INAPPROPRIATE T CELL APOPTOSIS: DIRECT HIV-INDUCED Cytopathicity and cd4 cross-linking

The idea that CD4⁺ T cell loss in HIV infection is due to direct killing of infected CD4⁺ T cells by the virus has been fueled by in vitro studies in which CD4⁺ T cells that were infected in culture were shown to undergo apoptosis⁸ and by the well-described positive correlation between HIV viral load and the rate of disease progression.⁹,¹⁰ A number of experimental observations cannot, however, easily be reconciled with this hypothesis.

First, if most CD4⁺ T cell loss were due to direct killing of HIV-infected cells, one would expect a strong correlation between the number of infected CD4⁺ T cells and disease progression. Surprisingly, however, the number of infected cells appeared to correlate poorly with plasma viral ribonucleic acid (RNA) load,¹¹ which is known to be one of the strongest predictors of disease progression. Additionally, the level of in vitro cytopathicity of HIV appeared not to correlate with the extent of CD4⁺ T cell depletion, as no difference in CD4⁺ T cell loss could be found between severe combined immunodeficient (SCID)-hu mice infected with noncytopathic or cytopathic HIV isolates.¹² Also, in simian immunodeficiency virus (SIV)-infected primates, viral cytopathicity did not correlate with disease progression. In vitro, SIV is equally cytopathic to rhesus macaque and sooty mangabey lymphocytes. However, SIV infection in rhesus macaques is associated with CD4⁺ T cell loss and progression to acquired immunodeficiency syndrome (AIDS), whereas CD4⁺ T cell numbers in sooty mangabeys are not affected by SIV infection.¹³

Second, several investigators have argued that the number of productively infected CD4⁺ T cells is too low to account for all the CD4⁺ T cell loss occurring during HIV infection. Hardly any (stem cell transplantation, we found no evi­dence for increased thymic function. T cell division was increased only in a subset of lymphopenic patients, the division was specifically related to clinical events, such as graft versus host disease or episodes of infectious diseases, and proportions of dividing cells declined rapidly after trans­plantation despite still very low T cell numbers.³² Together, these studies cast serious doubts on the natural homeostatic capacities of the immune system during lymphopenia.