Relative significance of different pathways of immune reconstitution in HIV type 1 infection as estimated by mathematical modeling

A major goal of antiretroviral HIV-1 therapy is the reversal of HIV-1-assoc iated immunological dysfunction, However, the pathogenetic mechanisms invol ved and their significance are largely unknown. On the basis of the life cy cle of naive, activated, and memory CD4(+) T cell subsets, a mathematical m odel of immune reconstitution was developed and applied to data for T cell subsets in individuals with acute or chronic HIV-1 infection receiving anti retroviral therapy. The final model that most accurately fitted the data, a nd resulted in realistic estimates for CD4(+) T cell turnover, considered t hree pathways of immune reconstitution for naive cells, including thymic pr oduction, peripheral expansion, and redistribution of naive cells from lymp hoid tissue. The reconstitution of the memory compartment. was fitted throu gh differentiation and expansion of naive cells and peripheral expansion of memory cells as well as redistribution of memory cells trapped in the lymp hoid tissue. Estimated median half-lives for naive and memory CD4(+) T cell s were 114 and 21 days, while total production rates were 9.1 x 10(7) and 2 .4 x 10(9) cells/day, respectively. Peripheral expansion and thymic product ion contributed equally to the regeneration of naive cells, but peripheral expansion of memory cells was larger than production of these cells by diff erentiation of naive cells. A comparison of immune reconstitution in acute and chronic HIV-1 infection revealed that, after adjustment for age, the ma in difference was the more rapid release of a larger number of naive cells in treated acute HIV-1 infection. Thymic function and peripheral expansion rates, however, were similar in both cohorts.