Complex regulation of immune responses to HIV and SIV

The function of regulatory T cells in infectious diseases is a hot topic at present. In retroviral infection, it is not clear whether regulatory T cells suppress appropriate immune responses, in which case the elimination of these cells might be beneficial, or whether they can have a protective role, in which case impaired generation of regulatory T cells would contribute to the aberrant T-cell activation that is a hallmark of HIV infection. Two recent studies emphasize the complexity of this issue in retroviral infections.

Reporting in The Journal of Immunology, Andersson and colleagues show that chronic infection with HIV can influence the tissue distribution of endogenous regulatory T (T_Reg) cells. The authors analysed the role of T_Reg cells in HIV infection by quantifying the lymphoid-tissue expression of three T_Reg-cell markers: CTLA4 (cytotoxic T-lymphocyte antigen 4), GITR (glucocorticoid-induced tumour-necrosis factor (TNF)-receptor-related protein) and the transcription factor FOXP3 (forkhead box P3). They found that, compared with patients who were treated with highly active antiretroviral therapy (HAART), patients in whom HIV was actively replicating had higher levels of these three T_Reg-cell markers in their lymphoid tissues. The authors suggest that T_Reg cells are recruited to lymphoid organs in which HIV is actively replicating and that these T_Reg cells could hamper the development of appropriate anti-HIV responses at these sites. This model indicates that elimination of T_Reg cells should be beneficial for the development of protective immune responses.

In another study, which was reported in The Journal of Clinical Investigation, Kornfeld and colleagues assessed the correlates of protection against simian immunodeficiency virus (SIV) infection of African green monkeys (using the isolate SIV_AGM). This SIV infection of a natural African host is non-pathogenic; only SIV infections of African primate species result in non-pathogenic infections, which is in contrast to infection of Asian macaques with SIV_MAC, even though the viral loads are similar in these systems. In this study, the authors focused on assessing the early stages of SIV_AGM infection in African green monkeys. They examined patterns of T-cell activation and cytokine profiles in various tissues during primary SIV_AGM infection. A transient increase in T-cell activation was detected but returned to a baseline level at ∼3 weeks after infection. In contrast to infection with HIV, there were no significant increases in the levels of the chemokines CC-chemokine ligand 3 (CCL3) and CCL4 or of the cytokine TNF. An early and strong induction of expression of transforming growth factor-β and FOXP3 was detected, and this correlated with an increase in the numbers of CD4⁺CD25⁺ and CD8⁺CD25⁺ T cells. Although functional studies are required to confirm the regulatory nature of these cells, the authors suggest that these results favour a protective role for regulatory T cells in controlling abnormal T-cell activation, which then leads to non-pathogenic infection. On the basis of this model, it might be possible to develop novel intervention strategies for the treatment of HIV infection.

Taken together, these studies, which investigated two different phases of retroviral infection, show the difficulties in identifying the correlates of protection against retroviral infection and in determining the role of regulatory T cells. It will be crucial to gain a better understanding of regulatory T-cell function at different stages of infection for the design of appropriate therapeutics.