Dataset Information

Genetic diversity of the highly variable V1 region interferes with Human Immunodeficiency Virus type 1 envelope functionality.

ABSTRACT: BACKGROUND: The HIV envelope (Env) promotes viral entry in the host cell. During this process, Env undergoes several conformational changes to ensure its function. At the same time, the gp120 component of Env is the protein of the virus presenting the largest genetic diversity. Understanding how the virus maintains the balance between the competing requirements for maintenance of functionality and antigenic variation of this protein is central for the comprehension of its strategies of evolution and can highlight vulnerable aspects of its replication cycle. We focused on the variable domains V1 and V2 of the HIV-1 gp120 that are involved in conformational changes and are critical for viral escape from antibody neutralization. RESULTS: Despite the extensive sequence diversity found in the epidemic for these regions and their location on the external face of the protein, we observed that replacing V1V2 of one primary isolate with that of another severely interferes with Env functionality in more than half of the cases studied. Similar results were obtained for intra- and intersubtype chimeras. These observations are indicative of an interference of genetic diversity in these regions with Env functionality. Therefore, despite the extensive sequence diversity that characterizes these regions in the epidemic, our results show that functional constraints seem to limit their genetic variation. Defects in the V1V2 chimeras were not relieved by the insertion of the V3 region from the same isolate, suggesting that the decrease in functionality is not due to perturbation of potential coevolution networks between V1V2 and V3. Within the V1V2 domain, the sequence of the hypervariable loop of the V1 domain seems to be crucial for the functionality of the protein. CONCLUSIONS: Besides the well-documented role of V1V2 in the interplay with the immune response, this work shows that V1 is also involved in the selection of functional envelopes. By documenting a compromise between the opposing forces of sequence diversification and retention of functionality, these observations improve our understanding of the evolutionary trajectories of the HIV-1 envelope gene.

SUBMITTER: Hamoudi M

PROVIDER: S-EPMC3826872 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic diversity of the highly variable V1 region interferes with Human Immunodeficiency Virus type 1 envelope functionality.

Hamoudi Meriem M Simon-Loriere Etienne E Gasser Romain R Negroni Matteo M

Retrovirology 20131024

<h4>Background</h4>The HIV envelope (Env) promotes viral entry in the host cell. During this process, Env undergoes several conformational changes to ensure its function. At the same time, the gp120 component of Env is the protein of the virus presenting the largest genetic diversity. Understanding how the virus maintains the balance between the competing requirements for maintenance of functionality and antigenic variation of this protein is central for the comprehension of its strategies of ev ...[more]

PMID: 24156625

Similar Datasets

Project description:For the rapid genetic analysis of feline immunodeficiency virus (FIV), we developed a heteroduplex mobility assay (HMA) that utilizes a PCR-amplified fragment of the FIV envelope gene spanning the third and fourth variable regions of the envelope surface protein coding sequence. Viral sequences were successfully amplified from blood specimens from 98 naturally infected cats from Australia, Canada, Germany, Italy, South Africa, and the United States. Eighty were clearly assignable to the A or B envelope sequence subtypes. Three belonged to subtype C, one was dually infected with viruses harboring the A and B env subtypes, and several were categorized as outliers to any of the established subtypes or as probable intersubtype recombinants. Some geographic clustering was evident, with subtypes A and B found in greater frequency in the western and eastern regions of the United States, respectively. Subtypes A, B, and C were found on more than one continent, and countries with more than two samples analyzed contained at least two subtypes. The broadest representation of subtypes was found in Munich, Germany, where three subtypes and one virus that was not classifiable by HMA were found. Thirteen samples were selected for DNA sequence determination over the same region of env used for HMA. Analysis of all available FIV env sequences from this and previous studies revealed the existence of recombinant viruses generated from subtype A/B, B/D, and A/C envelope gene sequences. Subtype A env sequences were less diverse than subtype B sequences, although both groups had well-supported clusters. Furthermore, the mutational pattern giving rise to diversification in the two subtypes differed, with the subtype A viruses showing half as many synonymous site mutations compared to subtype B yet showing similar levels of nonsynonymous site changes. These results are consistent with the hypothesis that FIV-B is an older virus group and is possibly more host adapted than FIV-A.

Project description:HIV elite controllers represent a remarkable minority of patients who maintain normal CD4+ T-cell counts and low or undetectable viral loads for decades in the absence of antiretroviral therapy. To examine the possible contribution of virus attenuation to elite control, we obtained a primary HIV-1 isolate from an elite controller who had been infected for 19 years, the last 10 of which were in the absence of antiretroviral therapy. Full-length sequencing of this isolate revealed a highly unusual V1 domain in Envelope (Env). The V1 domain in this HIV-1 strain was 49 amino acids, placing it in the top 1% of lengths among the 6,112 Env sequences in the Los Alamos National Laboratory online database. Furthermore, it included two additional N-glycosylation sites and a pair of cysteines suggestive of an extra disulfide loop. Virus with this Env retained good infectivity and replicative capacity; however, analysis of recombinant viruses suggested that other sequences in Env were adapted to accommodate the unusual V1 domain. While the long V1 domain did not confer resistance to neutralization by monoclonal antibodies of the V1/V2-glycan-dependent class, it did confer resistance to neutralization by monoclonal antibodies of the V3-glycan-dependent class. Our findings support results in the literature that suggest a role for long V1 regions in shielding HIV-1 from recognition by V3-directed broadly neutralizing antibodies. In the case of the elite controller described here, it seems likely that selective pressures from the humoral immune system were responsible for driving the highly unusual polymorphisms present in this HIV-1 Envelope.IMPORTANCE Elite controllers have long provided an avenue for researchers to reveal mechanisms underlying control of HIV-1. While the role of host genetic factors in facilitating elite control is well known, the possibility of infection by attenuated strains of HIV-1 has been much less studied. Here we describe an unusual viral feature found in an elite controller of HIV-1 infection and demonstrate its role in conferring escape from monoclonal antibodies of the V3-glycan class. Our results suggest that extreme variation may be needed by HIV-1 to escape neutralization by some antibody specificities.

Dataset Information

Genetic diversity of the highly variable V1 region interferes with Human Immunodeficiency Virus type 1 envelope functionality.

Publications

Genetic diversity of the highly variable V1 region interferes with Human Immunodeficiency Virus type 1 envelope functionality.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets