Programming T cell Killers for an HIV Cure: Teach the New Dogs New Tricks and Let the Sleeping Dogs Lie

Abstract

Despite the success of combination antiretroviral therapy (cART), a latent viral reservoir persists in HIV-1-infected persons. Unfortunately, endogenous cytotoxic T lymphocytes (CTLs) are unable to control viral rebound when patients are removed from cART. A “kick and kill” strategy has been proposed to eradicate this reservoir, whereby infected T cells are induced to express viral proteins via latency-inducing drugs followed by their elimination by CTLs. It has yet to be determined if stimulation of existing HIV-1-specific CTL will be sufficient, or if new CTLs should be primed from naïve T cells. In this review, we propose that dendritic cells (DCs), the most potent antigen presenting cells, act as dog trainers and can induce T cells (the dogs) to do magnificent tricks. We propose the hypothesis that an HIV-1 cure will require targeting of naïve T cells and will necessitate “teaching new dogs new tricks” while avoiding activation of potentially dysfunctional endogenous memory CTLs (letting the sleeping dogs lie).

So Pathogenic or So What?—A Brief Overview of SIV Pathogenesis with an Emphasis on Cure Research

“…Although they are not the primary reservoir for HIV/SIV, the interaction between CTLs and infected macrophages yields a new dilemma: the extended formation of the synapse induces further secretion of IFN-γ and other pro-inflammatory cytokines [737], thereby potentially increasing the chronic inflammation during HIV infection. Similarities to this are seen in dendritic cell: T cell interactions [738], and the priming of naïve CD8 + T cells is demonstrated to alleviate the lack of killing [739,740]. 6.12.3.…”

Dendritic Cells Focus CTL Responses Toward Highly Conserved and Topologically Important HIV Epitopes

“…We hypothesize that the DC used in HIV-1 immunotherapy trials to date have not been adequately equipped with the characteristics needed to specifically direct and support effective type 1-biased cellular immune responses that are required to successfully combat cancers and intracellular infections such as HIV-1 [6,[14][15][16][17]. In fact, the methods commonly used to generate mature DC for immunotherapies, including the use of maturation factors such as prostaglandin E2 (PGE2) and CD40L, typically give rise to mature DC that quickly become deficient in their capacity to produce IL-12p70 [18], a critical Th1 and CTL driving factor [19].…”

Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes

“…We hypothesize that the DC used in HIV-1 immunotherapy trials to date have not been adequately equipped with the characteristics needed to specifically direct and support effective type 1-biased cellular immune responses that are required to successfully combat cancers and intracellular infections such as HIV-1 [ 6 , [14] , [15] , [16] , [17] ]. In fact, the methods commonly used to generate mature DC for immunotherapies, including the use of maturation factors such as prostaglandin E2 (PGE2) and CD40L, typically give rise to mature DC that quickly become deficient in their capacity to produce IL-12p70 [18] , a critical Th1 and CTL driving factor [19] .…”