In this issue of Blood, Jiang and colleagues describe the use of humanized rag2-/-γC-/- mice to demonstrate the preferential infection and depletion of Tregs during acute HIV-1 infection.
The role of regulatory T cells (Tregs), phenotypically defined as CD4+CD25+FoxP3+, has been the subject of intense investigation with regard to HIV-1 pathogenesis. Treg numbers have been variably reported to be increased, decreased, or unchanged during HIV-1 infection. Likewise, contradictory studies have concluded Tregs to be beneficial or detrimental to the host based on correlations between clinical status and Treg number. These discrepancies are most likely multifactorial.
First, the phenotypic definition of Tregs has differed among studies and suppressor function, the gold standard assay for Tregs, has often not been demonstrated. Furthermore, studies differ in the tissues evaluated and there may be important differences in Treg percentages between blood, lymph nodes, and mucosa-associated lymphoid tissues. Undoubtedly, whether patients are being treated with antiretroviral drugs is a confounding factor but perhaps the stage of disease is more important.1
It is becoming evident that whether Tregs are increased or decreased and whether that is good or bad for the host may depend on clinical stage. For instance, it could be envisioned that rapid induction of a Treg response during acute infection may blunt the antiviral immune response and permit persistent infection. On the other hand, increased Tregs during chronic infection may suppress the systemic inflammation associated with disease progression. Finally, the wild card is whether Tregs themselves are preferential targets of HIV-1 infection and a potential reservoir during chronic disease. Resolution of these questions will undoubtedly require numerous experimental approaches and systems, but in the present report, Jiang et al validate a valuable in vivo model system and begin to answer some of these critical questions.
The authors had previously reported that Tregs express the HIV-coreceptor CCR5 and are highly susceptible to HIV infection and replication.2,3 They also found that FoxP3 enhances gene expression from the HIV-1 long terminal repeat by specifically binding NF-κB.4 These observations were important but required corroboration in an in vivo model system. After demonstrating the presence of Tregs phenotypically and functionally in the lymphoid tissues and blood of humanized rag2-/-γC-/- mice, the authors used a highly pathogenic CCR5/CXCR4 dual tropic HIV-1 strain to infect the mice. Tregs were preferentially and productively infected by HIV-1 and were depleted. Based on increased levels of active caspase 3 in the Treg population, Jiang et al propose the depletion is due to infection-induced apoptosis.
In additional experiments, in vivo depletion of Tregs using an IL2-toxin fusion protein prior to HIV-1 infection resulted in lower levels of HIV-1 replication. These interesting results suggest that Tregs are primary target cells during acute infection and a major contributor to viral load. The effect of Treg infection and depletion on the establishment of antiviral responses remains to be investigated in detail. It is likely that this unique in vivo model system will prove to be a valuable tool for further investigation of the interaction between HIV-1 and Tregs.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
