The focus of our group is to investigate host immunity to viral infections in the immune compromised host. This includes individuals with HIV infection as well as subjects undergoing solid organ transplantation, with or without concurrent HIV infection. In these immunological settings, the control over HIV as well as other viral co-pathogens can be lost and may lead to AIDS-related illnesses and death. In the setting of solid-organ transplantation in the HIV-infected host, the additional immune suppressive treatments may further accelerate a profound immune deficiency leading to life threatening reactivation of infections such as CMV and EBV. We aim at a better understanding of the casual relationship between CD4 T cell activity, anti-viral CTL responses and host genetics to provide guidance for therapeutic and, in the case of HIV infection, also prophylactic immune interventions.
The characterization of HIV-specific T cell immunity and the design of HIV vaccine immunogen sequences are based on a combination of in vitro test systems and ex-vivo immune analyses in samples from HIV infected individuals. These analyses employ specific peptide sets that represent the circulating viral diversity (“Toggle” peptides) as well as sensitive read-out systems that can assess the frequency, avidity and functionality of T cells reacting specifically with HIV antigens. The emerging data highlight the importance of T cell specificity and functional avidity in viral control. They also indicate that viral evolution is driven to a substantial portion by immune selection pressure, indirectly suggesting that functionally effective T cell responses can exert some level of viral control.
Using samples from extensive cohorts of HIV-infected individuals in Peru and Barcelona, T cells targeting specific regions of the viral proteome are being associated with superior ability to exert such viral control in vitro as well as in vivo. Some of these responses are now tested for their ability to inhibit in vitro HIV replication and are being contrasted to responses that targeted generally more variably regions of HIV. Putting these observed responses in the context of host genetics, especially HLA class I polymorphisms, will allow to assess whether focused immunogen selection is feasible while still covering the broad HLA diversity in the tested populations. As such, the studies will have considerable implications for HIV vaccine immunogen design and will further support the activities in the recently established HIVACAT program. Within this program, the group is working intensively on HIV immunogen design and the development of different immunogen delivery systems that could be moved into pre-clinical trials.
The analysis of immune reactivity to viral co-infections, particularly HCV, EBV and CMV, in HIV-infected solid organ transplant recipients suggest that HIV-infected transplant recipients may possess a surprising ability to replenish their diminished anti-viral T cell pool, particularly after T-cell depleting regimes pre-transplantation. However, the regenerated immune cells appear often functionally impaired and seem especially deficient in individuals who show herpesviral reactivation post-transplantation. These data suggest that a fine balance between immune-suppressive treatment, anti-viral reactivation and continued control of HIV replication needs to be established in order not to jeopardize the outcome of solid organ transplantation in this patient population. Ongoing work in this aspect is focusing on HCV specific immunity in the liver transplantation setting, where re-infection of the implanted liver is universal and which can considerable hamper outcome of liver transplantation.