Evaluation of immune responses and viral fitness in HIV-1⁺ individuals displaying different rates of disease progression

• Main Author: Grageda, Nathali
• Other Authors: Imami, Nesrina
• Published: Imperial College London 2015
• Subjects: 610
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.679695

Despite its great success, antiretroviral therapy (ART) fails to improve HIV-1-specific T-cell responses in treated individuals, although it does restore CMV-specific immunity. Furthermore, co-infection with CMV has been associated with increased risk of non-AIDS-related morbidities. This thesis comprehensively characterises HIV-1- and CMV-specific T-cell responses in HIV-1-infected subjects, in the context of both ART and different progression rates. Proliferative responses to CMV and HIV-1 were evaluated in HIV-1-infected and uninfected healthy controls (HC). ART led to a discordant increase in CMV-specific proliferation relative to that observed for HIV-1. High proliferative responses to both viruses in elite controllers contrasted the low CMV-specific proliferation in HC. Strong induction of the suppressive cytokine IL-10 was observed in response to CMV and HIV-1 Nef, but not to Gag, and this was higher in ART-naïve individuals compared to treated patients. Still, HC exhibited the highest levels of CMV-specific IL-10, pointing to a regulatory role for IL-10 in these responses, possibly explaining the low proliferative responses in HC. Analysis of T-cell activation, differentiation and exhaustion revealed similar frequencies of HIV-1-specific CD8 effector memory (TEM) cells between ART-naïve and treated individuals, but CMV- specific CD8 TEM cells were higher in treated individuals correlating with the increased anti-CMV T-cell function observed. Higher CD8 TEM and lower naïve CD8 T-cell frequencies were significantly associated with disease progression, whilst long-term non-progressors exhibited higher levels of CD8 terminally differentiated (TEMRA) cells. Moreover, CD8 T cells with an HLA-DR+CD38- phenotype were elevated in treated individuals compared to both HC and ART-naïve patients, and linked with cytotoxic activity in a non-progressor. Detection of replication-competent virus from HIV-1 controllers at different outgrowth rates suggests reduced replicative fitness. Overall, these results detail the complex interplay between CMV and HIV-1 co-infection, the difference between ART-mediated and spontaneous immune control and point to potential targets for immunotherapeutic interventions.