Fusion-induced apoptosis contributes to thymocyte depletion by a pathogenic human immunodeficiency virus type 1 envelope in the human thymus.
The mechanisms of CD4(+) T-cell depletion during human immunodeficiency virus type 1 (HIV-1) infection remain incompletely characterized. Of particular importance is how CD4(+) T cells are depleted within the lymphoid organs, including the lymph nodes and thymus. Herein we characterize the pathogenic mechanisms of an envelope from a rapid progressor (R3A Env) in the NL4-3 backbone (NL4-R3A) which is able to efficiently replicate and deplete CD4(+) thymocytes in the human fetal-thymus organ culture (HF-TOC). We demonstrate that uninterrupted replication is required for continual thymocyte depletion. During depletion, NL4-R3A induces an increase in thymocytes which uptake 7AAD, a marker of cell death, and which express active caspase-3, a marker of apoptosis. While 7AAD uptake is observed predominantly in uninfected thymocytes (p24(-)), active caspase-3 is expressed in both infected (p24(+)) and uninfected thymocytes (p24(-)). When added to HF-TOC with ongoing infection, the protease inhibitor saquinavir efficiently suppresses NL4-R3A replication. In contrast, the fusion inhibitors T20 and C34 allow for sustained HIV-1 production. Interestingly, T20 and C34 effectively prevent thymocyte depletion in spite of this sustained replication. Apoptosis of both p24(-) and p24(+) thymocytes appears to be envelope fusion dependent, as T20, but not saquinavir, is capable of reducing thymocyte apoptosis. Together, our data support a model whereby pathogenic envelope-dependent fusion contributes to thymocyte depletion in HIV-1-infected thymus, correlated with induction of apoptosis in both p24(+) and p24(-) thymocytes.
Meissner
Eric G
EG
Lineberger Comprehensive Cancer Center, CB#7295, Chapel Hill, NC 27599, USA.
Zhang
Liguo
L
Jiang
S
S
Su
Lishan
L
D019380:Anti-HIV Agents / Q000494:pharmacology; D017209:Apoptosis; D001216:Asparagine / Q000031:analogs & derivatives / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D053148:Caspase 3 / Q000032:analysis; D000077560:Enfuvirtide; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000378:metabolism; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity*; D006801:Humans; D008856:Microscopy, Fluorescence; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013950:Thymus Gland / Q000473:pathology* / Q000821:virology*; D053586:Virus Internalization; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D005456:Fluorescent Dyes; D016655:HIV Core Protein p24; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D011804:Quinolines; C407149:peptide C34; C508896:sequinavir; D000077560:Enfuvirtide; D001216:Asparagine; D053148:Caspase 3