Sex differences in soluble markers vary before and after the initiation of antiretroviral therapy in chronically HIV-infected individuals

Abstract

Objective To evaluate differences in soluble inflammatory markers between chronically HIV-infected men and women, with or without cognitive impairment, and in response to treatment. Design Soluble biomarkers were measured in cryopreserved plasma and cerebrospinal fluid (CSF) of 60 treatment-naïve individuals (25 males and 35 females) with chronic HIV infection and 18 HIV-uninfected controls (9 males and 9 females) from Thailand. Following enrollment, participants began combination antiretroviral therapy (cART) and were evaluated for expression of these markers after 48 weeks. Methods Plasma and CSF levels of 19 soluble biomarkers (IFN-γ, TNFα, TNF-RII, IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-15, MCP-1, t-Tau, IP-10, neopterin, IFNα, I-FABP, and sCD14) were measured using either a multi-parameter or standard ELISA assay. Results Prior to cART, females with impaired cognition had elevated levels of neopterin and TNF-RII compared to females with normal cognition in both the plasma and CSF, however levels did not differ between cognitively impaired or normal males. In a secondary outcome-hypothesis generating analysis, sex differences were also pronounced in plasma levels of MCP-1, IL-10, I-FABP, and sCD14 in response to treatment. Neopterin, IP-10, TNFα, TNF-RII, IFNα, MCP-1, IL-8, I-FABP, and sCD14 plasma levels remained elevated following 48 weeks of therapy in both sexes compared to uninfected controls. Conclusions We provide evidence of sustained immune activation after 48 weeks of treatment and identify possible sex differences in biomarkers previously linked to cognitive impairment, chronic inflammation, and gut integrity that may contribute to immunological differences between sexes in relationship to disease progression and response to therapy.

Monocyte Activation Is Associated With Worse Cognitive Performance in HIV-Infected Women With Virologic Suppression

“…These findings differ from those described in predominantly male cohorts, in which abnormalities are most frequently described in the domains of learning and executive functioning [1]. Differences in brain outcomes, by sex, have also been suggested in studies identifying increased frequency of ischemic stroke in HIV-infected women versus HIV-infected men [27] and the degree of inflammatory marker resolution following cART initiation, including that for sCD14 [28].…”

“…These findings differ from those described in predominantly male cohorts, in which abnormalities are most frequently described in the domains of learning and executive functioning [1]. Differences in brain outcomes, by sex, have also been suggested in studies identifying increased frequency of ischemic stroke in HIV-infected women versus HIV-infected men [27] and the degree of inflammatory marker resolution following cART initiation, including that for sCD14 [28].In this study, we therefore investigated the relationship between chronic immune activation and cognitive performance in a sample of HIV-infected and uninfected women from the WIHS. Our primary aim was to examine the association between chronic immune activation, using a monocyte activation marker (sCD163) and other markers (C-reactive protein [CRP] and interleukin 6 [IL-6]), and cognitive performance.…”

“…Furthermore, these findings are in a cohort of women whose race and ethnicity distribution reflects that of women living with HIV in the United States [38]. This is pertinent given that there are sex-associated alterations in immune activation in the setting of HIV infection [16,28,39]. Our data are less representative of HIV-infected men in the United States.…”

“…As such, we anticipated that associations would reflect those found for sCD14, a touted marker of gut integrity [43]. Prior studies have reported higher levels of plasma I-FABP in HIV-infected individuals [28,44,45], but no studies have investigated the relationship of I-FABP and cognitive performance in the context of HIV infection. Our inconsistent finding may be attributed to the specificity of sCD14 to gut damage rather than general monocyte activation or the degree to which I-FABP represents a propensity for inflammation related to enterocyte damage.…”

Depression and Anxiety are Common in Acute HIV Infection and Associate with Plasma Immune Activation

“…This depression can precede overt neurological symptoms, suggesting that inflammation and brain damage are linked to affective disturbance for some individuals with multiple sclerosis. While we found an association between plasma neopterin and affective symptoms prior to treatment, it is notable that plasma neopterin has been shown to reduce with cART initiation, but not down to levels of HIV-negative individuals, even after one year of treatment [54]. …”