Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape.
Single genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays, we found evidence in three subjects of neutralizing antibody (Nab) responses as early as 2 weeks post-seroconversion, with Nab titers as low as 1∶20 to 1∶50 (IC(50)) selecting for virus escape. In each of the subjects, Nabs targeted different regions of the HIV-1 envelope (Env) in a strain-specific, conformationally sensitive manner. In subject CH40, virus escape was first mediated by mutations in the V1 region of the Env, followed by V3. HIV-1 specific monoclonal antibodies from this subject mapped to an immunodominant region at the base of V3 and exhibited neutralizing patterns indistinguishable from polyclonal antibody responses, indicating V1-V3 interactions within the Env trimer. In subject CH77, escape mutations mapped to the V2 region of Env, several of which selected for alterations of glycosylation. And in subject CH58, escape mutations mapped to the Env outer domain. In all three subjects, initial Nab recognition was followed by sequential rounds of virus escape and Nab elicitation, with Nab escape variants exhibiting variable costs to replication fitness. Although delayed in comparison with autologous CD8 T-cell responses, our findings show that Nabs appear earlier in HIV-1 infection than previously recognized, target diverse sites on HIV-1 Env, and impede virus replication at surprisingly low titers. The unexpected in vivo sensitivity of early transmitted/founder virus to Nabs raises the possibility that similarly low concentrations of vaccine-induced Nabs could impair virus acquisition in natural HIV-1 transmission, where the risk of infection is low and the number of viruses responsible for transmission and productive clinical infection is typically one.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Katharine J
KJ
Bar
Chun-yen
CY
Tsao
Shilpa S
SS
Iyer
Julie M
JM
Decker
Yongping
Y
Yang
Mattia
M
Bonsignori
Xi
X
Chen
Kwan-Ki
KK
Hwang
David C
DC
Montefiori
Hua-Xin
HX
Liao
Peter
P
Hraber
William
W
Fischer
Hui
H
Li
Shuyi
S
Wang
Sarah
S
Sterrett
Brandon F
BF
Keele
Vitaly V
VV
Ganusov
Alan S
AS
Perelson
Bette T
BT
Korber
Ivelin
I
Georgiev
Jason S
JS
McLellan
Jeffrey W
JW
Pavlicek
Feng
F
Gao
Barton F
BF
Haynes
Beatrice H
BH
Hahn
Peter D
PD
Kwong
George M
GM
Shaw
D016915:AIDS Vaccines / Q000276:immunology; D056704:Adaptive Immunity; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D005814:Genes, Viral; D016678:Genome; D015483:HIV Antibodies / Q000276:immunology / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000187:drug effects / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D054884:Host-Pathogen Interactions; D057131:Immune Evasion / Q000187:drug effects* / Q000276:immunology; D009500:Neutralization Tests; D014779:Virus Replication / Q000187:drug effects*
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120