Thrombotic microangiopathy associated with unusual viral sequences in HIV-1-positive patients.
BACKGROUND
Thrombotic microangiopathy (TMA) is a rare disorder caused by endothelial cell damage. TMA has been associated with the human immunodeficiency virus 1 (HIV-1) infection, yet only a minority of all HIV-1 patients develops TMA. Since HIV-1 has been shown to interact with endothelial cells, we investigated whether certain mutations in the HIV-1 envelope protein are associated with the development of TMA in HIV-1-infected patients.


METHODS
Plasma was obtained from nine HIV-1-positive patients with TMA. Viral loads were determined from the samples and compared with the clinical data. Viral envelope protein sequences from the regions known to be responsible for viral tropism were isolated, sequenced and compared with known HIV-1 isolates. The isolates were expressed as synthetic fusion proteins; binding of these fusion proteins to CD4+ cells as well as to endothelial cell lines was investigated.


RESULTS
The viral loads in patients with HIV/TMA were highly variable with no correlation to the clinical status. Most patients carried macrophage-tropic viral envelope protein sequences and an unusual insertion was found in the V2 variable region. The isolates showed increased CD4 binding, but a direct binding to endothelial cells was not observed.


CONCLUSIONS
Although TMA is generally diagnosed in patients with advanced HIV-1 infection, viral loads per se were not predictive of TMA in this study. While a direct interaction with endothelial cells was not detectable, specific viral envelope mutations were found in a region known to influence viral tropism. Hence, viral-specific factors might contribute to the pathogenesis of HIV-associated TMA.
Beth Israel Deaconess Medical Center, Harvard Medical School, Department of Medicine, Boston, Massachusetts, USA. friederike.jochimsen@medizin.fu-berlin.de
Friederike
F
Jochimsen
Wolfram
W
Gruening
Thierry
T
Arnould
Mark S
MS
Segal
Margot S
MS
Kruskall
Robert
R
Colgrove
Gerd
G
Walz
D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000473:pathology*; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D015658:HIV Infections / Q000097:blood / Q000473:pathology*; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D011697:Purpura, Thrombotic Thrombocytopenic / Q000821:virology*; D012367:RNA, Viral / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019562:Viral Load
D017931:DNA Primers; D007074:Immunoglobulin G; D012367:RNA, Viral