UCSF

Immune activation and inflammation are predictive of a rapid pace of HIV disease progression, and host immunoregulatory factors that blunt immune activation and inflammation may contribute to delayed disease progression.

We hypothesized that host factors controlling HIV-associated inflammation might be protective during the course of disease and that amongst such factors, heme oxygenase-1 (HO-1) was a good candidate as an important stress-response enzyme. It is the rate-limiting enzyme that initiates heme degradation and maintains cellular homeostasis during stress through its depletion of pro-oxidant heme, via generation of cytoprotective carbon monoxide, and biliverdin.

The experiments discussed in this thesis aim to explain how the activity of HO-1 controls harmful immune activation in HIV-positive individuals primarily through its function in blood monocyte populations.

We show that HO-1 plays an important role in dampening nonspecific T cell activation in murine and human studies. Pharmacological alteration of HO-1 in mice as well as in circulating immune cells of humans leads to altered T cell proliferation, maturation, and survival profiles. This discovery sets the important groundwork for establishing HO-1 pharmacological agents as potential therapies for HIV disease.

Next, we show that inter-individual genetic variability in the HO-1 promoter region influences its transcriptional regulation. We conducted a candidate genotyping analysis of the HO-1 promoter polymorphisms during HIV-disease to show that African Americans with greater HO-1 GTn polymorphic repeats had higher plasma CD14 levels and viral loads on and off therapy, respectively.

HO-1 is regulated to a variable extent in the blood monocyte populations as defined by CD14 and CD16 expression, and we show that these circulating monocytes differentially predict HIV disease parameters.

Lastly, we determined how pharmacological inhibition of HO-1 influences virological and immunological consequences during pathogenic SIV disease. We administered the HO-1 inhibitor, tin mesoporphyrin (SnMP), to AGMs infected with the simian immunodeficiency virus (SIV). Treated animals had higher peak viral load during seroconversion, higher T cell activation, and higher absolute CD4+ T cell counts.

The results from this thesis show the importance of HO-1 activity in regulating homeostatic T cell activity as well as T cell function during inflammatory conditions such as HIV infection.