Lytic Granule Loading of CD8+ T Cells Is Required for HIV-Infected Cell Elimination Associated with Immune Control

Abstract

SUMMARY Virus-specific CD8+ T cells probably mediate control over HIV replication in rare individuals, termed long-term nonprogressors (LTNPs) or elite controllers. Despite extensive investigation, the mechanisms responsible for this control remain incompletely understood. We observed that HIV-specific CD8+ T cells of LTNPs persisted at higher frequencies than those of treated progressors with equally low amounts of HIV. Measured on a per-cell basis, HIV-specific CD8+ T cells of LTNPs efficiently eliminated primary autologous HIV-infected CD4+ T cells. This function required lytic granule loading of effectors and delivery of granzyme B to target cells. Defective cytotoxicity of progressor effectors could be restored after treatment with phorbol ester and calcium ionophore. These results establish an effector function and mechanism that clearly segregate with immunologic control of HIV. They also demonstrate that lytic granule contents of memory cells are a critical determinant of cytotoxicity that must be induced for maximal per-cell killing capacity.

Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8 + T cells and reduces chronic retroviral set points

“…By 1 wk following Treg depletion, significantly more activated CD8 + T cells from lymph nodes and spleen expressed granzyme B (Fig. 2C), a cytotoxic molecule known to be important in immune control of both FV (20) and HIV (21). This was also found for the subset of tetramer-positive CD8 + T cells recognizing the immunodominant FV epitope (Fig.…”

Correlating cellular and molecular signatures of mucosal immunity that distinguish HIV controllers from noncontrollers

“…45 Although not confirmed by real-time PCR, TAP1 was also up-regulated in the noncontrollers in the array analysis. Surprisingly, although having a more potent granzyme B-mediated cytolytic CD8 ϩ T-cell activity against HIV-infected CD4 ϩ T cells is thought to be a feature of viral controllers, 8 expression levels of granzyme K were significantly higher in the noncontrollers. In aggregate, these results suggest that, even though HIV-specific CTL activity may be enhanced in viral controllers, 8 the mucosal microenvironment of noncontrollers displays broad activation of host antiviral mechanisms.…”

“…Recent reports have shown that these persons (1) have a higher frequency of polyfunctional HIV-specific CD4 ϩ and CD8 ϩ T-cell responses in the peripheral blood and in gut-associated mucosal lymphoid tissues (GALT), [5][6][7] (2) present highly potent granzyme B-mediated cytolytic CD8 ϩ T-cell activity against HIV-infected CD4 ϩ T cells, 8 (3) display decreased expression of immunoregulatory receptors that negatively impact upon CD4 ϩ T-cell function, 9 (4) are enriched for protective class HLA haplotypes, 6,10 and/or (5) harbor HIV virions with reduced fitness. 11 There is, however, no individual factor that appears to be common to all controllers.…”

HIV Protective KIR3DL1 and HLA-B Genotypes Influence NK Cell Function Following Stimulation with HLA-Devoid Cells

“…However, the cytokine secretion and cytolytic functions are not exclusive to either cell subset (19)(20)(21). IFN-g and TNF-a secretion as well as cytolysis have documented antiviral activity and are functions attributable to both NK and CD8 + T cells (18,(22)(23)(24)(25)(26)(27). In HIV infection, where there is evidence that CD8 + T cells play a role in controlling virus, it is not so much the frequency or breadth of epitope recognition by these T cells, but rather the functional quality of their anti-HIV responses that correlates best with VL control (28,29).…”