Strong TH1-biased CD4 T cell responses are associated with diminished SIV vaccine efficacy

Abstract

Vaccine-induced IFNγ+ CD4 T cells migrate to and persist in mucosal tissue and negatively associate with protection against SIV. Troublesome T cells Many HIV vaccines aim to generate robust T cell responses, but two new studies show that this is not always straightforward. Chamcha et al. analyzed data from several nonhuman primate vaccine studies with SIV/SHIV challenges and discovered that achieving a certain threshold of vaccine-induced IFNγ+ CD4 T cells lowered vaccine efficacy, possibly by providing target cells for the virus. Kallas et al. vaccinated people with HIV Gag/Pol alone or with Env to see whether antigenic competition could interfere with CD4 T cell responses; lower responses to Gag/Pol were detected when Env was also administered, indicating that including multiple antigens in a vaccine may preclude maximal T cell responses. Together, these studies highlight how we must tread carefully on the path to an effective HIV vaccine. Activated CD4 T cells are a major target of HIV infection. Results from the STEP HIV vaccine trial highlighted a potential role for total activated CD4 T cells in promoting HIV acquisition. However, the influence of vaccine insert-specific CD4 T cell responses on HIV acquisition is not known. Here, using the data obtained from four macaque studies, we show that the DNA prime/modified vaccinia Ankara boost vaccine induced interferon γ (IFNγ+) CD4 T cells [T helper 1 (TH1) cells] rapidly migrate to multiple tissues including colon, cervix, and vaginal mucosa. These mucosal TH1 cells persisted at higher frequencies and expressed higher density of CCR5, a viral coreceptor, compared to cells in blood. After intravaginal or intrarectal simian immunodeficiency virus (SIV)/simian-human immunodeficiency virus (SHIV) challenges, strong vaccine protection was evident only in animals that had lower frequencies of vaccine-specific TH1 cells but not in animals that had higher frequencies of TH1 cells, despite comparable vaccine-induced humoral and CD8 T cell immunity in both groups. An RNA transcriptome signature in blood at 7 days after priming immunization from one study was associated with induction of fewer TH1-type CD4 cells and enhanced protection. These results demonstrate that high and persisting frequencies of HIV vaccine–induced TH1-biased CD4 T cells in the intestinal and genital mucosa can mitigate beneficial effects of protective antibodies and CD8 T cells, highlighting a critical role of priming immunization and vaccine adjuvants in modulating HIV vaccine efficacy.