Limited Neutralizing Antibody Specificities Drive Neutralization Escape in Early HIV-1 Subtype C Infection

PLoS Pathogens

the CAPRISA 002 study and the NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)¹  Elin S. Gray¹  Melissa-Rose Abrahams¹  Bronwen E. Lambson¹  Eleanor Cave¹  Penny L. Moore¹  Carolyn Williamson²  Salim S. Abdool Karim²  Koleka Mlisana³  Gama Bandawe³  Lynn Morris³  Nthabeleng Ranchobe⁴ 

[1] AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa;Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban, South Africa;Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa;University of the Witwatersrand, Johannesburg, South Africa

关键词: Cloning;    Chemical neutralization;    Antibodies;    HIV-1;    Antibody response;    Viral load;    Antibody specificity;    Glycosylation;   

DOI  :  10.1371/journal.ppat.1000598

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

We previously showed that HIV-1 subtype C viruses elicit potent but highly type-specific neutralizing antibodies (nAb) within the first year of infection. In order to determine the specificity and evolution of these autologous nAbs, we examined neutralization escape in four individuals whose responses against the earliest envelope differed in magnitude and potency. Neutralization escape occurred in all participants, with later viruses showing decreased sensitivity to contemporaneous sera, although they retained sensitivity to new nAb responses. Early nAb responses were very restricted, occurring sequentially and targeting only two regions of the envelope. In V1V2, limited amino acid changes often involving indels or glycans, mediated partial or complete escape, with nAbs targeting the V1V2 region directly in 2 cases. The alpha-2 helix of C3 was also a nAb target, with neutralization escape associated with changes to positively charged residues. In one individual, relatively high titers of anti-C3 nAbs were required to drive genetic escape, taking up to 7 weeks for the resistant variant to predominate. Thereafter titers waned but were still measurable. Development of this single anti-C3 nAb specificity was associated with a 7-fold drop in HIV-1 viral load and a 4-fold rebound as the escape mutation emerged. Overall, our data suggest the development of a very limited number of neutralizing antibody specificities during the early stages of HIV-1 subtype C infection, with temporal fluctuations in specificities as escape occurs. While the mechanism of neutralization escape appears to vary between individuals, the involvement of limited regions suggests there might be common vulnerabilities in the HIV-1 subtype C transmitted envelope.

【 授权许可】

CC BY