title: South African HIV-1 subtype C transmitted variants with a specific V2 motif show higher dependence on α4β7 for replication.
abstract: BACKGROUND
  The integrin α4β7 mediates the trafficking of immune cells to the gut associated lymphoid tissue (GALT) and is an attachment factor for the HIV gp120 envelope glycoprotein. We developed a viral replication inhibition assay to more clearly evaluate the role of α4β7 in HIV infection and the contribution of viral and host factors.
  
  
  RESULTS
  Replication of 60 HIV-1 subtype C viruses collected over time from 11 individuals in the CAPRISA cohort were partially inhibited by antibodies targeting α4β7. However, dependence on α4β7 for replication varied substantially among viral isolates from different individuals as well as over time in some individuals. Among 8 transmitted/founder (T/F) viruses, α4β7 reactivity was highest for viruses having P/SDI/V tri-peptide binding motifs. Mutation of T/F viruses that had LDI/L motifs to P/SDI/V resulted in greater α4β7 reactivity, whereas mutating P/SDI/V to LDI/L motifs was associated with reduced α4β7 binding. P/SDI/V motifs were more common among South African HIV subtype C viruses (35%) compared to subtype C viruses from other regions of Africa (<8%) and to other subtypes, due in part to a founder effect. In addition, individuals with bacterial vaginosis (BV) and who had higher concentrations of IL-7, IL-8 and IL-1α in the genital tract had T/F viruses with higher α4β7 dependence for replication, suggesting that viruses with P/SDI/V motifs may be preferentially transmitted in the presence of BV in this population.
  
  
  CONCLUSIONS
  Collectively, these data suggest a role for α4β7 in HIV infection that is influenced by both viral and host factors including the sequence of the α4β7 binding motif, the cytokine milieu and BV in the genital tract. The higher frequency of P/SDI/V sequences among South African HIV-1 subtype C viruses may have particular significance for the role of α4β7 in this geographical region.
authors.affiliation: Centre for HIV and STI's, National Institute for Communicable Diseases, A Division of the National Health Laboratory Service, 1 Modderfontein Road, Sandringham, Johannesburg, 2131, South Africa. simoner@nicd.ac.za.|Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. simoner@nicd.ac.za.
authors.forename: Simone I
authors.initials: SI
authors.lastname: Richardson
authors.affiliation: Centre for HIV and STI's, National Institute for Communicable Diseases, A Division of the National Health Laboratory Service, 1 Modderfontein Road, Sandringham, Johannesburg, 2131, South Africa. e.gray@ecu.edu.au.|ECU Melanoma Research Foundation, Edith Cowan University (ECU), Perth, WA, 6027, Australia. e.gray@ecu.edu.au.
authors.forename: Elin S
authors.initials: ES
authors.lastname: Gray
authors.affiliation: Centre for HIV and STI's, National Institute for Communicable Diseases, A Division of the National Health Laboratory Service, 1 Modderfontein Road, Sandringham, Johannesburg, 2131, South Africa. nonom@nicd.ac.za.|Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. nonom@nicd.ac.za.
authors.forename: Nonhlanhla N
authors.initials: NN
authors.lastname: Mkhize
authors.affiliation: Divison of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. daniel.sheward@uct.ac.za.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sheward
authors.affiliation: Centre for HIV and STI's, National Institute for Communicable Diseases, A Division of the National Health Laboratory Service, 1 Modderfontein Road, Sandringham, Johannesburg, 2131, South Africa. bronwenl@nicd.ac.za.|Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. bronwenl@nicd.ac.za.
authors.forename: Bronwen E
authors.initials: BE
authors.lastname: Lambson
authors.affiliation: Centre for HIV and STI's, National Institute for Communicable Diseases, A Division of the National Health Laboratory Service, 1 Modderfontein Road, Sandringham, Johannesburg, 2131, South Africa. kurtw@nicd.ac.za.|Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. kurtw@nicd.ac.za.
authors.forename: Constantinos Kurt
authors.initials: CK
authors.lastname: Wibmer
authors.affiliation: Divison of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. lindi.masson@gmail.com.
authors.forename: Lindi
authors.initials: L
authors.lastname: Masson
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa. Lise.Werner@caprisa.org.
authors.forename: Lise
authors.initials: L
authors.lastname: Werner
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa. Nigel.Garrett@caprisa.org.
authors.forename: Nigel
authors.initials: N
authors.lastname: Garrett
authors.affiliation: Divison of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. jo-ann.passmore@uct.ac.za.|Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa. jo-ann.passmore@uct.ac.za.|National Health Laboratory Service, Groote Schuur Hospital, Observatory, Cape Town, South Africa. jo-ann.passmore@uct.ac.za.
authors.forename: Jo-Ann S
authors.initials: JA
authors.lastname: Passmore
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa. Quarraisha.AbdoolKarim@caprisa.org.
authors.forename: Quarraisha Abdool
authors.initials: QA
authors.lastname: Karim
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa. Salim.AbdoolKarim@capisa.org.|Department of Epidemiology, Columbia University, New York, NY, USA. Salim.AbdoolKarim@capisa.org.
authors.forename: Salim S Abdool
authors.initials: SS
authors.lastname: Karim
authors.affiliation: Divison of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. Carolyn.williamson@uct.ac.za.|Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa. Carolyn.williamson@uct.ac.za.|National Health Laboratory Service, Groote Schuur Hospital, Observatory, Cape Town, South Africa. Carolyn.williamson@uct.ac.za.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
authors.affiliation: Centre for HIV and STI's, National Institute for Communicable Diseases, A Division of the National Health Laboratory Service, 1 Modderfontein Road, Sandringham, Johannesburg, 2131, South Africa. pennym@nicd.ac.za.|Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. pennym@nicd.ac.za.|Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa. pennym@nicd.ac.za.
authors.forename: Penny L
authors.initials: PL
authors.lastname: Moore
authors.affiliation: Centre for HIV and STI's, National Institute for Communicable Diseases, A Division of the National Health Laboratory Service, 1 Modderfontein Road, Sandringham, Johannesburg, 2131, South Africa. lynnm@nicd.ac.za.|Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. lynnm@nicd.ac.za.|Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa. lynnm@nicd.ac.za.
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
mesh_terms: D005260:Female; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D011446:Prospective Studies; D013019:South Africa; D014779:Virus Replication
chemical_list: D015699:HIV Envelope Protein gp120; D016023:Integrins; C514793:gp120 protein, Human immunodeficiency virus 1; C071777:integrin alpha4beta7