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Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals.

ABSTRACT: Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants^1,2. Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection^3,4. Although anti-HIV-1 antibodies constitute a potential alternative to ART^5,6, treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants^7-9. Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection^10-12. Here we report on a phase 1b clinical trial ( NCT02825797 ) in which two potent bNAbs, 3BNC117¹³ and 10-1074¹⁴, were administered in combination to seven HIV-1 viremic individuals. Infusions of 30 mg kg^-1 of each of the antibodies were well-tolerated. In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log₁₀ copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none of these individuals developed resistance to both antibodies. Larger studies will be necessary to confirm the efficacy of antibody combinations in reducing HIV-1 viremia and limiting the emergence of resistant viral variants.

SUBMITTER: Bar-On Y

PROVIDER: S-EPMC6221973 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals.

Bar-On Yotam Y Gruell Henning H Schoofs Till T Pai Joy A JA Nogueira Lilian L Butler Allison L AL Millard Katrina K Lehmann Clara C Suárez Isabelle I Oliveira Thiago Y TY Karagounis Theodora T Cohen Yehuda Z YZ Wyen Christoph C Scholten Stefan S Handl Lisa L Belblidia Shiraz S Dizon Juan P JP Vehreschild Jörg J JJ Witmer-Pack Maggi M Shimeliovich Irina I Jain Kanika K Fiddike Kerstin K Seaton Kelly E KE Yates Nicole L NL Horowitz Jill J Gulick Roy M RM Pfeifer Nico N Tomaras Georgia D GD Seaman Michael S MS Fätkenheuer Gerd G Caskey Marina M Klein Florian F Nussenzweig Michel C MC

Nature medicine 20180926 11

Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants1,2. Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection3,4. Although anti-HIV-1 antibodies constitute a potential alternative to ART5,6, treatment of viremic individual ...[more]

PMID: 30258217

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Project description:Topically applied microbicides may play a critical role in preventing sexual transmission of human immunodeficiency virus type 1 (HIV-1); however, their efficacy can be compromised by amyloid fibrils present in semen, which significantly increase HIV-1 infectivity. This phenomenon may have contributed to the failure of most microbicide candidates in clinical settings. Understanding the impact of semen on microbicide effectiveness is thus crucial. In our study, we evaluated the influence of semen on the neutralizing activity of broadly neutralizing antibodies (bNAbs), including PG16, PGT121, 10-1074, 3BNC117, and VRC01, which are potential microbicide candidates. We found that semen enhances infection of HIV-1 transmitted/founder viruses but only marginally affects the neutralizing activity of tested antibodies, suggesting their potential for microbicide application. Our findings underscore the need to consider semen-mediated enhancement when evaluating and developing microbicides and highlight the potential of incorporating HIV-1 bNAbs in formulations to enhance efficacy and mitigate HIV-1 transmission during sexual encounters.IMPORTANCEThis study examined the impact of semen on the development of microbicides, substances used to prevent the transmission of HIV-1 during sexual activity. Semen contains certain components that can render the virus more infectious, posing a challenge to microbicide effectiveness. Researchers specifically investigated the effect of semen on a group of powerful antibodies called broadly neutralizing antibodies, which can neutralize a large spectrum of different HIV-1 variants. The results revealed that semen only had a minimal effect on the antibodies' ability to neutralize the virus. This is promising because it suggests that these antibodies could still be effective in microbicides, even in the presence of semen. Understanding this interaction is crucial for developing better strategies to prevent HIV-1 transmission. By incorporating the knowledge gained from this study, scientists can now focus on creating microbicides that consider the impact of semen, bringing us closer to more effective prevention methods.

Project description: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 from their activity against pseudovirus panels. The data have significant implications for interpreting the results of ongoing HIV-1 prevention trials.IMPORTANCE HIV remains a major public health problem worldwide, and new therapies and preventive strategies are necessary for controlling the epidemic. Broadly neutralizing antibodies (bNAbs) have been developed in the past decade to fill this gap. The neutralizing activity of these antibodies against diverse HIV strains has mostly been measured using Env-pseudotyped viruses, which overestimate bNAb coverage and potency. In this study we measured the neutralizing activity of nine bNAbs against clade A, C, and D HIV isolates derived from cells of African patients living with HIV and produced in peripheral blood mononuclear cells. We found that the coverage and potency of bNAbs were often significantly lower than what was predicted by Env-psuedotyped viruses, and that this decrease was related to the bNAb biding site class. This data is important for the planning and analysis of clinical trials that seek to evaluate bNAbs for the treatment and prevention of HIV infection in Africa.

Dataset Information

Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals.

Publications

Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals.

Similar Datasets

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