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

Yew Ann Leong, Anurag Atnerkar, Di Yu, Yew Ann Leong, Anurag Atnerkar, Di Yu

Abstract

Human immunodeficiency virus (HIV) infects millions of people worldwide, and new cases continue to emerge. Once infected, the virus cannot be cleared by the immune system and causes acquired immunodeficiency syndrome. Combination antiretroviral therapeutic regimen effectively suppresses viral replication and halts disease progression. The treatment, however, does not eliminate the virus-infected cells, and interruption of treatment inevitably leads to viral rebound. The rebound virus originates from a group of virus-infected cells referred to as the cellular reservoir of HIV. Identifying and eliminating the HIV reservoir will prevent viral rebound and cure HIV infection. In this review, we focus on a recently discovered HIV reservoir in a subset of CD4+ T cells called the follicular helper T (TFH) cells. We describe the potential mechanisms for the emergence of reservoir in TFH cells, and the strategies to target and eliminate this viral reservoir.

Keywords: B cell follicle sanctuary; TFH reservoir; cytotoxic T lymphocytes; follicular helper T cells; human immunodeficiency virus reservoir.

Figures

Figure 1
Figure 1
Illustration of gating strategies for CD4+ T cells subsets and their relative viral reservoir among different studies. (A) Gating strategy and CD4+ T cells reservoir characteristic from the study by Buzon et al. (Left) Plots show the gating strategy used to isolate the different population of CD4+ T cells from peripheral blood mononuclear cell (PBMC) (sorted population indicated in red). Dotted line indicates the subgating of the different subsets. (Right) Level of integrated proviral DNA from the sorted CD4+ T cells subsets was determined by PCR after short-term or long-term combination antiretroviral therapeutic regimen (cART). (B) Gating strategy and CD4+ T cells reservoir characteristic from the study by Chomont et al. (Left) Plots show the gating strategy used to isolate the different population of CD4+ T cells from PBMC (sorted population indicated in red). Dotted line indicates the subgating of the different subsets. (Right) Level of integrated proviral DNA from the sorted CD4+ T cells subsets was determined by PCR. (C) Gating strategy and CD4+ T cells reservoir characteristic from the study by Banga et al. (Left) Plots show the gating strategy used to isolate the different population of CD4+ T cells from PBMC or lymph node (LN) tissues (sorted population indicated in red). Dotted line indicates the subgating of the different subsets. (Right) ELISA for viral antigen P24 was used to quantify the level of virus production from the sorted CD4+ T cells subsets after stimulation by anti-CD3/CD28 antibodies [quantitative viral outgrowth assay (QVOA)]. TN, naïve T cells; TTD, terminally differentiated T cells; TEM, effector memory T cells; DN, double-negative cells.
Figure 2
Figure 2
Mechanisms for the establishment of follicular T helper (TFH) cells as major human immunodeficiency virus (HIV) reservoir and proposed strategies to eliminate TFH reservoir. Green or blue arrows indicate pathways that are enhanced or inhibited, respectively, during the establishment of TFH reservoir. (1) Virus-immune complexes deposition on follicular dendritic cells (FDCs) via complement receptor type 2 (CR2) binding. Anti-CR2 can be used to displace virus-immune complexes. (2) Infection of TFH due to suboptimal antiretroviral drug penetration, which can be overcome by development of drugs with higher potency. (3) Increased integration of viral DNA in TFH cells. This can be overcome by inducing host restricting factors, such as SAMHD1, or treatment intensification with integrase inhibitor. (4) Reduced expression of viral genes, which can be overcome by latency reversal agent. (5) Long half-life and homeostatic renewal of latently infected TFH cells. Long-term survival can be inhibited by targeting specific pathways, such as modulation with cytokines and auranofin. (6) Reduced infiltration of CD8+ T lymphocytes (CTLs) into B cell follicles. Potency and follicular infiltration of CTLs can be boosted to control TFH infection. (7) Infection of non-TFH and differentiation of infected non-TFH to TFH. This can be blocked by preventing the differentiation of TFH cells.

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