T Cell Effector Responses in HIV-1 Cure Strategies

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Johns Hopkins University
HIV-1 is a virus that affects over 35 million individuals around the world, and yet despite present treatments, there remains a need for a cure. A current cure tactic widely researched is the “shock and kill” strategy, where cART-treated HIV-positive individuals would be given latency reactivating agents (LRAs) to induce HIV-1 production from latently-infected CD4+ T cells, allowing for the CD8+ T cell response to eliminate the latent reservoir. Here, I examined the capabilities of the CD8+ T cell response from HIV-positive individuals to eliminate macrophages, another cell type infected by HIV-1, and reactivated latently-infected primary CD4+ T cells, both reactivated with PMA and ionomycin and with LRAs. Both CD4+ and CD8+ T cells from elite suppressors, HIV-positive individuals with viral loads of less than 50 copies per milliliter of blood, were capable of suppressing virus production from HIV-infected monocyte-derived macrophages, with the CD8+ T cells actually killing the infected cells. As to the latently-infected CD4+ T cells, CD8+ T cells from chronic progressors were not consistently capable of eliminating the infected cells upon reactivation, although those from two of four viremic controllers were when PMA and ionomycin were used for stimulation. Treatment with LRAs such as bryostatin and romidepsin both alone and in combination significantly inhibited the CD8+ T cell response to HIV-1, with the mechanism for bryostatin inhibition being an increase in cell death, downregulation of CD3, and upregulation of exhaustion markers. Despite that the elite suppressor CD8+ T cell response was capable of inhibiting HIV-1 infection of macrophages and that the response of some viremic controllers and chronic progressors can do so for latently-infected CD4+ T cells, there remains a need for some sort of immunologic boost for the average individual with HIV-1 infection. Worse, some LRAs and combinations of LRAs decrease the ability of the CD8+ T cell response to eliminate infected CD4+ T cells. Therefore, any given LRA or combination of LRAs should be examined for their effects upon the adaptive immune response prior to use in clinical investigations of HIV-1 cure strategies.
HIV-1, T cell responses, HIV latency