Broad and potent neutralizing antibody responses elicited in natural HIV-2 infection.
Compared with human immunodeficiency virus type 1 (HIV-1), little is known about the susceptibility of HIV-2 to antibody neutralization. We characterized the potency and breadth of neutralizing antibody (NAb) responses in 64 subjects chronically infected with HIV-2 against three primary HIV-2 strains: HIV-2(7312A), HIV-2(ST), and HIV-2(UC1). Surprisingly, we observed in a single-cycle JC53bl-13/TZM-bl virus entry assay median reciprocal 50% inhibitory concentration (IC(50)) NAb titers of 1.7 × 10(5), 2.8 × 10(4), and 3.3 × 10(4), respectively. A subset of 5 patient plasma samples tested against a larger panel of 17 HIV-2 strains where the extracellular gp160 domain was substituted into the HIV-2(7312A) proviral backbone showed potent neutralization of all but 4 viruses. The specificity of antibody neutralization was confirmed using IgG purified from patient plasma, HIV-2 Envs cloned by single-genome amplification, viruses grown in human CD4(+) T cells and tested for neutralization sensitivity on human CD4(+) T target cells, and, as negative controls, env-minus viruses pseudotyped with HIV-1, vesicular stomatitis virus, or murine leukemia virus Env glycoproteins. Human monoclonal antibodies (MAbs) specific for HIV-2 V3 (6.10F), V4 (1.7A), CD4 binding site (CD4bs; 6.10B), CD4 induced (CD4i; 1.4H), and membrane-proximal external region (MPER; 4E10) epitopes potently neutralized the majority of 32 HIV-2 strains bearing Envs from 13 subjects. Patient antibodies competed with V3, V4, and CD4bs MAbs for binding to monomeric HIV-2 gp120 at titers that correlated significantly with NAb titers. HIV-2 MPER antibodies did not contribute to neutralization breadth or potency. These findings indicate that HIV-2 Env is highly immunogenic in natural infection, that high-titer broadly neutralizing antibodies are commonly elicited, and that unlike HIV-1, native HIV-2 Env trimers expose multiple broadly cross-reactive epitopes readily accessible to NAbs.
Departments of Microbiology and Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Rui
R
Kong
Hui
H
Li
Frederic
F
Bibollet-Ruche
Julie M
JM
Decker
Natalie N
NN
Zheng
Geoffrey S
GS
Gottlieb
Nancy B
NB
Kiviat
Papa Salif
PS
Sow
Ivelin
I
Georgiev
Beatrice H
BH
Hahn
Peter D
PD
Kwong
James E
JE
Robinson
George M
GM
Shaw
D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000917:Antibody Formation; D002460:Cell Line; D015483:HIV Antibodies / Q000276:immunology*; D019302:HIV Envelope Protein gp160 / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D015498:HIV-2 / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D016415:Sequence Alignment
D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D019302:HIV Envelope Protein gp160; C514798:gp160 protein, Human immunodeficiency virus 2