Short Communication: HIV Antigen-Specific Reactivation of HIV Infection from Cellular Reservoirs: Implications in the Settings of Therapeutic Vaccinations

Abstract

Therapeutic vaccinations using human immunodeficiency virus (HIV) antigens in HIV-infected patients on antiretroviral therapy (ART) have so far been attempted with the purpose of inducing CTL response. However, they can also be useful as a strategy for activation of latent HIV reservoir, which is thought to be mainly comprised of latently infected HIV-specific memory CD4 cells, eventually leading to elimination of the virus. The present study was carried out to explore the ability of different HIV antigens to activate HIV replication as assessed by intracellular P24 detection as well as to induce T cell responses in terms of cytokine expression by flow cytometry after stimulation of PBMCs from HIV-infected patients. HIV antigens were found to be able to activate most of the CD4 T cells harboring proviral DNA. HIV-1 Pol and Env were responsible for induction of higher HIV replication in terms of both magnitude and frequency followed by Gag and Nef. As opposed to this, Pol and Env contributed to fewer numbers of polyfunctional CD8 cells desirable for elimination of HIV-infected cells in comparison to Gag and Nef. Thus, HIV antigens may provide a strategy for the activation of a latent reservoir. It was observed that HIV replication started as early as half an hour after in vitro activation indicating a stringent need for maintaining effective concentrations of antiretroviral drugs to prevent further spread of HIV during this process. HIV-infected cells were found to be responsible for higher IL-10 secretion after activation, which could also serve as one of the reasons for suppressed CD8 responses to Pol and Env as more HIV-infected CD4 cells would be secreting IL-10 in response to these antigens. Since IL-10 blockade helped to improve immune responses in terms of cytokine secretion, it should be considered in settings of therapeutic vaccination to improve CTL responses, which will ultimately limit the persistence of the viral reservoir.

Peripheral T Follicular Helper Cells Are the Major HIV Reservoir within Central Memory CD4 T Cells in Peripheral Blood from Chronically HIV-Infected Individuals on Combination Antiretroviral Therapy

“…To obtain further proof for the role of pTfh cells as potential HIV reservoirs, we assessed whether HIV gag protein could be expressed in CD8-depleted PBMC with anti-CD3/anti-CD28 stimulation as a potential measure of inducible virus in patient cells (35,36,51). Using this assay, we could clearly identify PD1 ϩ pTfh cells as the subset with the highest frequencies of HIV p24 protein before cART that underwent substantial reduction at 48 weeks on cART.…”

Immune interventions in HIV infection

“…Anti-HIV reimmunization by itself might also reactivate the immune cells harboring the latent HIV reservoirs. Indeed, some HIV-1 antigens can activate most of the CD4 + T cells harboring proviral DNA and induce HIV replication (159). Therefore, the therapeutic vaccines might also fit with a shock and kill strategy and impact HIV transcription in tissue reservoirs.…”

CD56−CD16+ NK cells from HIV-infected individuals negatively regulate IFN-γ production by autologous CD8+ T cells

“…In addition, when TGF‐β binds to its receptor, FOXO3A‐SOCS3 signaling is activated; SOCS3 is an inhibitor of IFN‐γ signaling that can inhibit IFN‐γ production . Further, HIV‐1 Tat protein induces IL‐10 production by PBMCs, and Tat can also enhance TGF‐β secretion by NK cells. In addition, the percentage of CD56 − CD16 + NK cells in ART‐treated individuals was significantly decreased compared to untreated HIV‐infected individuals.…”