Soluble CD163 as a marker of CMV mediated immune activation
Gareth Hardy, HIV i-Base
Cytomegalovirus (CMV) may be a driver of harmful immune activation in HIV positive people, even after more than one year of successful ART, according to a study by Serena Vita and colleagues who investigated the relationship between plasma markers of immune activation and CMV serostatus in HIV positive people. 
Residual immune activation that persists after ART is a major concern because it is likely to play a role in age-related degenerative conditions such as dementia and cardiovascular disease. 
Vita and colleagues enrolled matched CMV+/HIV+ and CMV–/HIV+ people at a 2:1 ratio from the ICONA (Italian COhort Naïve of Antiretrovirals) Foundation Study cohort, which is a multicentre prospective HIV observational study. Participants underwent CMV serology at enrolment and plasma samples were taken for immunological testing at least one year after successful ART-induced suppression of viral load to below detection and increases in CD4 cell count to above 200 cells/mm3 blood. There was also an HIV negative control group who were almost all CMV+.
The researchers compared the levels of systemic inflammatory mediators that promote chronic inflammation such as TNF-alpha, IL-6, soluble (s) CD163 and sCD14, which have been shown to be independent predictors of morbidity and mortality in HIV infected people. While TNF-alpha and IL-6 are inflammatory cytokines produced by blood monocytes and their tissue-residing matured descendants macrophages, surface-bound CD163 and CD14 can be shed from monocytes and macrophages as a soluble protein following activation by pro-inflammatory stimuli.
A total of 69 HIV+ participants were recruited, 46 of whom were CMV+ and 23 CMV–, along with 16 HIV negative controls, of whom 12 were CMV+. Plasma levels of sCD163 were significantly higher in the CMV+/HIV+ group compared with the CMV–/HIV+ group (p<0.0001) or the HIV negative control group (p<0.0001). In contrast, levels of sCD14, IL-6 and TNF-alpha were not significantly different between CMV+/HIV+ people and CMV–/HIV+ people.
Plasma levels of sCD163 also correlated with levels of plasma CMV-specific IgG antibodies (r=0.49, p=0.0006). In addition, plasma CMV IgG antibodies correlated with IL-6 (r=0.42, p=0.0041) and TNF-alpha (r=0.34, p=0.021) but not sCD14.
Furthermore, differences were observed in traditional markers of HIV disease progression between those with HIV/CMV co-infection and those who were HIV+ without CMV infection. CD8 cell counts were significantly increased in CMV+/HIV+ people in contrast to CMV–/HIV+ people (p <0.0001).
CD4:CD8 ratios were lower for those with CMV/HIV co-infection (p <0.0001) compared to the CMV–/HIV+ group. Plasma CMV IgG antibody levels inversely correlated with CD4:CD8 ratios (r=0.40, p=0.0063) as well as with CD4 cell count (r= –0.39, p=0.0006) in CMV positive/HIV positive people. sCD163 levels inversely correlated with CD4:CD8 ratios (r=-0.38, p=0.0075). Interestingly, the researchers also found that the duration of HIV infection correlated with sCD163 levels for those with HIV and CMV coinfection (r=0.29, p=0.04), but not for who were CMV–/HIV+, suggesting that the two viral infections interact over time to cause monocyte/macrophage activation.
Elevated sCD163 levels have been described both as a marker of HIV activity before and after ART , as well as with ART-associated co-morbidities such as neurocognitive disorder. 
While the sample sizes in this report are small, the association of sCD163 with CMV/HIV coinfection described here suggests that CMV may be an important driver of macrophage activation which in turn critically contributes to inflammatory degenerative co-morbidities in HIV positive people, despite viral suppression with ART.
- Vita S et al. Soluble CD163 in CMV infected and uninfected subjects on virologically- suppressive antiretroviral therapy in the ICONA cohort. JAIDS (2017) EPub Ahead of Print: DOI: 10.1097/QAI.0000000000001232
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- Burdo TH et al. Elevated sCD163 in plasma but not cerebrospinal fluid is a marker of neurocognitive impairment in HIV infection. AIDS (2013) 27(9):1387-1395.