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Viruses. 2018 Nov 7;10(11). pii: E615. doi: 10.3390/v10110615.

Persistence and Intra-Host Genetic Evolution of Zika Virus Infection in Symptomatic Adults: A Special View in the Male Reproductive System.

Author information

1
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. danibruna@gmail.com.
2
Medical School Clinic Hospital, University of São Paulo, São Paulo, SP 05403-000, Brazil. giuliana.durigon@gmail.com.
3
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. ericaarmendes@gmail.com.
4
Center for Genome Sciences, US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA. jtladner@gmail.com.
5
The Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011-4073, USA. jtladner@gmail.com.
6
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. robert_andreata@hotmail.com.
7
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. daniellebastos@yahoo.com.br.
8
Virology Laboratory, Butantan Institute, São Paulo, SP 05503-900, Brazil. viviane.botosso@butantan.gov.br.
9
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. nicholasdipaola@gmail.com.
10
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. danielviro@gmail.com.
11
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. marieltondospassos@gmail.com.
12
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. cabraconi@gmail.com.
13
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. rubens.bmc@gmail.com.
14
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. modrigues4@gmail.com.
15
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. lennon_rp@hotmail.com.
16
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. stellmelo@gmail.com.
17
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. flavio.mesquita@usp.br.
18
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. vanessa.silveirabio@gmail.com.
19
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. lucmt@usp.br.
20
Pasteur Institute, State Health Department, São Paulo, SP 1103-000, Brazil. srfavoretto@usp.br.
21
Medical School Clinic Hospital, University of São Paulo, São Paulo, SP 05403-000, Brazil. fran_almonfrey@hotmail.com.
22
Medical School Clinic Hospital, University of São Paulo, São Paulo, SP 05403-000, Brazil. kader@usp.br.
23
Virology Laboratory, Butantan Institute, São Paulo, SP 05503-900, Brazil. joel.megalegabrili@gmail.com.
24
Immunochemistry Laboratory, Butantan Institute, São Paulo, SP 05503-900, Brazil. joel.megalegabrili@gmail.com.
25
Virology Laboratory, Butantan Institute, São Paulo, SP 05503-900, Brazil. denise.tambourgi@butantan.gov.br.
26
Department of Cellular and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. sfolivei@gmail.com.
27
Center for Genome Sciences, US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA. karla.prieto.ctr@mail.mil.
28
Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, NE 68198-4388, USA. karla.prieto.ctr@mail.mil.
29
Center for Genome Sciences, US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA. michael.r.wiley19.ctr@mail.mil.
30
Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, NE 68198-4388, USA. michael.r.wiley19.ctr@mail.mil.
31
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. lcsf@usp.br.
32
Institute of Infectology Emílio Ribas e Pontifícia Universidade Católica (PUC-SP), São Paulo, SP 01246-900, Brazil. mvsilva@pucsp.br.
33
Center for Genome Sciences, US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA. gustavo.f.palacios.ctr@mail.mil.
34
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. pzanotto@usp.br.
35
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil. eldurigo@usp.br.

Abstract

We followed the presence of Zika virus (ZIKV) in four healthy adults (two men and two women), for periods ranging from 78 to 298 days post symptom onset. The patients were evaluated regarding the presence of the virus in different body fluids (blood, saliva, urine and semen), development of immune responses (including antibodies, cytokines and chemokines), and virus genetic variation within samples collected from semen and urine during the infection course. The analysis was focused primarily on the two male patients who shed the virus for up to 158 days after the initial symptoms. ZIKV particles were detected in the spermatozoa cytoplasm and flagella, in immature sperm cells and could also be isolated from semen in cell culture, confirming that the virus is able to preserve integrity and infectivity during replication in the male reproductive system (MRS). Despite the damage caused by ZIKV infection within the MRS, our data showed that ZIKV infection did not result in infertility at least in one of the male patients. This patient was able to conceive a child after the infection. We also detected alterations in the male genital cytokine milieu, which could play an important role in the replication and transmission of the virus which could considerably increase the risk of ZIKV sexual spread. In addition, full genome ZIKV sequences were obtained from several samples (mainly semen), which allowed us to monitor the evolution of the virus within a patient during the infection course. We observed genetic changes over time in consensus sequences and lower frequency intra-host single nucleotide variants (iSNV), that suggested independent compartmentalization of ZIKV populations in the reproductive and urinary systems. Altogether, the present observations confirm the risks associated with the long-term replication and shedding of ZIKV in the MRS and help to elucidate patterns of intra-host genetic evolution during long term replication of the virus.

KEYWORDS:

Zika virus; arbovirus; flavivirus; host genetic variation; immune response; sexual transmission

PMID:
30405055
PMCID:
PMC6267439
DOI:
10.3390/v10110615
[Indexed for MEDLINE]
Free PMC Article

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