HIV-1 Tat induced immune responses and its effect on opportunistic infections

Acquired immunodeficiency syndrome (AIDS) is a major problem in our current society. There are over 35 million of the population that are currently living with human immunodeficiency virus (HIV), and the number of HIV-infected patients are still rising every year in spite of our efforts to control it. Furthermore, within the AIDS affected population, opportunistic infection is a major cause of complications and is the number one cause of death. The HIV trans-activator (Tat) protein plays a major role in the AIDS pathogenesis. HIV-1 Tat is known to cause dysregulation of cytokines such as TNF-α, IL-6, and IL-10 in AIDS patients. In this study we recognized a proto-oncogene, c-Myc, could regulate the cytokine dysregulation caused by HIV-1 Tat in primary blood monocyte derived macrophages (PBMac). By knocking down the expression of c-Myc with gene specific small-interfering RNA (siRNA), we demonstrated that c-Myc may be critical for the expression of the pro-inflammatory cytokines TNF-α and IL-6. HIV-1 Tat was subsequently found to regulate the expression of c-Myc via the activation of dsRNA-activated protein kinase (PKR), ERK1/2 and p38 mitogen-activated protein kinase (MAPK). Furthermore, c-Myc regulation of the pro-inflammatory cytokines was demonstrated to have a role in AIDS related opportunistic infections. HIV-1 Tat was shown to increase the intracellular growth of Mycobacteria avium complex (MAC) within PBMac. This increase in MAC growth was in turn found to be regulated by TNF-α expression controlled by c-Myc. HIV-1 Tat was also demonstrated to induce the expression of RIG-I, a common pattern recognition receptor of double stranded RNA viruses, in PBMac. RIG-I is known to activate the viral immune responses such as the type-I interferon (IFN) and pro-inflammatory cytokine pathways. This induction of RIG-I by HIV-1 Tat was found to be regulated by c-Myc, as well as through other signalling kinases such as p38 MAPK and PKR. Tat induction of RIG-I ultimately led to the induction of IFN-α2 and IFN-β through the expression and nuclear translocation of the interferon regulatory factor-7 (IRF-7). This alteration in type-I IFN expression regulated by HIV-1 Tat and RIG-I was also found to play a role against AIDS related opportunistic infections. HIV-1 Tat is known to increase the infectivity of Kaposi’s sarcoma-related herpesvirus (KSHV), a common opportunistic viral infection. We were able to demonstrate that this increase in KSHV infectivity was regulated by RIG-I and type-I IFN induced by HIV-1 Tat. Lastly, this study also demonstrated how HIV-1 Tat was able to manipulate the expression of IL-8 induced by KSHV in PBMac. HIV-1 Tat was able to mediate the production of IL-8 induced by KSHV by altering the phosphorylation of the p38 MAPK and the signal transducer and activator of transcription-1 (STAT-1). Taken together, the results of this study showed how c-Myc and RIG-I may be able to play critical roles in HIV-1 Tat induced cytokine dysregulation. Furthermore, the importance of these pathways is further demonstrated in their roles in regulating the immune responses against opportunistic infections in AIDS patients.published_or_final_versionPaediatrics and Adolescent MedicineDoctoralDoctor of Philosoph