Mitochondrial disruption and apoptosis in lymphocytes of an HIV infected patient affected by lactic acidosis after treatment with highly active antiretroviral therapy.
OBJECTIVE
Highly active antiretroviral therapy (HAART) can induce an increase in lactic acid concentrations that seems to be caused by mitochondrial dysfunction induced by the interaction of nucleoside reverse transcriptase inhibitors (NRTIs) with DNA polymerase gamma in the mitochondria. Mitochondrial alterations have been described in liver and muscle cells of NRTI treated human immunodeficiency virus (HIV) infected patients. Because lymphocytes are the main target for HIV and because mitochondria are involved in apoptosis, we studied mitochondrial morphology and apoptosis in the lymphocytes of an HIV infected patient with severe lactic acidosis after treatment with stavudine, didanosine, and indinavir.


METHODS
The patient was a 39 year old woman. After two years of treatment she developed rapid weight loss with severe fat wasting, peripheral neuropathy, and hyperlacticaemia, which persisted after treatment withdrawal. The numbers and the morphology of the mitochondria were evaluated by electronic microscopy; the percentage of apoptotic cells was calculated by flow cytometry after staining with annexine V and by fluorescent microscopy after staining with ethidium bromide and acridine orange.


RESULTS
The numbers of mitochondria in the lymphocytes were greatly decreased when compared with the lymphocytes of healthy individuals. The most important mitochondrial morphological alterations were swelling and the disruption of cristae and internal mitochondrial structure. These alterations were more evident during the period in which lactic acid values were very high. Moreover, a high percentage of apoptotic lymphocytes was seen. Morphological examination conducted one week after the normalisation of lacticaemia showed a pronounced increase in the number of mitochondria. The morphological alterations were no longer evident, although the size of each mitochondrion was smaller than normal. Moreover, the percentage of apoptotic cells was lower than 5%.


CONCLUSIONS
This report describes important morphological alterations in lymphocyte mitochondria in an HIV infected patient during a severe phase of HAART induced hyperlacticaemia. These alterations persisted for several weeks after treatment withdrawal and were associated with an increase in lymphocyte apoptosis. Considering the important role of mitochondria in the apoptotic pathway, the increase in lymphocyte apoptosis may be a consequence of proapoptotic factors released from altered mitochondria.
Tolomeo
M
M
Centro di Riferimento per AIDS e Sindromi Correlate, Facoltà di Medicina e Chirurgia, Policlinico P.Giaccone, Università di Palermo, 90127 Palermo, Italy. mtolomeo@hotmail.com
Mancuso
S
S
Todaro
M
M
Stassi
G
G
Catalano
M
M
Arista
S
S
Cannizzo
G
G
Barbusca
E
E
Abbadessa
V
V
D000140:Acidosis, Lactic / Q000139:chemically induced* / Q000473:pathology; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure
D019380:Anti-HIV Agents