title: Infection of ectocervical tissue and universal targeting of T-cells mediated by primary non-macrophage-tropic and highly macrophage-tropic HIV-1 R5 envelopes.
abstract: BACKGROUND
  HIV-1 variants carrying non-macrophage-tropic HIV-1 R5 envelopes (Envs) are predominantly transmitted and persist in immune tissue even in AIDS patients who have highly macrophage-tropic variants in the brain. Non-macrophage-tropic R5 Envs require high levels of CD4 for infection contrasting with macrophage-tropic Envs, which can efficiently mediate infection of cells via low CD4. Here, we investigated whether non-macrophage-tropic R5 Envs from the acute stage of infection (including transmitted/founder Env) mediated more efficient infection of ectocervical explant cultures compared to non-macrophage-tropic and highly macrophage-tropic R5 Envs from late disease.
  
  
  RESULTS
  We used Env+ pseudovirions that carried a GFP reporter gene to measure infection of the first cells targeted in ectocervical explant cultures. In straight titrations of Env+ pseudovirus supernatants, mac-tropic R5 Envs from late disease mediated slightly higher infectivities for ectocervical explants although this was not significant. Surprisingly, explant infection by several T/F/acute Envs was lower than for Envs from late disease. However, when infectivity for explants was corrected to account for differences in the overall infectivity of each Env+ pseudovirus (measured on highly permissive HeLa TZM-bl cells), non-mac-tropic early and late disease Env+ pseudoviruses mediated significantly higher infection. This observation suggests that cervical tissue preferentially supports non-mac-tropic Env+ viruses compared to mac-tropic viruses. Finally, we show that T-cells were the main targets for infection regardless of whether explants were stimulated with T-cell or monocyte/macrophage cytokines. There was no evidence of macrophage infection even for pseudovirions carrying highly mac-tropic Envs from brain tissue or for the highly mac-tropic, laboratory strain, BaL, which targeted T-cells in the explant tissue.
  
  
  CONCLUSIONS
  Our data support ectocervical tissue as a favorable environment for non-mac-tropic HIV-1 R5 variants and emphasize the role of T-cells as initial targets for infection even for highly mac-tropic variants.
authors.affiliation: Program in Molecular Medicine and Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Biotech 2, 373 Plantation Street, Worcester, MA, 01605-2377, USA. paul.peters@umassmed.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Peters
authors.affiliation: Program in Molecular Medicine and Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Biotech 2, 373 Plantation Street, Worcester, MA, 01605-2377, USA. mariapaz.gonzalez-perez@umassmed.edu.
authors.forename: Maria Paz
authors.initials: MP
authors.lastname: Gonzalez-Perez
authors.affiliation: Program in Molecular Medicine and Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Biotech 2, 373 Plantation Street, Worcester, MA, 01605-2377, USA. thomas.musich@nih.gov.
authors.forename: Thomas
authors.initials: T
authors.lastname: Musich
authors.affiliation: Department of Ob/Gyn, University of Massachusetts Memorial Health Care, 119 Belmont Street, Worcester, MA, 01605, USA. tiffanya.mooresimas@umassmemorial.org.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Moore Simas
authors.affiliation: School of Public Health and Health Sciences, University of Massachusetts, 411 Arnold House, 715 North Pleasant Street, Amherst, MA, 01003-9304, USA. rlin04@gmail.com.
authors.forename: Rongheng
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Ob/Gyn, University of Massachusetts Memorial Health Care, 119 Belmont Street, Worcester, MA, 01605, USA. anmorse@partners.org.
authors.forename: Abraham N
authors.initials: AN
authors.lastname: Morse
authors.affiliation: Department of Medicine, St Mary's Campus, Imperial College, Medical School Building, London, W21PG, UK. r.shattock@imperial.ac.uk.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory Vaccine Center at Yerkes National Primate Center, Emory University, 954 Gatewood Road, Atlanta, GA, 30329, USA. cderdey@emory.edu.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Derdeyn
authors.affiliation: Program in Molecular Medicine and Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Biotech 2, 373 Plantation Street, Worcester, MA, 01605-2377, USA. paul.clapham@umassmed.edu.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Clapham
mesh_terms: D002478:Cells, Cultured; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D013601:T-Lymphocytes / Q000821:virology*; D056189:Viral Tropism; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D054299:env Gene Products, Human Immunodeficiency Virus