Raising HLA-E-Restricted HIV-1-Specific Immune Responses through T Cell Vaccination: A Hypothesis

This essay draws on recent evidences from SIV vaccination studies in rhesus macaques to argue for the potential importance of HIV-1-specific CD8+ T cells restricted by the non-classical major histocompatibility complex, HLA-E, in controlling HIV-1 replication. It then seeks to present a possible method of inducing such responses through the procedure of T cell vaccination using activated autoimmune CD4+ T lymphocytes ‘infected’ with inactivated replication-incompetent structurally intact HIV-1 particles. It is hoped that the argument presented here will interest many of those involved in HIV/AIDS research and others in the general scientific community. DOI: 10.14302/issn.2690-4721.ijcm-17-1533 Corresponding Author: Ho Soon Hoe, Independent researcher, Email: hosoonhoe@gmail.com


Introduction
Recent advances in the field of SIV vaccinology have highlighted the role of MHC-1b/E-restricted CD8+ T cell responses in controlling SIV infection in rhesus macaques [1 -4], thereby raising the potential role of their human counterparts, HLA-E-restricted CD8+ T cells, in controlling HIV-1 infection. This is significant in light of the difficulty so far in controlling HIV-1 infection effectively through vaccines that attempt to induce broadly-neutralizing antibodies and/or classical MHC-1a-restricted CD8+ T lymphocytes [5]. Given the genetic lability of HIV-1 and its extremely rapid rate of replication, no effort should be spared on broadening the scope for its recognition by as many potentially useful cells of the immune system as possible.
HLA-E is a non-classical MHC class 1b antigen-presenting molecule with two predominant functional variants across the human population, differing only by the amino acid at position 107 of the α2 domain of the heavy chain (Arg/Gly), distinguishing it from its highly polymorphic classical MHC class 1a counterparts [6,7]. It binds naturally to self-peptides derived mainly from the signal sequences of MHC-1a molecules, but in times of cellular stress, may also bind to a much wider array of peptides, self or foreign in origin, including those from infecting agents [6 -9].
Additionally, HLA-E variants were found to be associated with susceptibility to HIV-1 acquisition [13].
HLA-E is known for its inhibitory effect on the based on their immune tolerogenic properties [3,4].  [19], and in addition, administering live recombinant cytomegaloviruses that can persist and replicate indefinitely raises safety concerns especially in immunocompromized individuals [23]. Secondly, the method of bacterial adjuvants could not be replicated in other subspecies of rhesus macaques except those of Chinese-origin [24], so there is no guarantee that it will work in humans. By contrast, TCV has already been tested in clinical trials and was shown to be safe and effective [25].
TCV as originally conceived was meant as a treatment for autoimmunity, by vaccinating individuals with autologous pathogenic autoimmune-causing T cells in the hope that their immune systems will be primed to recognize and respond to autoimmune T cell receptor (TCR) epitopes presented on HLA molecules [26]. The vaccine T cells have to be activated beforehand to provide necessary accessory signals to the immune system, and in cases where the vaccinating dose exceeds that required to adoptively transfer autoimmunity, the cells must be attenuated first by irradiation or hydrostatic pressure [26]. Other work revealed that TCV raises CD8+ T cells which recognize the TCR Vβ fragments of autoimmune cells in a Qa-1-restricted fashion [27]. That line of work eventually led Panoutsakopoulou et al to suggest that it might be possible to use '"universal" HLA-E+ cell lines pulsed with target peptides as a potentially convenient and effective approach to immunosuppressive cellular therapy' [28].
Given that HIV-1-derived peptides bearing HLA-E-binding motifs have been discovered [11,14], it might already be possible to do just that.
However I would like to propose a variant method that bypasses the need to identify and select the exact peptides to pulse CD4+ T cells with.
Examining the data of [3] closely, in particular Figure 2C of that article , one cannot escape the conclusion that

inactivated-SIV 'infection' of quiescent CD4+ T cells was
low, about 5% in [3], it can be increased through techniques like spinoculation [32]. This method of 'infecting' quiescent CD4+ T cells with free virus particles do not lead to infected-cell pyroptosis [33].
Elevating the population of HLA-E-restricted As mentioned, TCV may also induce immune responses towards self-peptides such as Hsp, which may be restricted by HLA-E and/or other HLA receptors of classes I and II [8,37]. These responses fall within the categories of anti-ergotypic and anti-'cell stress' immunity [9,37]. While not specific towards HIV-1 epitopes per se, they are interesting in my opinion because activated CD4+ T lymphocytes are the main cell type supporting productive HIV-1 replication in vivo, especially during the chronic phase of infection [33,38], and all infected cells do upregulate 'stress molecules' complexed to HLA-E on their surfaces [9]. Targeting