Studies in animal models and data in humans show that CD4 help in vivo
is critical for the persistence of effective, long lasting CTL and B cell responses [42
] and for mobilizing CTLs to infected mucosa [43
]. Through secretion of multiple cytokines, CD4 T cells also modulate functions of APCs and of cells that contribute to innate immunity, including monocytes/macrophages and NK cells. Whereas CD8 T cells recognize epitopes associated with MHC Class I, the TCR of CD4 T cells recognize epitopes associated with MHC Class II. Depending on the context of T cell activation, undifferentiated interleukin-2 (IL-2)-secreting CD4 T cells can differentiate into several subsets of CD4 T cells, which secrete different cytokines and mediate different functions. Th1 lymphocytes predominantly produce interferon-γ (IFN-γ) and tumor necrosis factor α (TNF-α) and preferentially activate cell-mediated responses; Th2 lymphocytes, which predominantly secrete interleukin-4 (IL-4), IL-5, and IL13, induce humoral responses whereas Th17 lymphocytes, which secrete IL-17, stimulate inflammatory responses with antibacterial and antifungal functions in many organs and tissues [44
]. More recently, another subset, called T follicular helper cells, which produce IL-21, has been identified. It is thought to play an important role for help to maturing B cells and CD8 T cells [45
]. CD4 T cells are the primary targets of HIV infection, and the dysfunction of this compartment is critical for HIV pathogenesis. Studies suggest that both the CD4 T cell subset as a whole and the HIV-specific CD4 T cell subset can present distinctive features in HIV controllers that play a causal role in their phenotype.
CD4 T cell lymphopenia, a hallmark of HIV infection, is due to combined effects of destruction of HIV-infected cells, increased cell death of uninfected CD4 T cells, and impaired renewal [46
]. The persistence of functional memory T cells represents the basis for a long-lasting protection after exposure to pathogens [11
]. A better preservation of the central memory (TCM
) CD4 T cell compartment was observed in HIV controllers than in individuals with untreated progressive HIV disease and subjects with controller viral load on therapy [47
of HIV controllers also showed a higher expression of the IL-7 receptor and of CCR7, which suggests differences in TCM
homing patterns [47
Reduced IL-2 production and a lack of response to this cytokine critically contribute to the anergy that is one of the first signs of the immune deficiency that precedes CD4 lymphopenia in HIV-infected patients [50
]. Furthermore, progressive HIV infection is associated with a decrease in responsiveness to IL-7 [53
], a cytokine that is crucial to the central production of CD4 lymphocytes and to their peripheral homeostasis (reviewed in [57
]). Interestingly, it has recently been shown that collagen deposition in lymphoid tissue restricted T cell access to IL-7 on the fibroblastic reticular cell network, resulting in apoptosis and depletion of T cells [58
]. Results from two clinical trials of IL-7 administration in ART-treated subjects gave promising results in terms of reconstitution of CD4 T cell subsets [59
]. Whether adjuvant therapy with cytokines like IL-7 could further functionally restore the immune system of HIV-infected subjects with progressive infection, in particular in individuals with persistently low CD4 T cell count in spite of viral control on therapy, and lead to an “HIV controller-like” status”, remains to be tested. Furthermore, although IL-7 has been recently shown to play an important role in viral control in the murine LCMV model of viral infection [61
], the direct role of IL-7 in viral suppression in HIV controllers remains to be determined.
Although the preferential infection of HIV-specific CD4 T cells raised the concern that this subset might fuel viral replication rather than contribute to its control [62
], this relative increase is small and the large majority of HIV-specific CD4 T cells are not infected in vivo
, even in the presence of high viral loads [62
]. It is thus likely that vaccine-induced HIV-specific CD4 T cells would significantly contribute to effective immune responses against HIV (reviewed in [63
]). As a cohort, HIV-specific CD4 T cells controllers have significantly more robust, polyfunctional HIV-specific CD4 T cells capable of secreting multiple cytokines (e.g, IFN-γ and IL-2) than subjects with progressive infection [24
]. The magnitude of HIV-specific CD4 T cell responses in controllers is stronger than in people with controlled viral load on ART [47
]. The maintenance of virus–specific CD4 T cell responses in HIV controllers suggests a more functional, long-lived memory T cell population and/or a better capacity to respond to limited antigen amounts. The importance of the cytokine IL-21 in mediating CD4 help to both CD8 T cells and B cells has been highlighted by a number of recent studies in both murine models and humans (reviewed in [66
]). IL-21 is primarily produced by subsets of activated CD4 T cells, including T follicular helper cells (TFH). Studies in the murine LCMV model demonstrated that IL-21 produced by virus-specific CD4 T cells was critical in controlling chronic infection and in preventing exhaustion of CD8 T cells. In HIV infection, decreased levels of plasma IL-21 have been observed in chronic progressors, with a positive correlation of plasma IL-21 levels with CD4 counts[67
]. Only controllers maintained normal plasma levels of IL-21 compared with HIV negative subjects and ART only partially restored production of this cytokine[68
]. Other studies have found somewhat contradictory results. Yue et al
] showed that in progressors, higher frequencies of IL-21 producing CD4 T cells correlated with lower viral load but that control of viremia in controllers and ARTC-treated subjects was associated with low frequency of IL-21-secreting HIV-specific CD4 T cells. In contrast, Chevalier et al
], using a different technical approach, found higher levels of IL-21 secretion by HIV-specific CD4 T cells incontrollers than individuals on ART, with the lowest levels detected in chronic progressors. Examining mechanisms of T cell help, the authors found that IL-21 increased perforin, granzyme A and B, and the degranulation marker CD107 in HIV-specific CTL and that addition of IL-21 increased the capacity of CTLs to inhibit viral replication in vitro
. Another report compared IL-21 production by HIV-specific CD4 and CD8 T cells[71
]. Both subsets were able to produce IL-21 in response to HIV-1 infection, with IL21+ CD8 T cells more closely associated with viral control. Furthermore, IL-21-producing HIV-1-specific CD4 T cells (compared to those producing other cytokines) were the best indicator of functional CD8 T cells. These data suggest that HIV-specific IL-21+ T cells contribute to the control of viral replication in controllers and may be important for an effective vaccine.
Focusing on immunodominant HIV CD4 epitopes, growth kinetics and avidity for antigen of HIV-specific CD4 T cell lines derived from PBMC of HIV controllers and progressors was examined [72
]. HIV-specific CD4 T cells from HIV controllers divided more rapidly than comparable lines from viremic patients or patients receiving effective antiviral treatment. This study also identified a subpopulation of HIV-specific CD4 T cells in HIV Controllers endowed with a higher functional avidity compared to non-controllers. Assessing differences for a Gag epitope previously shown to be immunodominant for HIV-specific CD4 T cell responses [73
], a higher TCR binding avidity to the HLA class II-peptide complex was also demonstrated in controllers. This capacity to respond to minimal amounts of HIV antigen may contribute to the higher magnitudes of HIV-specific CD4 T cell responses in controllers compared to ART-treated subjects. The high TCR avidity may also facilitate the rapid induction of recall responses upon transient increases in HIV replication (“viral blips”), and may thus limit the cumulative damage inflicted by HIV on the immune system. Whether HIV-specific CD4 T cells can also have significant antiviral effects in vivo remain to be determined.
In the setting of HIV infection and other chronic infections, T cell exhaustion, defined as the progressive loss of functions in antigen-specific T cells leading to ineffective T-cell responses, is thought to play an important role in the lack of pathogen clearance. Various inhibitory molecules have been shown to contribute to this exhaustion and to mediate an active suppression of HIV-specific CD4 T cell responses. Identified molecules include PD-1 [74
] and IL-10 [77
] (reviewed in [78
]). These pathways have been shown to be less active in HIV controllers than in progressors, suggesting that these cells are not exhausted. One of these molecules, CTLA-4, has been shown to be significantly less expressed by HIV-specific CD4 T cells of elite controllers compared to those of subjects with treated or untreated progressive disease [6
]. Clinical trials to assess the impact of blockade of the PD-1 pathway with a blocking antibody in ART-treated patients are currently under consideration.
In contrast to the robust HLA Class I data, the association between specific HLA Class II alleles and HIV controller status has been less clearly demonstrated. Higher prevalences of HLA-DRB*13 [80
], have been reported in some cohorts, though such associations remain to be confirmed in larger studies. A recent investigation of individuals chronically infected by HIV-1 Clade B and C strains showed an association of DRB1*1303 with lower viral loads [82
], but a recent large GWAS study did not find class II association reaching genome-wide significance [7
]. However, as the same epitopes can frequently be presented by multiple HLA alleles (so-called “promiscuous” epitopes), such a lack of genetic association should not be retained as an argument against the importance of virus-specific CD4 T cell responses in HIV control.