title: Humoral Immune Pressure Selects for HIV-1 CXC-chemokine Receptor 4-using Variants.
abstract: Although both C-C chemokine receptor 5 (CCR5)- and CXC chemokine receptor 4 (CXCR4)-using HIV-1 strains cause AIDS, the emergence of CXCR4-utilizing variants is associated with an accelerated decline in CD4+ T cells. It remains uncertain if CXCR4-using viruses hasten disease or if these variants only emerge after profound immunological damage. We show that exclusively CXCR4- as compared to cocirculating CCR5-utilizing variants are less sensitive to neutralization by both contemporaneous autologous plasma and plasma pools from individuals that harbor only CCR5-using HIV-1. The CXCR4-utilizing variants, however, do not have a global antigenic change because they remain equivalently susceptible to antibodies that do not target coreceptor binding domains. Studies with envelope V3 loop directed antibodies and chimeric envelopes suggest that the neutralization susceptibility differences are potentially influenced by the V3 loop. In vitro passage of a neutralization sensitive CCR5-using virus in the presence of autologous plasma and activated CD4+ T cells led to the emergence of a CXCR4-utilizing virus in 1 of 3 cases. These results suggest that in some but not necessarily all HIV-1 infected individuals humoral immune pressure against the autologous virus selects for CXCR4-using variants, which potentially accelerates disease progression. Our observations have implications for using antibodies for HIV-1 immune therapy.
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA, United States.
authors.forename: Nina
authors.initials: N
authors.lastname: Lin
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA, United States.
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Gonzalez
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA, United States.
authors.forename: Ludy
authors.initials: L
authors.lastname: Registre
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, United States.
authors.forename: Carlos
authors.initials: C
authors.lastname: Becerril
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA, United States.
authors.forename: Behzad
authors.initials: B
authors.lastname: Etemad
authors.affiliation: Aaron Diamond AIDS Research Center, New York, NY, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.affiliation: Aaron Diamond AIDS Research Center, New York, NY, United States.
authors.forename: Xueling
authors.initials: X
authors.lastname: Wu
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, United States; Harvard School of Public Health, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Shahin
authors.initials: S
authors.lastname: Lockman
authors.affiliation: Harvard School of Public Health, Boston, MA, United States; Botswana Harvard AIDS Institute, Gaborone, Botswana.
authors.forename: Myron
authors.initials: M
authors.lastname: Essex
authors.affiliation: Botswana Harvard AIDS Institute, Gaborone, Botswana.
authors.forename: Sikhulile
authors.initials: S
authors.lastname: Moyo
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kuritzkes
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA, United States. Electronic address: msagar@bu.edu.
authors.forename: Manish
authors.initials: M
authors.lastname: Sagar
mesh_terms: D018791:CD4 Lymphocyte Count; D015483:HIV Antibodies / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000209:etiology* / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral; D009500:Neutralization Tests; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015728:Receptors, HIV / Q000378:metabolism*; D019562:Viral Load; D056189:Viral Tropism; D014779:Virus Replication
chemical_list: D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; D015728:Receptors, HIV
keywords: Co-receptor; Envelope; Evolution; HIV; Neutralization; Resistance; Tropism