Viral Genetic Determinants of Nonprogressive HIV Type 1 Subtype C Infection in Antiretroviral Drug-Naive Children

Abstract

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.

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

“…A similar reversion has been observed in a laboratory worker accidentally contaminated with a vpr-deficient strain of HIV-1 (15,16). Several studies also reported mutations in the vpr gene in long-term nonprogressor (LTNP) patients (17)(18)(19)(20). Several lines of evidence indicate that Vpr interferes with DNA repair pathways (21).…”

Vpr Enhances Tumor Necrosis Factor Production by HIV-1-Infected T Cells

“…A similar reversion was observed in a laboratory worker accidentally contaminated with a vpr-deficient strain of HIV-1 (36,37). Several researchers also reported mutations in the vpr gene in patients who were long-term nonprogressors (LTNP) (38)(39)(40)(41). Many activities have been described for Vpr.…”

Functional Analysis of HIV Type 1 Nef Gene Variants from Adolescent and Adult Survivors of Perinatal Infection

“…16 In a recent genetic analysis involving six children ranging in age from 7 to 10 years old, two South African children infected with subtype C virus were also found to have mutations in nef predicted to alter function. 17 We hypothesized that some HIV-infected children survived from infancy to adolescence and adulthood because they were initially infected with nef-defective HIV variants, slowing the progression of disease until the availability of potent antiretroviral therapy in the late 1990s. A related possibility was considered, that the relative immaturity of cellular immune function in early childhood would render dispensable Nef functions required for immune evasion, allowing HIV to acquire mutations that impair its function.…”