The pathogenesis of HIV-1 infection reflects the dynamic interaction between the virus and the host. Viral replication that accounts for many aspects of viral pathogenesis generally mirrors a balance between stimulatory and inhibitory host factors, which include endogenous cytokines and chemokines. HIV-1 infection itself may further modulate this balance. The long-term goal of this project is to characterize the interactions between the virus and endogenous chemokines and the impact of this interactive network on HIV-1 pathogenesis. Several members of the chemokine family possess a potential anti-HIV-1 activity, while others stimulate HIV-1 infection. Our data show that the TH2 chemokine, CCL18 is significantly increased in HIV-1- infected patients and selectively enhances replication of X4 viruses in sub-optimally activated T cells, most likely via activation of intracellular signaling pathways. Our data further suggest that in macrophages, HIV-1 infection increases expression of CCL18, which can be further upregulated by TH2 cytokines and by self- amplification capability of CCL18. The goal of this proposal is to define the mechanisms by which CCL18 enhances replication of X4 viruses and determine pathways involved in enhanced production of CCL18.
The specific aims will test the hypothesis that HIV-1 infection directly and indirectly (by modulating cytokine levels) triggers increased expression of CCL18 in macrophages, which in turn selectively increases replication of HIV-1 X4 strains in T cells via activation of intracellular signaling pathways that enhance viral replication. Using primary lymphocytes and macrophages, in aim 1 we will define step(s) in viral life cycle enhanced by CCL18 in T cells and determine signaling pathways activated by CCL18 involved in the enhancement of the defined step(s) of viral replication.
In aim 2, we will determine intracellular pathways involved in increased expression of CCL18 in HIV-1-infected, IL-4, IL-10, and CCL18-treated macrophages. Using combined approaches, we will define common pathways and their potential interactions triggering increased expression of CCL18. Together, the proposed studies are expected to generate novel findings defining the mechanisms involved in the interplay between CCL18 and the virus.
Increased levels of CCL18 detected in HIV-1-infected patients may play a role in HIV-1 pathogenesis by supporting emergence of more pathogenic X4 viruses during HIV-1 infection. Therefore, studies proposed in this application focus on underlying basis of this observation and are expected to provide novel findings defining the mechanisms by which HIV-1 infection increases expression of CCL18 and the mechanisms by which CCL18 in turn selectively enhances replication of HIV-1 X4 viruses. We anticipate that proposed studies will provide a strong foundation for future in vivo studies and the results from both are expected to generate a new knowledge exploitable in novel approaches targeting expansion of X4 viruses during HIV-1 infection.
