Neutralizing activity of broadly neutralizing anti-HIV-1 antibodies against primary African isolates

Abstract

Novel therapeutic and preventive strategies are needed to contain the HIV-1 epidemic. Broadly neutralizing human antibodies (bNAbs) with exceptional activity against HIV-1 are currently being tested in HIV-1 prevention trials. The selection of anti-HIV-1 bNAbs for clinical development was primarily guided by their in vitro neutralizing activity against HIV-1 Env pseudotyped viruses. Here we report on the neutralizing activity of 9 anti-HIV-1 bNAbs now in clinical development against 126 Clade A, C, D PBMC-derived primary African isolates. The neutralizing potency and breadth of the bNAbs tested was significantly reduced compared to pseudotyped viruses panels. The difference in sensitivity between pseudotyped viruses and primary isolates varied from 3-to nearly 100-fold depending on the bNAb and the HIV-1 clade. Thus, the neutralizing activity of bNAbs against primary African isolates differs and cannot be predicted from their activity against pseudovirus panels. The data have significant implications for interpreting the results of ongoing HIV-1 prevention trials.

Neutralization Diversity of HIV-1 Indian Subtype C Envelopes Obtained From Cross Sectional and Followed up Individuals Against Broadly Neutralizing Monoclonal Antibodies Having Distinct Gp120 Specificities

“…Our hypothesis is supported by the fact that different classes of bnAbs isolated from HIV-1 infected individuals were in uenced by both the infecting subtypes [23] and also by the ethnic origin [24] [42]. In addition, the possibility of increasing resistance to bnAbs as observed [25,26] in recent studies over the course of the epidemic warrants the necessity for continued surveillance of virus evolution that would impact ability of the promising bnAbs mediated neutralization coverage of region-speci c HIV-1 diversities.…”

“…HIV-1 subtype C accounts for approximately half of the global infections [24], which predominates in India and South Africa. Recently very few studies have attempted to understand a few selected bnAbs for their extent to neutralize HIV-1 subtype C of African origin either singly and/or in combinations [25][26][27], however those studies did not include pseudoviruses expressing envs representing Indian subtype C. It is possible that an intra-clade C speci c neutralization patterns may exist. For example, Rademeyer et al [28] have shown that subtype C viruses of African origin have become more resistant to VRC01, PG9 and 4E10 compared to CAP256-VRC26.…”

Uses and Challenges of Antiviral Polyclonal and Monoclonal Antibody Therapies

“…However, as mentioned earlier, biosafety concerns may limit the use of authentic BSL3-3 and BSL4-4 pathogens. The use of pseudotyped viruses and/or VLP can offer less restrictive biosafety requirements and may facilitate antibody characterization in several additional ways: a. pseudotyped viruses/VLP can be more readily manipulated allowing faster assessment of potential mutations in the virus surface glycoproteins b. the level of entry may be easier to quantify, and c. panels of pseudotyped VLP, representing a wide range of virus strains that are generated using the same packaging system, can be created and tested for their neutralization susceptibility 126,[141][142][143] . Ideally, the pseudotyped viruses or VLP should closely resemble the corresponding authentic viruses, but certain differences may exist regarding shape, glycosylation, and density of the envelope glycoproteins due to the packaging system and/or producer cells used.…”

Broadly Neutralizing Antibodies for HIV-1 Prevention

“…These predictions were primarily based on in vitro testing of VRC01 against panels of HIV-1 Env pseudoviruses. Several studies have demonstrated that pseudoviruses produced via transfection of 293T cells are considerably more sensitive to neutralization by patient serum and bnAbs when compared to matched isolates expanded in peripheral blood mononuclear cells (PBMC) (113,114). This point should be taken into consideration when incorporating in vitro neutralization data into clinical efficacy estimations for HIV-1 bnAbs.…”