Strain-Specific V3 and CD4 Binding Site Autologous HIV-1 Neutralizing Antibodies Select Neutralization-Resistant Viruses.
The third variable (V3) loop and the CD4 binding site (CD4bs) of the HIV-1 envelope are frequently targeted by neutralizing antibodies (nAbs) in infected individuals. In chronic infection, HIV-1 escape mutants repopulate the plasma, and V3 and CD4bs nAbs emerge that can neutralize heterologous tier 1 easy-to-neutralize but not tier 2 difficult-to-neutralize HIV-1 isolates. However, neutralization sensitivity of autologous plasma viruses to this type of nAb response has not been studied. We describe the development and evolution in vivo of antibodies distinguished by their target specificity for V3 and CD4bs epitopes on autologous tier 2 viruses but not on heterologous tier 2 viruses. A surprisingly high fraction of autologous circulating viruses was sensitive to these antibodies. These findings demonstrate a role for V3 and CD4bs antibodies in constraining the native envelope trimer in vivo to a neutralization-resistant phenotype, explaining why HIV-1 transmission generally occurs by tier 2 neutralization-resistant viruses.
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: moody007@mc.duke.edu.
M Anthony
MA
Moody
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: feng.gao@dm.duke.edu.
Feng
F
Gao
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Thaddeus C
TC
Gurley
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Joshua D
JD
Amos
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Amit
A
Kumar
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Bhavna
B
Hora
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Dawn J
DJ
Marshall
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
John F
JF
Whitesides
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Shi-Mao
SM
Xia
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Robert
R
Parks
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Krissey E
KE
Lloyd
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Kwan-Ki
KK
Hwang
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Xiaozhi
X
Lu
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Mattia
M
Bonsignori
Centre de Recherche du CHUM and Department of Microbiology, Infectology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada and Department of Microbiology and Immunology, McGill University, Montreal, QC H2X 1P1, Canada.
Andrés
A
Finzi
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Nathan A
NA
Vandergrift
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
S Munir
SM
Alam
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Guido
G
Ferrari
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Xiaoying
X
Shen
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Georgia D
GD
Tomaras
University of North Carolina Project, Kamuzu Central Hospital, Lilongwe, Malawi.
Gift
G
Kamanga
Departments of Medicine, Epidemiology, Microbiology, and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
Myron S
MS
Cohen
Kilimanjaro Christian Medical Center, Moshi 25102, Tanzania.
Noel E
NE
Sam
London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
Saidi
S
Kapiga
National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
Elin S
ES
Gray
National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
Nancy L
NL
Tumba
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
Lynn
L
Morris
Department of Pathology, New York University School of Medicine, New York, NY 10010, USA; Veterans Affairs New York Harbor Healthcare System, New York, NY 10010, USA.
Susan
S
Zolla-Pazner
Department of Pathology, New York University School of Medicine, New York, NY 10010, USA.
Miroslaw K
MK
Gorny
Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
John R
JR
Mascola
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Beatrice H
BH
Hahn
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
George M
GM
Shaw
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Joseph G
JG
Sodroski
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Hua-Xin
HX
Liao
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
David C
DC
Montefiori
Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Peter T
PT
Hraber
Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Bette T
BT
Korber
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: hayne002@mc.duke.edu.
Barton F
BF
Haynes
D057134:Antibodies, Neutralizing / Q000276:immunology*; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D009154:Mutation; D012367:RNA, Viral / Q000235:genetics; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D053585:Virus Attachment
D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D012367:RNA, Viral; C514793:gp120 protein, Human immunodeficiency virus 1