Biological determinants of long-term immune reconstitution following combination antiretroviral therapy (cART)

CD4+ T-cell reconstitution following suppressive combination antiretroviral therapy (cART) is highly variable and is an important determinant of long-term clinical outcomes in HIV-infected patients. In this thesis we explored the relative importance on long-term CD4+ T-cell recovery of two mechanisms that have different effects on T-cell homeostasis namely; microbial translocation driven immune activation and genetic factors associated with IL-7 mediated homeostasis,. The association of these factors with CD4+ T-cell recovery was assessed using a Kaplan Meier approach where a clinically relevant outcome of time to achieve CD+ T-cell counts >500 cells/µl was used as the study endpoint. In a largely Caucasian cohort, we found the IL-7Rα haplotype 2 which is associated with lower sIL-7Rα levels, was associated with faster CD4+ T-cell recovery, while levels of lipopolysaccharide (LPS) and soluble CD14 (sCD14) on treatment were not. Additionally, pre-cART factors including higher baseline CD4 T-cell counts, lower pre-cART LPS and IL-7, higher pre-cART sCD14 and younger age at cART initiation, were all associated with faster recovery. Using a kinetic model with LPS and sCD14 data from patients receiving up to 11 years of suppressive cART, we predicted LPS and sCD14 levels will eventually normalize in patients receiving long-term cART and do not contribute to impaired CD4+ T-cell recovery. In a replicate study involving African patients however, we were unable to find a similar association between the IL-7Rα haplotype 2 and CD4+ T-cell recovery, although haplotype 2 in Africans was also associated with lower concentrations of sIL-7Rα compared to non-haplotype 2 carriers as previously described in Caucasians. The reason for the lack of the same genetic association is not entirely clear but may be due to differences in linkage disequilibrium patterns in the IL-7Rα gene between Africans and Caucasians which may lead to different gene-gene interactions no solely reflected by sIL-7Rα levels. Additionally, there were differences in the immunological characteristics of the two cohorts studied including the difference in the degree of immunological suppression at cART initiation and the duration on cART. Our method of analysis using a Kaplan Meier approach was then validated in a separate large clinic-based cohort receiving prolonged cART. In this study, we assessed clinical factors associated with CD4+ T-cell recovery and again found higher baseline CD4+ T-cell counts and younger age to be associated with faster CD4+ T-cell recovery. Additionally, we found patients initiating cART with a PI-based regimen was also associated with faster recovery. In summary, we have identified multiple biological and clinical factors that are associated with CD4+ T-cell recovery. We have also highlighted the importance of performing replicate genetic studies in cohorts of different ethnicities. This is particularly important as we start to consider immune-based therapies as additional therapy to improve CD4+ T-cell recovery in patients who continue to experience immune suppression despite receiving standard cART regimens