Interactions of human immunodeficiency virus-1 and mycobacteria result in dysregulation of immune response and enhancement of mycobacterial growth

Abstract

Acquired Immunodeficiency Syndrome (AIDS) is the leading cause of death, threatening nearly 33 million people who are living with human immunodeficiency virus-1 (HIV-1) worldwide. HIV-1 cripples the immune defense by dysregulating various cytokines that causes the host to be more susceptible to opportunistic infections by pathogens such as mycobacteria. In response to infections, the host’s immunity releases cytokines to establish a strong immune network for pathogen eradication.

Previous research from our laboratory demonstrated that IL-10 is hyperinduced by viral infection. That means the immune defense is taken advantage of by the pathogen and turned into its own immunity evasion strategy. Here, the mechanism of IL-10 dysregulation was investigated to demonstrate how HIV-1 perturbs the immune response. I hypothesize that IL-10 interferes with the IFN-γ-induced cell surface molecule of major histocompatibility complex class II (MHC-II) in primary human blood macrophages. My data showed that the suppressive effect of IL-10 on IFN-γ-induced MHC-II surface expression was independent of both JAK2/STAT1 and NF-κB signaling pathways. Upon further investigation, IFN-γ-induced expression of cathepsin S protein, a protease which participates in antigen processing, was demonstrated to be inhibited by IL-10. Following knock-down of STAT3 with its specific siRNA, the expressions of IFN-γ-induced surface MHC-II antigens and cathepsin S levels were restored, even in the presence of IL-10. Thus, IL-10 exerts its immunosuppressive effects by its primary mediator STAT3 on MHC-II antigen presentation, which may occur via the inhibition of cathepsin S expression.

With the emergence of HIV-1 infection, the number of Tuberculosis (TB) cases has increased tremendously. The crisis of co-infection of HIV-1 and TB exacerbates the global and economic threat than ever. Thus, I hypothesize that HIV-1 may play a role in promoting the mycobacterial intracellular growth. My data showed that HIV-1 Tat enhanced M. avium intracellular growth in primary human blood macrophages, which was dependent on extracellular signal-regulated kinases 1 and 2 (ERK1/2), but not p38MAPK. Different cellular defense mechanisms were shown to be perturbed by HIV-1 Tat to enhance M. avium growth. The inhibitory effect of HIV-1 Tat on TNF-α is potentially beneficial to M. avium growth as TNF-α is known to elicit anti-mycobacterial responses. For example, the expression of TNF-α plays a role in inducing autophagy. My data has also demonstrated that HIV-1 Tat suppressed M. avium-induced LC3B and -activated vacuolar H+-ATPase (v-H+-ATPase) protein expression. This suppressive effect of HIV-1 Tat on these two cellular defense mechanisms was shown to be dependent on ERK1/2 signaling.

Taken together, HIV-1 induces IL-10 to exert immunosuppressive effect on perturbing antigen presentation via inhibition of cathepsin S expression. HIV-1 Tat in turn enhances mycobacterial growth, which was dependent on ERK1/2 signaling, by downregulating phagosome acidification and autophagy. These findings suggest that HIV hijacks different host defense mechanisms by promoting mycobacterial elimination and suppressing antigen presentation, which elicits adaptive immunity for further mycobacterial eradiation. This results in a permissive milieu for opportunistic infections.