nef/long terminal repeat quasispecies from HIV type 1-infected Mexican patients with different progression patterns and their pathogenesis in hu-PBL-SCID mice.
To examine the genetic features of the long terminal repeat (LTR) derived from six HIV-1-infected individuals enrolled in the Mexico City Cohort, we cloned and sequenced a 505-bp fragment of the proviral LTR from their peripheral blood mononuclear cells (PBMCs). All patients harbored HIV-1 LTR quasispecies corresponding to the B subtype. Three patients with high CD4+ T cell counts (>500/mm3) presented LTR sequences with point mutations in the TAR bulge. The LTR sequence from a patient classified as a long-term nonprogressor (LTNP) presented the most frequent naturally occurring length polymorphism (MFNLP) and two substitutions in the TAR region that were predicted to result in two alternative secondary RNA structures. A novel 18-bp deletion, which eliminates part of the putative binding site for the nuclear factor of activated T cells (NFAT-1), was identified in the overlapping nef/LTR sequence derived from a patient progressing to AIDS. This deletion coincides with the ability of this virus to consistently replicate at low levels in vivo (viral load <500 RNA copies/ml) and in vitro (unsuccessful virus isolation). On one occasion, when virus isolation was successful, the 18-bp deletion was no longer evident and LTR sequences with intact NFAT-1-binding sites were observed. Inoculation of hu-PBL-SCID mice with viruses from several Mexican patients resulted in differential CD4+ T cell depletion patterns 15 days postinfection, which agree with the in vivo CD4+ T cell count data from each patient.
Gómez-Román
V R
VR
Unidad de Investigación en Retrovirus Humanos, Instituto de Investigaciones Biomédicas, Universidad Nacional Autonoma de México, DF Mexico.
Vázquez
J A
JA
del Carmen Basualdo
M
M
Estrada
F J
FJ
Ramos-Kuri
M
M
Soler
C
C
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology*; D000818:Animals; D001483:Base Sequence; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005500:Follow-Up Studies; D017353:Gene Deletion; D015754:Genes, nef / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008800:Mexico; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011110:Polymorphism, Genetic; D011533:Proviruses / Q000235:genetics*; D020079:Terminal Repeat Sequences / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D019562:Viral Load
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors