A study published in Nature in August 2022 stated that research into curing HIV focuses on “reactivating latent proviruses to enable elimination by CD8+ cytotoxic T-cells.” In recent research by scientists from the USA and Canada, they found that the mRNA vaccine BNT162b2 “activates the RIG-=I/TLR – TNF – NFκb axis”. This resulted in “transcription of HIV proviruses with minimal perturbations of T-cell activation and host transcription”.
They observed that T-cells specific to “early gene-product HIV-Nef” demonstrated increased frequency and effector function in lifelong antiretroviral therapy (ART) treated patients following the vaccination. Furthermore, they noted “significant decreases in cell-associated HIV mRNA”, which they concluded suggested “killing or suppression of cells transcribing HIV”.
The study states that although ART has “transformed” HIV into a “manageable chronic condition” there is still no safe cure with demonstrable success. The authors note that identifying “meaningful latency reversal” is “confounded” by the fact that HIV RNA “does not necessarily equate to antigen expression”. Thus, investigating CD8+ T-cells might be the key to “assessing whether these cells have been engaged”.
Previous studies indicated that vaccination influences HIV latency, but mRNA vaccines had not been explored in such detail. In this most recent study, the Pfizer/BioNTech mRNA Covid-19 vaccine (BNT162b2) was linked to “innate immune sensing of mRNA and downstream activation of NFκb”. This took place without recorded T-cell activation and with limited perturbation of the host transcription. By contrast, the influenza vaccine that they compared it to “induced robust T-cell activation and host transcriptional changes, without detectable HIV reactivation” in assay.
“The observations presented here advance the shock and kill concept, by providing evidence for the productive engagement of HIV-specific T-cells with their antigens in ART-suppressed donors following receipt of an mRNA vaccine”.
The authors acknowledge that mRNA vaccines that target HIV antigens are under development for prophylactic and therapeutic capacities. Their results indicate that “innate immune sensing of the mRNA vaccine platform” may contribute to therapeutic outcomes by “acting as a built-in LRA” (latency reversal agent).
The results indicate the importance of measuring “granzyme-B-producing Nef-specific responses in latency reversal studies”. They also “add impetus to developing HIV-targeted mRNA therapeutic vaccines that leverage built-in LRA activity”. The study suggests that HIV cure research can advance using the results of the paper. The authors hope that this will enable the field to continue working towards “reductions in HIV reservoirs”. This is an important development for the industry, but more importantly, for the 37.7 million people living with HIV.