Modulation of HIV-specific T cell responses during standard antiretroviral treatment and immunotherapy

Only a small fraction of individuals infected with the human immunodeficiency virus (HIV) develops effective immune responses able to control the virus. In most individuals, the virus escapes the antiviral immune response and HIV-specific CD8+ T cell responses become exhausted. Untreated progressive HIV infection also leads to alterations in HIV-specific CD4+ T cells. This includes increased expression of co-inhibitory receptors  and skewing towards a T follicular helper cell (Tfh) signature. Antiretroviral therapy (ART) is highly effective in controlling the HIV viral load at undetectable levels in the plasma. However, ART does not represent a cure as the virus integrates into the genome of infected cells from where the virus rebounds once ART is stopped. This demonstrates that the HIV-specific T cell immunity is not restored. However, the changes that are introduced during progressive infection and that are maintained after viral suppression with ART are poorly known. Broadly neutralizing antibodies (bNAbs) represent a potential alternative to ART. In addition to virus neutralization and unlike ART, bNAbs to do not limit HIV antigen availability and can engage the immune system. bNAb administration elicited adaptive immune responses that were associated with long-lasting viral control in a simian animal model but this has not been established in HIV-infected individuals. In this thesis, we therefore proceeded to study the modulation of HIV-specific T cell responses during standard ART and after an immunotherapeutic intervention using bNAbs. The first objective was to better understand persistent modulation of HIV-specific CD4+ T cell responses in ART-treated individuals. Our results demonstrated the persistent expansion of HIV-specific Tfh cell responses with multiple phenotypic and functional features that differed from Tfh cells specific for comparative viral antigens (cytomegalovirus, hepatitis B virus). These features were induced during chronic untreated HIV infection, persisted during ART and correlated with the translation-competent HIV reservoir. This suggests that persistent HIV antigen expression, despite effective ART, maintains these altered immunological features specifically for Tfh responses. For the second objective, we characterized changes in the HIV-specific CD8+ and CD4+ T cell immunity after bNAb treatment and analytical treatment interruption (ATI). For this, we used samples obtained from participants enrolled in a clinical phase Ib study that received combined infusion of bNAbs 10-1074 and 3BNC117 and demonstrated prolonged viral suppression after ATI. In these individuals, we detected an increase of HIV-specific CD8+ and CD4+ T cell responses during ART interruption when compared to baseline. Increased T cell responses were due to both expansion of pre-existing responses and the emergence of responses to new epitopes. In contrast, HIV-specific T cell responses remained unchanged in ART-treated individuals who did not receive bNAb infusions. This suggests that bNAb treatment and ATI is associated with increased HIV-specific T cell immunity while viral suppression is maintained. Together our results contribute to a better understanding of HIV-specific T cell responses during ART and immunotherapy treatment. Our findings may help to develop more effective HIV treatment strategies to improve the host’s immune system so that HIV can be controlled without the need for ART.

Keyphrases: HIV, HIV-specific T cells, Antiretroviral therapy, Broadly neutralizing antibodies, T follicular helper cells