Within the context of sustained viral suppression after 4 years of HAART, we found that suboptimal responders exhibit lower levels of T-cell proliferation than optimal responders. We showed significant differences when PBMCs were stimulated with SEB and PPD. Our results are consistent with previous reports of impaired in-vitro HIV-specific CD4 T-cell proliferation among HIV-infected cells although these were not in a setting of suppressive HAART[2, 16, 17]. In addition to HIV-specific responses, this study analysed T-cell responses to common antigen (SEB, PPD, CMVpp65) to which majority of HIV-infected patients are exposed. Our findings imply that despite sustained viral suppression, the persistently low CD4 T-cell function is likely to predispose suboptimal responders to opportunistic infections and severe Staphylococcus aureus infections. This could explain previous reports that HAART-treated individuals with poor CD4 recovery despite viral suppression were at increased risk of opportunistic infections and mortality. Given the low proliferation levels among suboptimal responders, we postulate that suboptimal responders could potentially benefit from longer periods of cotrimoxazole prophylaxis for opportunistic infections as well as additional vaccines of common bacterial infections such as pneumococcal vaccines. With the increasing numbers of individuals on HAART in sub-Saharan Africa, there is clearly need for prospective studies to understand therapeutic interventions for the emerging population of 30-40% suboptimal responders despite viral suppression[12, 18] in order to maximise immune recovery during first-line antiretroviral therapy.
The mechanisms of functional impairment of surviving CD4 and CD8 T-cells during chronic HIV infection need to be understood to support the development of targeted interventions. For example, Boasso et al. show that Indoleanine 2,3 dioxyenase (IDO), an immunosuppressive enzyme, plays a role in inhibition of T-cell proliferation and its in-vitro inhibition increased CD4 T-cell responses in PBMCs from HIV-infected patients. Immune activation–induced fibrosis of lymphoid tissue in advanced HIV disease is thought to contribute to depletion of naive T-cells and increased apoptosis and subsequently perpetuate cumulative loss of T-cells that may persist despite antiretroviral therapy[19, 20]. In addition, recent evidence from mouse studies suggests that lymphoid tissue inducer cells are a relatively newly recognised family of innate lymphoid cells that may have a role in CD4 T-cell responses. Furthermore, HIV-infected dendritic cells produce gp120 that contributes to impaired CD4 T-cell immune responses in-vivo; therefore agents that block the gp120-mediated immune suppression could potentially modulate immune responses in HIV-infected individuals and their role in HAART-treated adults may be worth investigation. There is clearly a need to understand and explore the role of these mechanisms in CD4 T-cell function recovery within the setting of long-term suppressive HAART. This study contributes to the increasing evidence that monitoring of immune activation levels, viral loads and CD4 function recovery are relevant to compliment the current widely used CD4 count monitoring[3, 22] in order to optimise long-term immune recovery within HIV treatment programs in SSA.
We found that CD4 T-cell proliferation decreased with increasing levels of immune activation. Although the exact mechanism is yet to be understood, this data is consistent with our previous report that immune activation and exhaustion were significantly associated with suboptimal CD4 recovery. Similarly, CD8 T-cell proliferation reduced with increasing immune exhaustion. We hypothesize that in addition to low T-cell proliferative ability, the persistently high immune activation and exhaustion levels drive the inflammatory death pathways and subsequently the impairment in CD4 count and functional recovery; however the reverse could also be true. We therefore need to further understand the prevalent T-cell death pathways among suboptimal responders with persistent immune activation.
Our findings are consistent with previous follow-up studies in European and American cohorts that reported failure in long-term restoration of numeric CD4 counts, with the recovery process reaching a plateau after 4–5 years of therapy[5, 24–26]. The patients in this study had been on treatment for 4 years which is the likely period for the plateau phenomenon. There is need for follow-up data on specific T-cell responses from this HAART cohort to provide the trends of CD4 count and functional recovery beyond 5 years of therapy. It is also important to note that the patients we studied had initiated HAART in the advanced stages of HIV disease which might be a contributing factor to suboptimal immune recovery[5, 25, 26] due to the collagen deposition and fibrosis of lymphoid tissue during later stages of HIV infection[4, 19, 27]. It will be interesting to perform similar assays among patients that initiate HAART at higher CD4 counts (>350 cells as per 2012 national antiretroviral therapy guidelines) or during acute HIV infection, which associated with enhanced likelihood of CD4 count recovery. Due to the limitations of the four color flowcytometry used in this study, we were not able to describe all the T-cell subsets including the memory T-cells of the specific antigens used. This would probably provide more insight into the mechanism of suboptimal immune recovery. For example, previous studies, among HAART-treated individuals with CMV retinitis, showed that memory CMV-specific CD4 and CD8 T-cells expanded several years after HAART initiation.
To date, there is no consensus on when and how to treat immunological failure in a setting of viral suppression. Suboptimal responders pose several clinical questions, including questions about the clinical risk associated with persistent immunodeficiency and about possible interventions to optimise clinical and immunological benefits of HAART[12, 30]. From a clinical point of view, it is reasonable to hypothesise that adjuvant therapy with anti-immune activation agents[31, 32] may improve T-cell proliferation potential among suboptimal responders. Our work presents an interface between clinical care and basic science research. We also add to the evidence that immune modulation could potentially maximize immunological recovery during suppressive antiretroviral therapy.