Final Activity Report Summary - HIV AND CTLS ESCAPE (Interraccions between citotoxic T lymphocytes (CTLs) and human immunodeficiency virus (HIV): Viral cost of escape from immune system ...) Project OverviewCD8 specific T cells (CTLs) play a crucial role in controlling many viral infections. CTL effector function is based on the recognition of viral peptides presented by HLA class I molecules on the surface of infected cells. In the context of Human Immunodeficiency Virus (HIV) infection only the minority of individuals infected control the virus to low levels. Immuno genetic studies of large cohorts have identified associations between HLA class I molecules and control of HIV infection. Our project has aimed to increase our knowledge in the role of CTLs in HIV infection concentrate our attention in those HLA alleles associated with viral control. Based on previous results by our group and others, we have mainly focus in the potential role of HIV attenuation by CTL mutational escape as a possible mechanism contributing to HIV immune control.Aims And Overall Results1.Identify CTL escape mutations that reduce viral replicative capacity (RC).We have defined in detail new mutational pathways of HIV escape from CTL responses. We focus in individuals carrying B*5703 and B*13. These HLA alleles are associated with control of HIV infection. We have show that selection of CTL escape mutations in conserved regions of HIV proteome, mainly Gag reduce replicative capacity. The mechanism underlying this fitness cost can be structural (B*5703 Gag KF11) or functional (B*13 Gag RI9). Moreover, we have identified CTL escape mutants in the context of Cw*0303/0304 to contribute to our understanding in HLA-C driving HIV evolution.2.Address the evolutionary consequences of escape mutations that reduce viral RC.We have investigated the capacity of HIV to adapt to CTL responses. We have demonstrated that HIV evolves to overcome the fitness cost associated to certain escape mutations (B*5703 and KF11). In other cases the fitter escape virus will out compete the others variants (B*13 and RI9). Accumulation of compensatory mutations and transmission of those variants will contribute to the lost of epitopes as the epidemic evolves. Another effect of viral evolution and selection of escape virus will be virus adaptation to HLA.3.Define the contribution to HIV control of low fitness escape variants transmitted during early paediatric infection.We have adjusted our cohort studies in the context of early paediatric HIV infection. We have studied the virologic and immunologic characteristics of a group of progressors vs non-progressor in early paediatric infection. Virus isolates show a significative reduction in viral replication in the group of non-progressors. Moreover, the presence of B*57 footprints may have contributed to viral control in non-progressors. In contrast, viruses from progressors have better replicative capacity. Two of the progressors share HLA-alleles with their mothers losing any chance to mount a potent immune response if escape variants have been transmitted.Relevant AchievementsDuring the period of the Marie Curie contract the topic of our research, the cost to HIV of immune escape, has been a field of increase interest in the HIV scientific community. We have been one of leading groups to illustrate the apparent trade-off available to the virus between evasion of Gag CTL recognition and the consequences on viral fitness. Viral attenuation is reach through CTL escape but at the same time selection of compensatory mutations and viral evolution counterpart the fitness cost. All the findings achieve during this period increase our understanding of protective immunity and will be of direct relevance to vaccine design. Specially, following the recent failure of the most promising CTL-based vaccine candidate in the STEP trial.