Pathogenesis and Treatment of HIV Infection

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Baseline markers of inflammation and coagulation have been shown to be powerful predictors of adverse outcomes in patients with HIV infection. In a comparison of patients with HIV infection randomized to immediate versus delayed initiation of antiretroviral therapy levels of D-dimer, but not interleukin-6 or high sensitivity C-reactive protein declined significantly after starting therapy. HIV infection is associated with a pronounced activation of the immune system. This activation differentially affects CD4 and CD8 T cells. Using in vivo labeling with bromodeoxyuridine we were able to study the kinetics of different subsets within the CD4 and CD8 T cell pools and their relationships to viral load and CD4 depletion. HIV viral load was found to be a driving force behind the proliferation of memory and naive subsets of CD8 T cells and the memory subset of CD4 T cells while CD4 depletion was found to be the driving force behind naive CD4 T cell proliferation. IL-15 is a cytokine involved in the regulation of the immune system with particularly striking effects on the proliferation and activation of NK and CD8 T cells. The IL-15 receptor utilizes its own unique alpha chain and the same beta- and gamma-chains as IL-2. To prepare for human trials in patients with HIV infection, recombinant human IL-15 was produced under conditions of good manufacturing practices (GMP). In a safety study involving 24 rhesus macaques randomized to control or different iv bolus doses of IL-15, the major toxicity that was observed was transient neutropenia that appeared to be secondary to redistribution of cells. Transient 2-4 fold increases in the size of the peripheral blood CD4, CD8 and NK cell pools were noted. HIV-1 evolution was examined by studying changes in viral quasi-species in two monozygotic twins infected at birth with an HIV-1 population from a shared blood transfusion source. Despite the identical host genetic background of the twins and the identical source of infection and timing of HIV-1 infection, the resulting HIV populations differed in genetic diversity, growth rate, recombination rate and types of selective pressures indicating the significant impact of random epigenetic selection in early HIV-1 infection dynamics. Utilizing a human cell line it was discovered that the transfection of any plasmid DNA was associated with induction of type III IFN (interferon-lambda). This induction was found to be induced by the cytosolic protein Ku70 and regulated by another cytosolic protein Ku80. Computational models have been developed that are able to predict the virologic response of patients with HIV infection to new drug combinations using antiretroviral treatment history, baseline CD4 count, viral load and viral genotype. These models have been used to develop an online treatment selection tool that is superior to that of the standard tool, a genotypic sensitivity score. In a retrospective study, physicians found that the use of this system would have led to the consideration and likely eventually selection of different treatment regimens in approximately 1/3 of cases. In those instances, the regimens selected by the model were predicted to provide better virologic responses than the regimens that had been chosen.