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The aim of this study was to develop a computational model of HIV infection able to simulate the natural history of the disease and to test predictive parameters of disease progression. We describe the results of a numerical simulation of the cellular and humoral immune response to HIV-1 infection as an adaptive pathway in a "bit-string" space. A total of 650 simulations of the HIV-1 dynamics were performed with a modified version of the Celada-Seiden immune system model. Statistics are in agreement with epidemiological studies showing a log normal distribution for the time span between infection and the development of AIDS. As predictive parameters of disease progression we found that HIV-1 accumulates "bit" mutations mainly in the peptide sequences recognized by cytotoxic CD8 T cells, indicating that cell-mediated immunity plays a major role in viral control. The viral load set point was closely correlated with the time from infection to development of AIDS. Viral divergence from the viral quasispecies that was present at the beginning of infection in long-term nonprogressors (LTNP) was found to be similar to that found in rapid progressors at the time CD4 T cells drop below the critical value of 200 cells/microl. In contrast, the diversity indicated by the number of HIV strains present at the same time was higher for rapid and normal progressors compared to LTNP, suggesting that the early immune response can make the difference. This computational model may help to define the predictive parameters of HIV dynamics and disease progression, with potential applications in therapeutic and vaccine simulations.

Circulating Vgamma2/Vdelta2(+) T cells, normally constituting 3-6% of all CD3(+) T cells in blood, are severely depleted after HIV infection. The mechanism(s) for Vgamma2/Vdelta2(+) T cell depletion are unknown, partly because these cells are CD4(-) and resistant to HIV infection. To determine whether this cell depletion was general for all Vgamma2(+) cells or specific for an individual subset, we analyzed the Vgamma2 repertoire and found consistent differences between HIV(+) and uninfected control samples. The change in Vgamma2 repertoire was the result of preferentially depleting only those Vgamma2 cells that express the Jgamma1.2 segment. The specific loss of Vgamma2-Jgamma1.2(+) cells was polyclonal, as the Vgamma subset retained normal diversity even after HIV infection, and loss occurred without significant changes in the paired chain (Vdelta2) repertoire, or in the alternate Vdelta1 chain repertoire. Specific depletion of Vgamma2-Jgamma1.2/Vdelta2 T cells is the first evidence of a common, T cell receptor-dependent cell loss in HIV disease and it provides a clear example of bystander cell depletion. Vgamma2-Jgamma1.2/Vdelta2 T cells mediate potent responses to microbial pathogens including HIV, and loss of this subset is an important aspect of AIDS pathogenesis.

HIV and hepatis C virus (HCV) coinfection is frequently associated with rapid progression of HCV-related disease, resulting in a higher risk of cirrhosis. Data suggest that natural T cells expressing the Vdelta1 T cell receptor rearrangement are recruited in the liver of chronically HCV-infected patients and are increased in the peripheral blood of HIV-infected persons. We studied gammadelta T cell distribution in the peripheral blood and liver of HCV-infected and HIV/HCV-coinfected patients in the presence and absence of antiretroviral therapy. We observed that Vdelta1+ T cells releasing helper T cell type 1 cytokines are compartmentalized not only in the liver of HCV+ patients, but also of HIV/HCV-coinfected persons. HIV/HCV patients showed an increased frequency of both peripheral and intrahepatic Vdelta1 natural T lymphocytes, resulting in a higher degree of hepatic inflammation when compared with patients with other liver diseases. Finally, highly active antiretroviral therapy (HAART) was unable to restore Vdelta1T cell circulation to normal levels in chronically HIV-infected persons. We conclude that gammadelta T lymphocytes released from tissue to the bloodstream circulation under the influence of chronic HIV infection may contribute to intrahepatic Vdelta1 compartmentalization and progression of liver disease, independently of HAART.