HIV-1-Specific CTL Responses: Insights from Elite Controllers and identification of Nef-Resistant CTLs for therapeutic vaccine development

Cytotoxic T Lymphocytes (CTLs) are pivotal components of the immune response against HIV- 1, particularly in the initial stage of infection. CTL response is heavily influenced by Human Leukocyte Antigen-I (HLA-I) allele variation in HIV-I-infected subjects, which affects epitope binding and presentation to CTLs. HLA-I-B alleles show a greater selection pressure on HIV-I, mainly HLA-B*57, HLA-B*27, HLA-B*52, or HLA-B*13, which correlate with HIV-1 control or slower disease progression. However, CTL response among individuals with HIV-1 is heterogeneous and highly varies not only among patients expressing different HLA-I alleles, but also among patients expressing the same alleles. To assess the importance of recognition of specific epitopes, HIV-1-specific CTL response was analyzed in a large cohort of HIV-1-infected patients at the Department of Medicine 3 of the University Hospital in Erlangen. In addition, a detailed study of HIV-1-specific CTLs was performed in three elite controllers and a new HLA- B*52-restricted CTL Rev epitope (RQRQIRSI) could be defined. A significant obstacle to effective CTL targeting of HIV-1 epitopes arises from HLA-I-A/B downregulation in infected cells by the viral protein Nef. This immune evasion strategy diminishes antigen presentation, thereby attenuating or evading the CTL responses. Nevertheless, certain epitopes such as HLA- B*57-restricted Gag epitopes and a HLA-B*13-restricted Nef-epitope were well recognized by CTL despite Nef expression and HLA-I downregulation, presumably due to a highly efficient presentation of these peptides. The recognition of these epitopes correlates with superior HIV-1 control and more favorable clinical outcomes and they are frequently targeted by high CTL frequencies in Elite controllers. The identification of such Nef-resistant HIV-1 epitopes holds great promise for the development of efficient vaccines and therapeutic strategies. Nef-resistant epitopes can also play a crucial role in the “shock and kill” strategy, as their resilience against Nef-mediated immune evasion enables the targeting of latent HIV-1 reservoirs. In addition to their role as immune effectors, CTLs may also serve as valuable diagnostic tool. A polyclonal CTL response against multiple HIV-1 epitopes was detected in a vertically HIV-1-infected patient who was seronegative for HIV-1-specific antibodies after 13 years of antiretroviral treatment (ART). This discovery demonstrates the presence of an ongoing HIV-1 infection despite persistent seronegativity, providing justification for not interrupting ART too soon. By elucidating the interplay between CTL responses and HIV-1 infection, my research advances the understanding of these complex dynamics. These insights support the development of precision interventions, offering new avenues for diagnostic, preventive, and therapeutic strategies.