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Differential functional phenotypes of two primary HIV-1 strains resulting from homologous point mutations in the LLP domains of the envelope gp41 intracytoplasmic domain.

ABSTRACT: We previously reported that selected mutations of highly conserved arginine residues within the LLP regions of HIV-1(ME46) gp41 had diverse effects on Env function. In the current study, we sought to test if the observed LLP mutant phenotypes would be similar in HIV-1(89.6). The results of the current studies revealed that the LLP-1 mutations conferred reduced Env incorporation, infectivity, and replication phenotypes in both viruses, while homologous LLP-2 mutations had differential phenotypical effects between the two strains. In particular, several of the 89.6 LLP-2 mutant viruses were replication defective in CEMX174 cells despite having increased levels of Env incorporation, and with both strains, there were differential effects on infectivity. This comparison of homologous point mutations in two different strains of HIV supports the role of LLPs as determinants of Env function, but reveals for the first time the influence of virus strain on LLP mutant phenotypes.

SUBMITTER: Newman JT

PROVIDER: S-EPMC2034414 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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Differential functional phenotypes of two primary HIV-1 strains resulting from homologous point mutations in the LLP domains of the envelope gp41 intracytoplasmic domain.

Newman Jason T JT Sturgeon Timothy J TJ Gupta Phalguni P Montelaro Ronald C RC

Virology 20070619 1

We previously reported that selected mutations of highly conserved arginine residues within the LLP regions of HIV-1(ME46) gp41 had diverse effects on Env function. In the current study, we sought to test if the observed LLP mutant phenotypes would be similar in HIV-1(89.6). The results of the current studies revealed that the LLP-1 mutations conferred reduced Env incorporation, infectivity, and replication phenotypes in both viruses, while homologous LLP-2 mutations had differential phenotypica ...[more]

PMID: 17582453

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Project description:Dominant antibody responses in vaccinees who received the HIV-1 multiclade (A, B, and C) envelope (Env) DNA/recombinant adenovirus virus type 5 (rAd5) vaccine studied in HIV-1 Vaccine Trials Network (HVTN) efficacy trial 505 (HVTN 505) targeted Env gp41 and cross-reacted with microbial antigens. In this study, we asked if the DNA/rAd5 vaccine induced a similar antibody response in rhesus macaques (RMs), which are commonly used as an animal model for human HIV-1 infections and for testing candidate HIV-1 vaccines. We also asked if gp41 immunodominance could be avoided by immunization of neonatal RMs during the early stages of microbial colonization. We found that the DNA/rAd5 vaccine elicited a higher frequency of gp41-reactive memory B cells than gp120-memory B cells in adult and neonatal RMs. Analysis of the vaccine-induced Env-reactive B cell repertoire revealed that the majority of HIV-1 Env-reactive antibodies in both adult and neonatal RMs were targeted to gp41. Interestingly, a subset of gp41-reactive antibodies isolated from RMs cross-reacted with host antigens, including autologous intestinal microbiota. Thus, gp41-containing DNA/rAd5 vaccine induced dominant gp41-microbiota cross-reactive antibodies derived from blood memory B cells in RMs as observed in the HVTN 505 vaccine efficacy trial. These data demonstrated that RMs can be used to investigate gp41 immunodominance in candidate HIV-1 vaccines. Moreover, colonization of neonatal RMs occurred within the first week of life, and immunization of neonatal RMs during this time also induced a dominant gp41-reactive antibody response.IMPORTANCE Our results are critical to current work in the HIV-1 vaccine field evaluating the phenomenon of gp41 immunodominance induced by HIV-1 Env gp140 in RMs and humans. Our data demonstrate that RMs are an appropriate animal model to study this phenomenon and to determine the immunogenicity in new HIV-1 Env trimer vaccine designs. The demonstration of gp41 immunodominance in memory B cells of both adult and neonatal RMs indicated that early vaccination could not overcome gp41 dominant responses.

Dataset Information

Differential functional phenotypes of two primary HIV-1 strains resulting from homologous point mutations in the LLP domains of the envelope gp41 intracytoplasmic domain.

Publications

Differential functional phenotypes of two primary HIV-1 strains resulting from homologous point mutations in the LLP domains of the envelope gp41 intracytoplasmic domain.

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