 17) in WIHS undergo the same follow-up procedures as the HIV infected women, and have HIV serology performed every 6 months. HCV serology was performed at study entry, and HCV plasma RNA quantitation was per- formed on seropositive women to determine if infection was ongoing versus resolved. Participants for the current study were chosen from the total WIHS cohort of 3,766 women to match within the three study groups (NEG, HAART, and NC) based on ethnicity (African-American versus other), age, body mass index, HCV antibody status at study entry, and time of follow-up in the cohort (within one year).
Discussion
This study showed that serum levels of the innate immune system pro-inflammatory modulators TNF-a and IP-10 were elevated, increased among untreated HIV patients, compared with uninfected comparisons, a finding that is consistent with a broad inflammatory response. Additionally, serum IL-12(p40) and IL-15, important for T cell homeostasis and function, were decreased in chronic, untreated HIV infection compared to otherwise similar HIV-uninfected women. When compared with untreated women the HAART recipients showed fewer detectable differences in cytokines from HIV uninfected persons (2 vs. 5 analytes), though TNF-a and FGF-2 were still different in the HAART compared to NEG group. Finally, while as expected many factors correlated with both plasma viral burden and CD4+ T cell counts, some factors correlated with one or the other. Interestingly, the growth factors VEGF, EGF, and FGF-2 showed a positive correlation with higher CD4+ T cell counts.
Analytes found to be elevated in chronic infection in this study have been shown to be elevated using separate test methodologies for TNF-a [19 - 21] and IP-10 [34]. During primary infection IP-10 and TNF-a correlated positively with quantitative viral load [35]. We found that the only factor to show a significant positive correlation with viremia in untreated women during chronic HIV infection was IP-10, underlining the importance of this chemokine in the response to HIV and consistent with in vitro experiments demonstrating its ability to stimulate HIV replication [36]. Elevated IP-10 also has been detected in multiple viral infections, including acute West Nile virus [37], severe influenza infection [38,39] acute HCV [26] and chronic, persistent HCV in this study, suggesting a general role for this chemokine in the immune response to viral infections. Elevated IP-10 levels in chronic HIV infection could be deleterious and contribute to ongoing immune activation and T cell depletion, supported by the strong negative correlation between IP-10 levels and CD4+ T cell count we found in this study (Fig. 2b). Finally, the suppression of plasma IL- 12 levels in untreated HIV-infected participants is consistent with published work demonstrating cellular defects in production of these cytokines in chronic HIV infection [40,41].
While most of the cytokine changes previously described to be elevated or reduced during chronic HIV infection were confirmed in our cohort of women with uncontrolled HIV replication, we did not find significant elevations reported by others in predominantly male populations using ELISA tests for or IL-6 [42,43], IL-10 [44,45], or FGF-2 [46]. Although median IL-10 levels in our untreated HIV-infected group were nearly two-fold higher compared to the HIV-negative participants, this difference was not statistically significant. In contrast, median IL-6 and FGF-2 values were lower in the NC than NEG group. The IL-6 data are consistent with our recent study of acute HIV infection, where only a subset of participants showed elevations in IL-6 levels [26], though the different assay format (ELISA vs. Luminex)
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