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The presence of persistent, latent HIV reservoirs in [CD4.sup.+] T cells obstructs current efforts to cure infection. The so-called kick-and-kill paradigm proposes to purge these reservoirs by combining latency-reversing agents with immune effectors such as cytotoxic T lymphocytes. Support for this approach is largely based on success in latency models, which do not fully reflect the makeup of latent reservoirs in individuals on long-term antiretroviral therapy (ART). Recent studies have shown that [CD8.sup.+] T cells have the potential to recognize defective proviruses, which comprise the vast majority of all infected cells, and that the proviral landscape can be shaped over time due to in vivo clonal expansion of infected [CD4.sup.+] T cells. Here, we have shown that treating [CD4.sup.+] T cells from ART-treated individuals with combinations of potent latency-reversing agents and autologous [CD8.sup.+] T cells consistently reduced cell-associated HIV DNA, but failed to deplete replication-competent virus. These [CD8.sup.+] T cells recognized and potently eliminated [CD4.sup.+] T cells that were newly infected with autologous reservoir virus, ruling out a role for both immune escape and [CD8.sup.+] T cell dysfunction. Thus, our results suggest that cells harboring replication-competent HIV possess an inherent resistance to [CD8.sup.+] T cells that may need to be addressed to cure infection., Introduction Eradicating latent HIV reservoirs will require the elimination of persistent populations of cells with integrated HIV proviruses. The major barrier impeding viral eradication is thought to be a reservoir [...]

HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal. [ABSTRACT FROM AUTHOR]

Resting CD4+ T-cells harboring inducible HIV proviruses are a critical reservoir in antiretroviral therapy (ART)-treated subjects. These cells express little to no viral protein, and thus neither die by viral cytopathic effects, nor are efficiently cleared by immune effectors. Elimination of this reservoir is theoretically possible by combining latency-reversing agents (LRAs) with immune effectors, such as CD8+ T-cells. However, the relative efficacy of different LRAs in sensitizing latently-infected cells for recognition by HIV-specific CD8+ T-cells has not been determined. To address this, we developed an assay that utilizes HIV-specific CD8+ T-cell clones as biosensors for HIV antigen expression. By testing multiple CD8+ T-cell clones against a primary cell model of HIV latency, we identified several single agents that primed latently-infected cells for CD8+ T-cell recognition, including IL-2, IL-15, two IL-15 superagonists (IL-15SA and ALT-803), prostratin, and the TLR-2 ligand Pam3CSK4. In contrast, we did not observe CD8+ T-cell recognition of target cells following treatment with histone deacetylase inhibitors or with hexamethylene bisacetamide (HMBA). In further experiments we demonstrate that a clinically achievable concentration of the IL-15 superagonist ‘ALT-803’, an agent presently in clinical trials for solid and hematological tumors, primes the natural ex vivo reservoir for CD8+ T-cell recognition. Thus, our results establish a novel experimental approach for comparative evaluation of LRAs, and highlight ALT-803 as an LRA with the potential to synergize with CD8+ T-cells in HIV eradication strategies. [ABSTRACT FROM AUTHOR]

It is widely accepted that an effective HIV-1 preventative vaccine must elicit antibodies that can block virus acquisition. Although, anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been isolated, unfortunately, no vaccine immunogens have been designed that can elicit these bnAbs in uninfected at-risk individuals. Some studies have suggested that other antibody functionalities, besides neutralization, such as antibody-dependent cellular cytotoxicity (ADCC), may prevent HIV-1 acquisition. In contrast to bnAbs, ADCC-inducing antibodies may be more amenable to elicitation by current vaccine technologies. This review will provide clarity about the role of nAbs and ADCC-inducing antibodies in preventing transmission, highlight mechanisms that potentially explain how ADCC-mediating antibodies may work, and speculate about the generation of these novel protective antibodies. Anti-HIV-1 ADCC-inducing antibodies may provide a new avenue for developing an effective HIV-1 vaccine., Competing Interests: CONFLICT OF INTEREST STATEMENT No author has a commercial or other association that might pose a conflict of interest.