Lymph Node T Cell Dynamics and Novel Strategies for HIV Cure

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Background

HIV-1 was reported three decades ago and has killed over 20 million people worldwide. Currently an estimated 33 million people are infected with HIV. The development of highly active anti-retroviral therapy (HAART) has led to substantial advances in the clinical management of HIV infected individuals. HAART drugs can normally control HIV in chronically infected people, but they cannot completely eliminate the virus. This is because CD4+ T helper cells, harboring the virus, remain dormant reservoirs. These reservoirs are difficult to measure, and are present even in cases of HAART-treated HIV infected individuals in which there are no detectable levels of HIV in the blood. Moreover, the accessibility of HAART drugs to isolated areas such as follicles, is limited.

T follicular helper cells are a subset of memory CD4+ T cells that are localized in the B-cell follicles of secondary lymphoid tissues and provide help for B cells mediated by either cell-cell contact interactions (i.e. CD40-CD40L, ICOS-ICOSL) or soluble factors (i.e. IL-21, IL-4). Tfh–B cell interactions allow the production of high affinity, class-switched antibodies following natural infection or vaccination. Tfh cells are defined by their expression of high levels of the cell surface markers, program death-1 (PD-1) and chemokine receptor CXCR5, which enable these cells to migrate into B cell follicles, especially within germinal centers (GCs). Uncontrolled chronic HIV infection results in selective accumulation of GC-Tfh cells in the lymph nodes. These cells are highly permissive to HIV infection and produce higher levels of virus compared to other CD4 T cell subsets from tissues or in circulation. Importantly these Tfh cells represent a major viral reservoir of HIV infection since they carry higher levels of HIV DNA. Although ART therapy effectively reduces plasma viral RNA to undetectable levels, it does not necessarily reflect viral suppression in lymphoid tissues. Eradication of HIV is still unachievable due to low-level viral replication in sanctuary sites (GCs) and reactivation of virus from the latent HIV DNA reservoir.

Vaccine trials conducted so far have demonstrated that it is difficult to elicit high magnitude of HIV-specific broadly heterologous neutralizing antibodies in vaccinated individuals and their levels soon decline. These vaccines may also be important within the frame of a possible cure for HIV, to mobilize the immunological memory of a HIV infected individual to control HIV infection. Although T cells are known to fight chronic viral infections, the exact requirements for this process remain a mystery. Recognition of antigen epitopes expressed on virus infected cells can potentially lead to their killing by antigen specific cytotoxic CD8 T cells. Several studies have provided strong evidence for the importance of HIV-specific CTLs. Therefore, therapeutic strategies aiming to enforce the cytolytic arm of the immune responses could be critical for the elimination of virus to achieve functional cure.

Recently, studies have identified a population of CD8+ T cells that express the chemokine receptor CXCR5, enabling them to migrate into B cell follicles. These CXCR5+ CD8+ T cells (Tfc) are located in the secondary lymphoid system and rapidly expand to control chronic viral infection in particular HIV/SIV infection. These CXCR5+ CD8+ T cells are unique in their properties as these cells express the PD-1 inhibitory receptor, but also express several co-stimulatory molecules. These CXCR5+ CD8+ T cells are characterized by a unique gene signature that is related to that of Tfh cells, and display stem cell-like characteristics. Data obtained on CXCR5+ CD8+ T cells for HIV/SIV infections could lead to the generation of a marker for predicting functional CD8+ T cells and to evaluate the efficacy of interventions such as therapeutic strategies or vaccination (different dose, concentration of antigen, adjuvants). Considering the unique properties of CXCR5+ CD8 T cells during chronic infections, further investigations on these cells are vital.

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