Killing of Latently HIV-Infected CD4 T Cells by Autologous CD8 T Cells Is Modulated by Nef

Abstract

The role of HIV-specific CD8 T cell activity in the course of HIV infection and the way it affects the virus that resides in the latent reservoir resting memory cells is debated. The PBMC of HIV-infected patients contain HIV-specific CD8 T cells and their potential targets, CD4 T cells latently infected by HIV. CD4 T cells and CD8 T cells procured from PBMC of HIV-infected patients were co-incubated and analyzed: Formation of CD8 T cells and HIV-infected CD4 T cell conjugates and apoptosis of these CD4 T cells were observed by fluorescence microscopy with in situ PCR of HIV LTR DNA. Furthermore, conjugation of CD8 T cells with CD4 T cells and apoptosis of CD4 T cells was observed and quantified by imaging flow cytometry using anti-human activated caspase 3 antibody and TUNEL assay. The conjugation activity and apoptosis were found to be much higher in patients with acute HIV infection or AIDS compared to patients in chronic infection on antiretroviral therapy (ART) or not. Patients on ART had low grade conjugation and apoptosis of isolated CD69, CD25, and HLA-DR-negative CD4 T cells (latent reservoir cells) by CD8 T cells. Using in situ PCR The latent reservoir CD4 T cells were shown to contain most of the HIV DNA. We demonstrate in HIV-infected patients, that CD8 T cells conjugate with and kill HIV-infected CD4 T cells, including HIV-infected resting memory CD4 T cells, throughout the course of HIV infection. We propose that in HIV-infected patients CD4 T cell annihilation is caused in part by ongoing activity of HIV-specific CD8 T cells. HIV Nef protein interacts with ASK 1 and inhibits its pro-apoptotic death signaling by Fas/FasL, thus protecting HIV-infected cells from CD8 T cells killing. A peptide that interrupts Nef-ASK1 interaction that had been delivered into CD4 T cells procured from patients on ART resulted in the increase of their apoptosis inflicted by autologous CD8 T cells. We suggest that elimination of the HIV-infected latent reservoir CD4 T cells can be achieved by Nef inhibition.

Longitudinal study reveals HIV-1–infected CD4+ T cell dynamics during long-term antiretroviral therapy

“…The HIV-1 proviral landscape does not change dramatically over time on ART. Activated CD4 + T cells harboring intact proviruses and certain types of defective proviruses may be subject to negative selection by HIV-1-specific CTLs in people on suppressive ART (17,27,28,34,54,55). If selection operates on cells comprising the latent reservoir, perhaps during transient periods of cellular activation, a decreased proportion of intact proviruses might be observed over time, while proviruses with very large deletions encompassing many ORFs might increase in proportion.…”

The protective and pathogenic roles of IL-17 in viral infections: friend or foe?

“…CD8 + cytotoxic T cells are pivotal components of antiviral immunity and play a crucial role in mediating virus clearance [4]. CD8 + T cells eliminate invading viruses via two primary mechanisms: direct cytotoxicity of infected cells and via production of multiple cytokines to induce local or systemic antiviral responses [25,26]. In scenarios such as tumour development [27], cigarette smoke-induced emphysema [28] and parasite infection [29], IL-17 has been shown to play a critical role in the activation and survival of cytotoxic CD8 + T cells.…”

Lymphopenia an important immunological abnormality in patients with COVID‐19: Possible mechanisms

“…Among immune cells, T lymphocytes perform a principal role in viral infections. The CD4 + T lymphocytes provide help for B cells to produce anti‐viral antibody, whereas CD8 + T lymphocytes and natural killer (NK) cells kill virus‐infected cells to decrease viral load 6–8 . The quantitative and functional disorders of lymphocytes can impair the immune responses against viruses and may lead to the development of immunopathologic responses 9–11 …”