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.
aDepartement of Medicine and Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), University of Montreal, Montréal, Quebec, Canada
bUniversity of Colorado, Research Complex 2, room 10007 (B164), 12700 E 19th Ave, Aurora, Colorado 80045 USA.
cThe Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
Correspondence to Daniel E. Kaufmann, MD, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), 900, St-Denis Street, Room 09–418, Montreal, QC H2X 0A9, Canada. Tel: +1 514 890 8000 x35261; fax: +1 514 412 7377; e-mail: firstname.lastname@example.org, Brent E. Palmer, PhD, University of Colorado, Research Complex 2, room 10007 (B164), 12700 E 19th Ave, Aurora, Colorado 80045 USA. Tel: +1 303 724 7203; fax +1 303 724 7217; e-mail: email@example.com