Immune activation, as defined by expression of HLA-DR and CD38 by T-cells typically normalizes several months following successful initiation of ART . However, we describe high levels of immune activation in a cohort of HIV infected Ugandan adults four years following ART; a report that is consistent with several other studies from the Western cohorts [21, 22]. Contrary to previous studies from the West , this study demonstrated that suboptimal CD4 reconstitution is strongly associated elevated T cell activation, regardless of initial clinical parameters. Various immunosuppressive agents have been investigated in the interest of "turning off" excessive immune activation [23, 24] as an intervention to improve patients' responses to ART. Therefore down-regulation of immune activation is a potential strategy to optimize immune recovery among ART-treated patients with suboptimal CD4 reconstitution. Noteworthy, the study participants were started on ART at CD4 counts < 250 cells/μl. This is clearly severe immune suppression considering the growing evidence initiation of ART at higher CD4 counts yields better clinical and immunological outcomes [25, 26]. This study adds evidence to the current evidence that early initiation of ART not only increases CD4 counts and survival [6, 25–27], but also lowers the levels of T-cell activation and possibly improves T-cell function recovery. Therefore early targeted and aggressive intervention in the population with suboptimal immune recovery may be beneficial [28–30].
The high levels of T-cell immune-activation did not correlate with the presence of co-infections including tuberculosis, cryptococcal meningitis, Pneumocystis iiroveci pneumonia, toxoplasmosis, oro-esophageal candidiasis and malaria. This result is consistent with our previous report that AIDS-related events were no more among patients with and without suboptimal CD4 reconstitution . Similarly, none of the patients was found to have intestinal helminthiasis despite living in a region where the infection is endemic. The authors attribute this to the fact that this was a selected population that receives comprehensive screening, treatment and prevention of co-infections that includes among others; cotrimoxazole prophylaxis, regular de-worming and a safe water vessel; all of which reduce the risk of the co-infections [31–34].
Expression of programmed cell death 1 (PD-1) was significantly up-regulated on T-cells of suboptimal responders relative to super-optimal responders. Significant difference in T-cell immune activation and exhaustion was observed despite undetectable viremia. This implies that ongoing viral replication may not be the driver of PD-1 expression as previously reported . However, our results are in agreement with evidence that increased apoptosis and intrinsic T-cell death play a role in incomplete CD4 count recovery . There is need for further studies to determine other potential drivers of both immune activation and PD-1 expression among HIV-infected patients on successful ART. Similarly, advances to regulate these immunological abnormalities may modify CD4 count recovery among ART-treated HIV-infected patients with suboptimal CD4 reconstitution.
Our study design did not permit determination of the causation of immune dysregulation. Although majority of available data suggests that immune activation is most likely a cause of the damaged immune system rather than a consequence , it is possible that lack of CD4 recovery could be the cause and not a consequence of the immune impairment . We did not compare levels of immune activation among patients with and without viral suppression however there is already evidence that ART decreases immune activation levels over time [1, 37].