Dataset Information

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

ACCESS DATA

Publications

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

Similar Datasets

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.

Project description:Human cytomegalovirus (HCMV) possesses low pathogenic potential in an immunocompetent host. In the immunosuppressed host, however, a wide spectrum of infection outcomes, ranging from asymptomatic to life threatening, can follow either primary or nonprimary infection. The variability in the manifestations of HCMV infection in immunosuppressed individuals implies that there is a threshold of host antiviral immunity that can effectively limit disease potential. We used a nonhuman primate model of CMV infection to assess the relationship between CMV disease and the levels of developing anti-CMV immunity. Naive rhesus macaques were inoculated with rhesus cytomegalovirus (RhCMV) followed 2 or 11 weeks later by inoculation with pathogenic simian immunodeficiency virus SIVmac239. Two of four monkeys inoculated with SIV at 2 weeks after inoculation with RhCMV died within 11 weeks with simian AIDS (SAIDS), including activated RhCMV infection. Neither animal had detectable anti-SIV antibodies. The other two animals died 17 and 27 weeks after SIV inoculation with either SAIDS or early lymphoid depletion, although no histological evidence of activated RhCMV was observed. Both had weak anti-SIV antibody titers. RhCMV antibody responses for this group of monkeys were significantly below those of control animals inoculated with only RhCMV. In addition, all animals of this group had persistent RhCMV DNA in plasma and high copy numbers of RhCMV in tissues. In contrast, animals that were inoculated with SIV at 11 weeks after RhCMV infection rarely exhibited RhCMV DNA in plasma, had low copy numbers of RhCMV DNA in most tissues, and did not develop early onset of SAIDS or activated RhCMV. SIV antibody titers were mostly robust and sustained in these monkeys. SIV inoculation blunted further development of RhCMV humoral responses, unlike the normal pattern of development in control monkeys following RhCMV inoculation. Anti-RhCMV immunoglobulin G levels and avidity were slightly below control values, but levels maintained were higher than those observed following SIV infection at 2 weeks after RhCMV inoculation. These findings demonstrate that SIV produces long-lasting insults to the humoral immune system beginning very early after SIV infection. The results also indicate that anti-RhCMV immune development at 11 weeks after infection was sufficient to protect the host from acute RhCMV sequelae following SIV infection, in contrast to the lack of protection afforded by only 2 weeks of immune response to RhCMV. As previously observed, monkeys that were not able to mount a significant immune response to SIV were the most susceptible to SAIDS, including activated RhCMV infection. Rapid development of SAIDS in animals inoculated with SIV 2 weeks after RhCMV inoculation suggests that RhCMV can augment SIV pathogenesis, particularly during primary infection by both viruses.

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

OmicsDI is part of the ELIXIR infrastructure

Tweets