Abstract
To study how virus evolution affects neutralization sensitivity and to determine changes that occur in and around epitopes, we tested the ability of 13 anti-HIV-1 gp120 (anti-V2, anti-V3, anti-CD4bd and anti-carbohydrate) human monoclonal antibodies (mAbs) to neutralize sequential viruses obtained from five HIV-1 chronically infected drug naïve individuals. Overall, primary viruses collected from patients at first visit were resistant to neutralization by all anti-HIV-1 mAbs with the exception of one virus sensitive to IgG1b12. Four of the five patients' viruses evolved increased sensitivity to neutralization by anti-V3 mAbs. Virus collected from a patient obtained 31 months later, evolved increased sensitivity to anti-V2, anti-V3, and anti-CD4bd mAbs. Furthermore, the anti-V2 and anti-CD4bd mAbs also exhibited increased neutralization capacities against virus collected from a patient 29 months later. Of the seven anti-V3 mAbs, five showed increased potency to neutralize the evolved virus from a patient collected after 11 months, and three exhibited increased potency against viruses from two patients collected 29 and 36 months later. Anti-V3 mAbs exhibited the most breadth and potency in neutralizing the evolving viruses. Sequence analysis of the envelope regions revealed amino acid conservation within the V3 loop, while most of the changes identified occurred outside the core epitopes and in particular within the C3 region; these may account for increased neutralization sensitivity. These studies demonstrate that in vivo, HIV-1 can evolve increased neutralization sensitivity to mAbs and that the spectrum of neutralization capacities by mAbs can be broader when studied in longitudinal analysis.
Highlights
To date, almost all studies that have examined the sensitivity of human immunodeficiency virus type 1 (HIV-1) isolates to antiHIV-1 human monoclonal antibodies have been crosssectional and they show that only a few mAbs neutralize HIV-1 primary isolates
Our present study demonstrates that both subtype B and CRF02_AG viruses in some HIV-1 chronically-infected individuals evolve to become more sensitive to neutralization by antibodies directed at epitopes in the V2, V3 and CD4-binding domain (CD4bd) (Figures 2 and 3)
HIV Evolution and Neutralization Sensitivity snapshots of mAb neutralization capacities taken in cross sectional studies are inadequate to define the neutralization spectrum of mAb neutralization with primary HIV-1 isolates
Summary
Almost all studies that have examined the sensitivity of human immunodeficiency virus type 1 (HIV-1) isolates to antiHIV-1 human monoclonal antibodies (mAbs) have been crosssectional and they show that only a few mAbs neutralize HIV-1 primary isolates. The lack of neutralization by most antibodies has been attributed to a variety of reasons such as the occlusion of the neutralization sensitive epitopes on primary HIV-1 isolates by carbohydrate moieties, the absence of the specific epitope on the intact HIV-1 virion and the differences in conformational structures on the virions [1,2]. In addition to these factors that contribute to neutralization resistance, HIV-1 primary isolates can evolve over time to escape from autologous neutralization through changes due to insertions and deletions, point mutations, changes in glycan shielding and nonsynonymous changes [3,4,5,6,7,8]. Several immunochemical studies have revealed that many of these antibodies, especially anti-V3 mAbs, bind to peptides, soluble proteins, recombinant proteins and intact virions, suggesting that the epitopes are present but in different forms [19]
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