Distinctive features of CD4+ T cell dysfunction in chronic viral infections

To describe recent advances in the understanding of virus-specific CD4 T cell dysfunction in chronic viral infections, with an emphasis on HIV disease. We highlight features that are distinctive for CD4 T cells, as opposed to their CD8 T cell counterparts.

CD4 T cell activation and differentiation are tightly controlled. Regulation of these processes depends on the context of initial encounter of the naïve CD4 T cell with the cognate antigen and on ongoing external cues to the antigen-experienced CD4 T cell, in particular the inflammatory environment, which is prominent in HIV infection. Virus-specific CD4 T cell dysfunction results from a combination of an exhaustion program and skewing in T helper lineage differentiation which impact function. The CD4 and CD8 T cell exhaustion programs present similarities and distinct features. The sets of inhibitory coreceptors expression differ, although programmed-death 1 (PD-1) and T cell immunoglobulin mucin-3 (Tim-3) are upregulated on both HIV-specific CD4 and CD8 T cells, cytotoxic T-lymphocyte antigen 4 (CTLA-4) is largely specific to CD4 T cells, whereas 2B4 and CD160 are biased toward CD8 T cells.

Understanding the molecular basis of HIV-specific CD4 T cell exhaustion and identifying key differences with CD8 T cell impairment will be critical to design effective therapeutic and preventive immunotherapies against HIV.