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Anti-HIV antibodies: predicting in vivo efficacy in vitro

A study by an IDMIT team (CEA-Jacob) provided an
in vitro approach for predicting the in vivo efficacy of antibodies used to prevent HIV-1 transmission. The work identified antibodies capable of efficaciously blocking intercellular viral transmission in infected semen. The work, published in EBioMedicine, gives new perspectives for HIV infection prevention and treatment.

Published on 7 August 2020

​Human immunodeficiency virus (HIV) infection, must frequently due to the type 1 variant (HIV-1)1, is still a major public health issue. Since the identification of the first cases more than 35 years ago, 78 million people have been infected by HIV and 35 million have died of AIDS-related diseases2. HIV research is progressing, but the development of an efficacious vaccine has proved difficult due to the extensive genetic variability of the virus; indeed this latter is particularly talented for adaptation and mutation. Understanding HIV infection mechanisms is essential for disease control and prevention.

Propagation initiated by HIV-infected cells is 10 to 100-fold more efficacious than that initiated by free-floating viral particles. The principal HIV transmission vector is the semen of infected men. Therein, both infected cells and free-floating particles are to be found. During sexual intercourse, the infected cells interact with exposed mucous membranes, thus transmitting the virus. Because they are both viral reservoirs and important players in immune antibody response pathways, infected leukocytes in the semen play a particularly important role in this transmission.

For several years now, researchers have been focusing on broadly neutralizing antibodies (bNAbs), which are produced naturally by certain infected patients and able to neutralize several viral strains. Technological advances have enabled the synthesis of a range of bNAbs panels targeting proteins in the HIV envelope. These bNAbs thus open doors to novel prevention and therapeutic strategies. Understanding how they function will advance research on vaccines that activate their production, and furthermore enable the exploration of immunotherapies involving combinations of bNAbs to thwart viral mutations.

To reach those goals, researchers need physiologically-pertinent in vitro systems that are capable of predicting the in vivo efficacy of bNAbs. To date, in vitro studies seem to suggest that bNAbs are less efficacious in preventing cell-to-cell transmission than they are in preventing free particle transmission, but that finding is not coherent with in vivo observations. However, few studies have specifically explored intercellular transmission and none have looked at viral transmission in vitro in in vivo-harvested infected leukocytes.  

Researchers from the Immunity and Transmission Laboratory of IDMIT (CEA-Jacob) piloted a study, published in EBioMedicine, in which they and their partners sought to identify in vitro the bNAbs that, alone or in combination, offered the best efficacy against intercellular HIV-1 transmission in vivo. The study was the first to perform experiments on cells infected in vivo instead of in vitro. Specifically, the team harvested spleen cells (rich in immune cells) and leukocytes from the semen of cynomolgus macaques infected with SHIV162P3, a simian equivalent of and thus a model for HIV-1.

First, using routine in vitro systems, the researchers examined the infectious potential of the infected splenocytes to optimize test conditions. Complementary analyses confirmed that the immune cell contents of the spleen and semen where similar, thus ensuring that the test conditions optimized via the splenocytes would also function correctly for the semen leukocytes. In vivo, the inoculation of cells from the spleen, like those from the semen, caused infection, confirming the pertinence of the in vitro test.

Thereafter, bNAbs with different specificities for different elements of the viral envelope were selected. Their abilities, when used individually or in combination, to inhibit transmission by infected splenocytes were evaluated in vitro and compared to available data on transmission by free viral particles.

The team's efforts identified a promising combination of three bNAbs as well as a bNAb highly efficacious against intercellular transmission in both infected spleen cells and semen leukocytes.

The researchers unprecedentedly demonstrated that bNAbs can prevent intercellular HIV-1 transmission in infected semen. Their work lends credence to the use of bNAbs in preventative or therapeutic studies looking to block not only free-particle but also intercellular transmission. The team's experimental system could be deployed to predict the in vivo efficacy and sensitivity of bNAbs.

1     There are two human immunodeficiency viruses, HIV-1 and HIV-2, which differ by certain molecular aspects. In France, more than 98% of HIV infections are due to HIV-1. This latter is also categorized into four groups, M, N, O and P. The most prominent of them, group M, is further divided into more than 10 subtypes. HIV-2 appears to be less virulent and communicable. It is encountered primarily in western Africa.  

2     Data taken from Global HIV & AIDS statistics — 2020 fact sheet published by UNAIDS 

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