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Genetic imprint of vaccination on simian/human immunodeficiency virus type 1 transmitted viral genomes in rhesus macaques.

ABSTRACT: Understanding the genetic, antigenic and structural changes that occur during HIV-1 infection in response to pre-existing immunity will facilitate current efforts to develop an HIV-1 vaccine. Much is known about HIV-1 variation at the population level but little with regard to specific changes occurring in the envelope glycoprotein within a host in response to immune pressure elicited by antibodies. The aim of this study was to track and map specific early genetic changes occurring in the viral envelope gene following vaccination using a highly controlled viral challenge setting in the SHIV macaque model. We generated 449 full-length env sequences from vaccinees, and 63 from the virus inoculum. Analysis revealed a different pattern in the distribution and frequency of mutations in the regions of the envelope gene targeted by the vaccine as well as different patterns of diversification between animals in the naïve control group and vaccinees. Given the high stringency of the model it is remarkable that we were able to identify genetic changes associated with the vaccination. This work provides insight into the characterization of breakthrough viral populations in less than fully efficacious vaccines and illustrates the value of HIV-1 Env SHIV challenge model in macaques to unravel the mechanisms driving HIV-1 envelope genetic diversity in the presence of vaccine induced-responses.

SUBMITTER: Varela M

PROVIDER: S-EPMC3743870 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Genetic imprint of vaccination on simian/human immunodeficiency virus type 1 transmitted viral genomes in rhesus macaques.

Varela Mariana M Verschoor Ernst E Lai Rachel P J RP Hughes Joseph J Mooj Petra P McKinley Trevelyan J TJ Fitzmaurice Timothy J TJ Landskron Lisa L Willett Brian J BJ Frost Simon D W SD Bogers Willy M WM Heeney Jonathan L JL

PloS one 20130814 8

Understanding the genetic, antigenic and structural changes that occur during HIV-1 infection in response to pre-existing immunity will facilitate current efforts to develop an HIV-1 vaccine. Much is known about HIV-1 variation at the population level but little with regard to specific changes occurring in the envelope glycoprotein within a host in response to immune pressure elicited by antibodies. The aim of this study was to track and map specific early genetic changes occurring in the viral ...[more]

PMID: 23967111

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Project description:The major obstacle to more-definitive treatment for HIV infection is the early establishment of virus that persists despite long-term combination antiretroviral therapy (cART) and can cause recrudescent viremia if cART is interrupted. Previous studies of HIV DNA that persists despite cART indicated that only a small fraction of persistent viral sequences was intact. Experimental simian immunodeficiency virus (SIV) infections of nonhuman primates (NHPs) are essential models for testing interventions designed to reduce the viral reservoir. We studied the viral genomic integrity of virus that persists during cART under conditions typical of many NHP reservoir studies, specifically with cART started within 1?year postinfection and continued for at least 9?months. The fraction of persistent DNA in SIV-infected NHPs starting cART during acute or chronic infection was assessed with a multiamplicon, real-time PCR assay designed to analyze locations that are regularly spaced across the viral genome to maximize coverage (collectively referred to as "tile assay") combined with near-full-length (nFL) single-genome sequencing. The tile assay is used to rapidly screen for major deletions, with nFL sequence analysis used to identify additional potentially inactivating mutations. Peripheral blood mononuclear cells (PBMC) from animals started on cART within 1 month of infection, sampled at least 9?months after cART initiation, contained at least 80% intact genomes, whereas those from animals started on cART 1?year postinfection and treated for 1?year contained intact genomes only 47% of the time. The most common defect identified was large deletions, with the remaining defects caused by APOBEC-mediated mutations, frameshift mutations, and inactivating point mutations. Overall, this approach can be used to assess the intactness of persistent viral DNA in NHPs.IMPORTANCE Molecularly defining the viral reservoir that persists despite antiretroviral therapy and that can lead to rebound viremia if antiviral therapy is removed is critical for testing interventions aimed at reducing this reservoir. In HIV infection in humans with delayed treatment initiation and extended treatment duration, persistent viral DNA has been shown to be dominated by nonfunctional genomes. Using multiple real-time PCR assays across the genome combined with near-full-genome sequencing, we defined SIV genetic integrity after 9 to 18?months of combination antiretroviral therapy in rhesus macaques starting therapy within 1?year of infection. In the animals starting therapy within a month of infection, the vast majority of persistent DNA was intact and presumptively functional. Starting therapy within 1 year increased the nonintact fraction of persistent viral DNA. The approach described here allows rapid screening of viral intactness and is a valuable tool for assessing the efficacy of novel reservoir-reducing interventions.

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Dataset Information

Genetic imprint of vaccination on simian/human immunodeficiency virus type 1 transmitted viral genomes in rhesus macaques.

Publications

Genetic imprint of vaccination on simian/human immunodeficiency virus type 1 transmitted viral genomes in rhesus macaques.

Similar Datasets

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