Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies

Abstract

Cytolytic CD8 T cells play a crucial role in the control and elimination of virus-infected cells and are a major focus of HIV cure efforts. However, it has been shown that HIV-specific CD8 T cells are infrequently found within germinal centers (GCs), a predominant site of active and latent HIV infection. We demonstrate that HIV infection induces marked changes in the phenotype, frequency, and localization of CD8 T cells within the lymph node (LN). Significantly increased frequencies of CD8 T cells in the B cell follicles and GCs were found in LNs from treated and untreated HIV-infected individuals. This profile was associated with persistent local immune activation but did not appear to be directly related to local viral replication. Follicular CD8 (fCD8) T cells, despite compromised cytokine polyfunctionality, showed good cytolytic potential characterized by high ex vivo expression of granzyme B and perforin. We used an anti-HIV/anti-CD3 bispecific antibody in a redirected killing assay and found that fCD8 T cells had better killing activity than did non-fCD8 T cells. Our results indicate that CD8 T cells with potent cytolytic activity are recruited to GCs during HIV infection and, if appropriately redirected to kill HIV-infected cells, could be an effective component of an HIV cure strategy.

Targeting the Latent Reservoir for HIV-1

“…These engineered constructs contain a broadly neutralizing antibody to HIV-1 Env linked to a monoclonal antibody to CD3. DARTS can mediate in vitro lysis of infected cells that are cultured with autologous CD8 + T cells (Sloan et al 2015; Petrovas et al 2017). Ex-vivo studies have also shown that DARTs can reduce viral outgrowth from the latent reservoir (Sung et al 2015b; Sung et al 2017).…”

“…However, even in the setting of minimal to absent persistent antigen, such as in individuals on suppressive cART, effector functions may not be completely restored. In the lymph node, for example, non-follicular and follicular CD8 + T cells express high levels of PD-1 and TIGIT, and blocking the PD-1/PDL-1 axis in vitro restores HIV-1-specific CD8 + T cell function in these cells (Petrovas et al 2017). Intriguingly, certain IC markers are also present on specific memory CD4 + T cells and are associated with higher HIV-1 DNA content, suggesting that these ICs somehow promote latency in these subsets (Chomont et al, 2009; Fromentin et al, 2016).…”

“…Fewer terminally differentiated effector CD8 + T cells are present in the lymph nodes of HIV + individuals than in their blood (Reuter et al 2017). Moreover, lymph node CTLs have a limited ability to kill targets and express lower levels of perforin, an essential mediator of cytolysis (Petrovas et al 2017; Reuter et al 2017). Similar findings have been obtained from studies on the human gastrointestinal mucosa of HIV + individuals (Kiniry et al 2017).…”

Human Immunodeficiency Virus Playing Hide-and-Seek: Understanding the TFH Cell Reservoir and Proposing Strategies to Overcome the Follicle Sanctuary

“…In these studies, CXCR5 + CD8 + T cells from SIV-infected macaques (131) and HIV-infected patients (128) were found to eliminate virus-infected T FH cells when cocultured in vitro . Moreover, the anti-HIV activity of CXCR5 + CD8 + T cells from HIV-infected patients was significantly enhanced by a bispecific antibody (128).…”

Protective role of follicular CXCR5+CD8+ T cells against dengue virus 2 infection

“…At present, the expression of PD-1 on CXCR5 + CD8 + T cells during viral infections remains controversial. Some studies (Im et al, 2016;Petrovas et al, 2017) reported high PD-1 expression on CXCR5 + CD8 + T cells compared to CXCR5-CD8 + T cells during chronic viral infections, whereas He et al (He et al, 2016) reported that CXCR5-CD8 + T cells expressed significantly lower levels of inhibitory molecules Tim-3 and PD-1 but higher levels of proinflammatory cytokines TNF-α and IFN-g.…”