Immune deterioration in HIV-1 and HIV-2 infection with a focus on CD8 T cell exhaustion

Thanks to the development of antiretroviral treatment (ART), human immunodeficiency virus (HIV) infection is now considered a chronic infection rather than the death sentence it used to be. Despite constant expansion and improvement of treatment options, even optimal therapy cannot prevent the impact of HIV on the human immune system. Persistence of latently infected cells, low-level residual viral replication and long-term impact from initial tissue damage lead to chronic immune activation, which in turn drives a number of comorbidities and complications that lower the patient´s quality of life. The hallmark of HIV infection is the depletion of CD4 T cells, also called helper T cells. In addition to immune activation due to the virus itself, the lack of support by CD4 T cells impairs numerous immune cell types. As the main defender against viral infections, CD8 T cells play a central role in ending the peak of viral replication during acute HIV infection. However, during the subsequent chronic phase, they become exhausted, which impairs not only immune responses against HIV, but also other viral infections and malignant cells.

In paper I we investigate the role of the immune receptor TIGIT in HIV type 1 (HIV-1) infection. As an exhaustion marker, it is increased in HIV-1 infection, co-expressed with other inhibitory receptors and fails to return to normal levels despite viral suppression by ART. It is also part of a regulation network together with the complementary co-stimulator CD226 and their shared ligand PVR. All members of this network are skewed in HIV-1 infection and contribute to CD8 T cell exhaustion and immune deterioration. Of the few human genetic factors beneficial in HIV-1 infection, HLA-B*57 has the potential to slow down disease progression. Paper II investigates the connection between HLA-B*57 and exhaustion of HIV-specific CD8 T cells. Delayed co-expression of TIGIT and PD-1 might be one factor contributing to slower disease progression often seen in people positive for the HLA-B*57 allele. HIV type 2 (HIV-2) is associated with slower disease progression and a higher chance of virus control by the host immune system than HIV-1. In paper III, we found signs of CD8 T cell pathogenesis, especially a skewed balance of co-stimulation and inhibition, in HIV-2 infection despite controlled viral replication. HIV-1 pathogenesis in children after mother-to-child transmission shows differences from pathogenesis in adult patients and leads to unique complications. To better understand the unique aspects of pediatric HIV infection and potentially find candidates for therapeutic intervention, we investigated plasma biomarkers in well treated children in paper IV. Their treatment prevents high levels of dysregulation in comparison to HIV-negative children. However increased levels of sTRAIL, a marker for T cell activation with potential to induce apoptosis, shows the capacity to further optimize treatment in HIV infected children.

List of scientific papers

I. Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals. Tauriainen J, Scharf L, Frederiksen J, Naji A, Ljunggren H-G, Sönnerborg A, Lund O, Reyes-Terán G, Hecht FM, Deeks SG, Betts MR, Buggert M and Karlsson AC. Scientific Reports. 7, 40354 (2017).
https://doi.org/10.1038/srep40354

II. Delayed Expression of PD-1 and TIGIT on HIV-Specific CD8 T Cells in Untreated HLA-B*57:01 Individuals Followed from Early Infection. Scharf L, Tauriainen J, Buggert M, Hartogenesis W, Nolan DJ, Deeks SG, Salemi M, Hecht FM and Karlsson AC. Journal of Virology. 94:e02128-19 (2020).
https://doi.org/10.1128/JVI.02128-19

III. Inverted balance of CD8 T-cell exhaustion and co-stimulation markers differentiate aviremic HIV-2-infected from seronegative individuals. Scharf L, Pedersen CB, Lindman JL, Olsen LR, Buggert M, Wilhelmson S, Månsson F, Esbjörnsson J, Biague A, Medstrand P, Norrgren H, Karlsson AC, Jansson M, and the SWEGUB CORE Group. [Manuscript]

IV. Plasma biomarkers identifying immunological reconstitution in perinatally HIV-infected children undergoing antiretroviral treatment. Scharf L, Olofsson A, Soeria-Atmadja S, Thalme A, Navér L, and Karlsson AC. [Manuscript]