Patients with Discordant Responses to Antiretroviral Therapy Have Impaired Killing of HIV-Infected T Cells

PLoS Pathogens

Sekar Natesampillai¹  Gary D. Bren¹  Andrew D. Badley¹  Nathan W. Cummins¹  Jonathan B. Angel²  Dirk Jochmans³  Zilin Nie⁴ 

[1] Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, United States of America;Immunodeficiency Clinic, Ottawa Hospital, Ottawa, Ontario, Canada;Tibotec BVBA, Mechelen, Belgium;University of Michigan, Ann Arbor, Michigan, United States of America

关键词: Proteases;    HIV;    T helper cells;    Yellow fluorescent protein;    HIV infections;    Point mutation;    Cell death;    Apoptosis;   

DOI  :  10.1371/journal.ppat.1001213

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

In medicine, understanding the pathophysiologic basis of exceptional circumstances has led to an enhanced understanding of biology. We have studied the circumstance of HIV-infected patients in whom antiretroviral therapy results in immunologic benefit, despite virologic failure. In such patients, two protease mutations, I54V and V82A, occur more frequently. Expressing HIV protease containing these mutations resulted in less cell death, caspase activation, and nuclear fragmentation than wild type (WT) HIV protease or HIV protease containing other mutations. The impaired induction of cell death was also associated with impaired cleavage of procaspase 8, a requisite event for HIV protease mediated cell death. Primary CD4 T cells expressing I54V or V82A protease underwent less cell death than with WT or other mutant proteases. Human T cells infected with HIV containing these mutations underwent less cell death and less Casp8p41 production than WT or HIV containing other protease mutations, despite similar degrees of viral replication. The reductions in cell death occurred both within infected cells, as well as in uninfected bystander cells. These data indicate that single point mutations within HIV protease which are selected in vivo can significantly impact the ability of HIV to kill CD4 T cells, while not impacting viral replication. Therefore, HIV protease regulates both HIV replication as well as HIV induced T cell depletion, the hallmark of HIV pathogenesis.

【 授权许可】

CC BY