A major goal of this project has been to quantify stages of the HIV-1 life cycle and understand how infection kinetics is affected by viral and cellular structures. We used a variety of biophysical, cellular and molecular biology techniques combined with mathematical modeling. We further developed our mathematical model of HIV-1 infection kinetics to describe quantitatively the appearance and spread of mutant virus, particularly in presence of selective pressure due to immune response or drug treatment. We used this model to analyze data for AIDS patients and monkey models of AIDS. The results indicated that combination therapy may successfully prevent emergence of drug resistant virus if the number of drugs acting at different target sites is larger than 3 and they completely block virus infection. We also measured the telomere length of blood cells from pediatric AIDS patients obtained over several years in order to find out whether telomere length can be used as a marker of HIV-1 pathogenesis. The results demonstrated that a slowly progressing patient showed no appreciable change in telomere length while two rapidly progressing patients showed a decrease in telomere length. This suggests that the increased leukocyte turnover associated with rapid disease progression may be reflected in an accelerated decline in telomere length. These preliminary results may indicate that telomere length could be used as a marker of the disease progression and eventually provide information for the turnover rate of lymphocytes in AIDS patients. We also studied the role of the HIV-1 coreceptors in entry. We have previously found that phorbol esters-induced downmodulation of tailless CD4 requires prior binding of gp120, suggesting a novel approach for identification of accessory fusion molecules. This year our collaborative effort lead to the isolation of a 45 kDa membrane-associated protein which we found is identical to fusin - the recently discovered T cell line tropic HIV-1 coreceptor. Our data provided the first direct evidence that fusin interacts with gp120 and CD4 forming a tri-molecular complex (n Science, in press). Based on these and other results we proposed a model of the interactions of fusin with CD4 and the HIV-1 envelope glycoprotein and also outlined possible approaches how to use this information for development of new drugs and vaccines. (Nature Medicine 2:640) These findings have implications for understanding the mechanisms controlling the HIV-1 life-cycle and the development of AIDS, and for a rationale design of antiviral drugs.
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