CD26/DPPIV is a multifunctional protein ubiquitously expressed in both soluble and cell surface forms in various endothelial and epithelial cells including T-cells and exert it different functions depending on cell type and conditions it is expressed [20
]. It acts as a proteolytic enzyme, receptor and co-stimulatory protein and its substrates have been reported to be involved in various physiological process including immunomodulation and homeostasis. Dysregulation of CD26/DPPIV has been suggested to result in various pathophysiological process including rheumatoid arthritis, melanoma and Crohn's disease among others [20
]. Its association with Type 2 diabetes is however well confirmed with DPPIV inhibitors being used worldwide as approved regimens for anti-type 2 diabetes treatment [22
]. Our observation of high CD26/DPPIV expression, significant down expression of genes in the insulin signaling pathway and impaired fasting glucose state (IFG) implied an evolving type 2 diabetes condition among the HIV resistant commercial sex workers. The duration for evolution to full type 2 diabetes from an IFG state is however controversial. While some studies indicate that IFG conditions often lead to diabetes within 3 years, others have suggested a 50% risk over a ten year period [23
]. The Nairobi female sex worker cohort has been followed up biannually for periods longer than ten years, and though blood sugar analysis has not been a routine feature, cases of overt Type 2 diabetes has rarely been observed. We postulate that this population, despite its high CD26/DPPIV levels may not be at risk of developing type 2 diabetes. There will however be a need to incorporate type 2 diabetes evaluations in future follow-up to determine the validity of this assertion taking into account specific DPPIV enzyme activity which we did not evaluate in this study.
Although an association of high CD26/DPPIV expression with HIV resistance is well supported by our data at the gene, soluble protein and cell surface level, the mechanism by which it protects against HIV acquisition remains unclear. One possibility is the key role it plays in cleaving off dipeptides from amino termini containing proline or alanine moieties at the penultimate position [24
]. A number of chemokines have been shown to share this sequence at their termini including RANTES, an interleukin 8 superfamily chemokine has been shown to inhibit HIV infection by competing with the virus for its coreceptor CCR5. Previous data has shown that in contrast to intact RANTES, a DPPIV truncated RANTES inhibited in vitro HIV infection of mononuclear cells by M-tropic HIV strains fivefold efficiently [15
]. Similarly several workers have shown that HIV infected subjects have defective CD4+ T cells with a poor ability to recognize and respond to antigens [25
]. Antigen recognition is the preserve of CD4+ T-cells expressing CD26/DPPIV which proliferate in response to soluble antigens and activate MHC-restricted cytotoxic T cells resulting in annihilation of virally infected cells [20
]. This has been supported by findings that antigen response in HIV-1 infected individuals could be restored by addition of soluble CD26/DPPIV in vitro, suggesting an important role for CD26/DPPIV in HIV-specific immunity [28
The probable mechanism of CD26/DPPIV activity against HIV acquisition in the Nairobi cohort may however add a new dimension to the above observations. Our recent findings indicate a significantly lowered immune activation state among the HIV-R female sex workers as compared to HIV negative controls [13
]. This lowered activation state or immune quiescence has also been observed among HIV exposed seronegative partners of HIV infected spouses [7
] and HIV uninfected hemophiliacs transfused with HIV seropositive donor blood [30
]. The contribution of CD26/DPPIV to a lowered immune activation state among the HIV-R female sex workers is puzzling.
There is substantial evidence that CD26/DPPIV can act as the trigger to immune activation [31
]. This has been supported by studies showing that reversible DPPIV inhibitors suppress proliferation of human PBMCs s and enhance production of cytokines that inhibit antigen stimulation of T-cells [35
]. Our findings of high CD26/DPPIV expression in vivo
in an environment of lowered T-cell immune activity is hence intriguing. One possible explanation maybe due to the perturbations of the insulin signaling pathway in these women which induced the down expression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and other pro-inflammatory enhancers (calgranulin and ICOS). NF-κB is a protein complex that regulates the expression of a multitude of immune response genes including cytokines, chemokines, antigen presenting cells and adhesion receptors [36
]. In response to a variety of stimuli, including cytokines, viral and bacterial pathogens, a latent inactive NF-κB complex is activated in the cytoplasm through phosphorylation and translocates to the nucleus, where it stimulates transcription of genes. Activation of NFκB by the inflammatory cytokine alpha tumor necrosis factor (TNFα) has been shown to involve the phosphotidylinositol pathway together with its downstream targets-Akt, TSC1 and TSC2 through IRS 1 [37
]. Quantitative real time PCR confirmed low expression in IRS1, PI4K TSC and, NFκB among the HIV resistant female sex workers (Figure ). We hypothesize that in presence of high CD26/DPPIV, the reduced insulin signaling leads to a low activity of phosphatidylinositol cascade system which in turn resulted in a lower expression of TSC-2, a build-up of the MTORC1 and subsequent repression of NFκB. In-depth functional studies will be required to test this assertion. Our observations suggest that metabolic and signaling pathways that predispose to an impaired glucose fasting state and Type 2 diabetes may be new correlates of HIV resistance. In addition, it underscores the key role of a systems biology in discovery of novel candidate biological markers that may be crucial in the design of effective preventive strategies against HIV/AIDS.