Viral genetic determinants of nonprogressive HIV type 1 subtype C infection in antiretroviral drug-naive children.
Characterization of HIV-1 from slow progressors is important to facilitate vaccine and antiviral drug development. To identify virus attenuations that may contribute to slower rates of disease progression, the full-length viral genomes from primary isolates of six slow progressing HIV-positive children were sequenced. Proviral DNA was extracted from cocultured peripheral blood mononuclear cells and used to PCR amplify, sequence, and extensively analyze the near full-length genomes and LTR regions. All primary HIV-1 isolates were HIV-1 subtype C throughout their genome, and amino acid (AA) sequence analysis revealed open reading frames for all genes. However, all isolates had at least one unusual gene/protein. For example, isolate LT5 had a 2AA insertion in the Vpr mitochondriotoxic domain. Isolate LT21 contained an additional 5AA in the C-terminus of tat exon 2, while integrase in isolate LT39 had an additional 4AA at the C-terminus. Rev from isolates LT45 and LT46 did not have the characteristic subtype C 16AA truncation, and in addition, had a further 3AA. Furthermore, altered functional domains were noted in several isolates, such as the cAMP-dependent kinase PKA phosphorylation site in Nef (LT5), a Vpr mutation involved in decreased proapoptotic activity (all isolates), and the Nef ExxxLL motif involved in the interaction with AP-1 and AP-2 (LT46). The slower HIV-1 disease progression in these six children may be attributed to altered protein functions. For example, LT46 Nef is unable to bind AP-1 and AP-2 and therefore is inactive on CD4 endocytosis. The biological relevance of these findings requires further investigation.
Tzitzivacos
D B
DB
HIV Pathogenesis Research Laboratory, Department of Molecular Medicine and Haematology, University of the Witwatersrand Medical School, Parktown, Johannesburg 2193, South Africa.
Tiemessen
C T
CT
Stevens
W S
WS
Papathanasopoulos
M A
MA
D019380:Anti-HIV Agents / Q000627:therapeutic use; D002648:Child; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D016679:Genome, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000145:classification* / Q000235:genetics* / Q000472:pathogenicity; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D017422:Sequence Analysis, DNA
D019380:Anti-HIV Agents; D004279:DNA, Viral; D054298:Human Immunodeficiency Virus Proteins