To our knowledge, this is the first study investigating the potential role of ART initiation strategy on circulating LPS, host LPS-control molecules and T cell activation in HIV-infected infants up to 1 year of age.
In agreement with previous reports from us and others,15,26
we found in the first semester of life higher plasma LPS concentration in HIV-infected infants compared with controls of similar age. In contrast to our previous report showing higher concentration of LPS in ART naïve adults compared with ART-suppressed subjects,15
LPS concentration in both HIV-infected Groups in the first semester of life was not statistically different. This could be explained by the presence of viremia in both Groups independent of ART and by the fact that due to the rapid deterioration of CD4% in Group 1, many children assigned to this Group were already undergoing treatment at the time of first sampling.24
The detection of LPS in all infants in the first semester, independent of HIV infection status, suggests a basal level of bacterial translocation, which is higher in HIV-infected. This basal level of bacterial translocation into circulation could be attributed either to increased vulnerability of the immature immune system,27
or, since all infants were formula fed and did not fast before sample’s collection, to increased permeability of the gut due to high fat diet,28-30
presence of LPS in the formula,31
or presence of LPS in the water used for formula preparation. Overall though, the above factors, although explaining the basal translocation observed in all groups, cannot account for the increased levels observed in HIV-infected, as infants in all groups were age-matched and part of the same nutritional program, further supporting the association between HIV infection and increased microbial translocation.
The detected LPS concentration was similar to that reported in adults15
yet higher than that reported by Wallet et al in older HIV-infected children.26
Our findings suggest a comparable impact of HIV infection on plasma LPS concentration between HIV-infected infants and adults despite different disease progression outcomes. However, the presence of viremia and increased LPS concentration in HIV-infected infants during the first semester of life may have a greater significance for health as the CHER study showed increased death rate and HIV progression in Group 1 compared with Group 2, a finding that triggered the initiation of ART in all infants initially randomized in Group 1 and influenced treatment guidelines worldwide (i.e. ART is initiated as soon as possible after HIV diagnosis regardless of CD4% levels or disease progression).24
T cell activation was higher in HIV-infected infants and in positive correlation to viral load confirming that early ART initiation is beneficial in reducing cellular activation, even if its effect on LPS concentration is not immediately evident. Exposure to other pathogens or nutrition-related factors such as bottle feeding, which was common to all infants, could also contribute to increased inflammation due to lack of breast milk IgAs32
or of other soluble maternal components that could mediate anti-inflammatory effects.26,33
Lack of association between T cell activation and LPS or between T cell activation rate of change and LPS rate of change, although in agreement with our previous findings in adults15
and the report from Wallet et al.,26
stands in contrast to the study of Brenchley et al6
, a difference which could be due, in part, to differences in study design.
Host LPS-control molecules were higher in HIV-infected infants with deferred ART compared with HIV-negative infants born of HIV-infected mothers and were correlated with viral load suggesting an early development of a defensive neutralizing response to LPS in conjunction with higher concentration of LPS. This is consistent with previous reports in adults showing increased EndoCAb IgM concentration in conditions of microbial translocation,21,34-36
and increased sCD14 concentration in HIV-infected adults.6,15,26,37,38
Furthermore, in light of recent data suggesting that sCD14 is an independent predictor of mortality in HIV infection,39
our data showing in HIV-infected infants with deferred ART higher levels of sCD14, LPBP and EndoCAb in the first semester of life, together with significantly greater values of sCD14 and LBP over the first year, further support the need for longitudinal studies investigating whether these molecules could be more clinically relevant than LPS as they serve as measures of the host response to microbial translocation. We interpret the lack of direct association between plasma concentration of LPS and LPS-host molecules to reflect an insufficient clearance of LPS due to sustained microbial translocation above levels neutralized by host LPS-control molecules.26,40
Lack of LPS detection in the second semester was independent of HIV infection and cannot be attributed to technical problems, as samples for both semesters were tested at the same time in a blinded fashion. This finding contrasts with the results of Wallet et al.26
showing persistent microbial translocation following ART-mediated immune reconstitution, a difference which could be attributed to differences in patient cohorts. The lack of detectable LPS in the second semester in all groups suggests a possible role of other factors besides ART in decreasing LPS (i.e. cease of the formula program and transition to solid foods in all infants at 180 days, efficient LPS control by sustained levels of LPS-host molecules, or immune system maturation). The lack of second semester values for LPS in all subjects where first semester values are reported, could raise the potential for informative dropout. We interpret this not to be likely, as LPS measurements after 180 days were undetectable and no a priori reason was identified for missing values when present. Importantly, our study does not address long-term effects of sustained viremia after 180 days as ART was introduced in 84.3% of the HIV-1-infected infants.
In summary, in the first semester of life we show higher LPS concentration in all HIV-infected infants independently of ART initiation strategy as compared with controls of similar age, together with a decrease in LPS concentration to undetectable levels by one year of age in all infants.