Soluble CD163 as a marker of CMV mediated immune activation

27 February 2017. Related: Basic science and immunology.

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. [1]

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. [2]

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 [3], as well as with ART-associated co-morbidities such as neurocognitive disorder. [4]

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.

References:

1. 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
   https://www.ncbi.nlm.nih.gov/pubmed/27828874
2. Deeks S et al. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ (2009) 338:a3172.
   http://www.bmj.com/content/338/bmj.a3172
3. Burdo TH et al. Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after anti-retroviral therapy. J Infect Dis (2011) 204(1):154-63.
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105035/pdf/jir214.pdf (PDF)
4. 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.
   http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC3844286&blobtype=pdf (PDF)