Anti-HIV type 1 Glycoprotein 120 Monoclonal antibody, Clone GD0.F6

Human Immunodeficiency Virus 1 (HIV-1) evades adaptive immunity by means of its extremely high mutation rate, which allows the HIV envelope glycoprotein to continuously escape from the action of antibodies. However, some broadly neutralizing antibodies (bNAbs) targeting specific viral regions show the ability to block the infectivity of a large number of viral variants. The discovery of these antibodies opens new avenues in anti-HIV therapy; however, they are still suboptimal tools as their amplitude of action ranges between 50% and 90% of viral variants. In this context, being able to discriminate between sensitive and resistant strains to an antibody would be of great interest for the design of optimal clinical antibody treatments and to engineer potent bNAbs for clinical use. Here, we describe a hierarchical procedure to predict the antibody neutralization efficacy of multiple viral isolates to three well-known anti-CD4bs bNAbs: VRC01, NIH45-46 and 3BNC117. Our method consists of simulating the three-dimensional binding process between the gp120 and the antibody by using Protein Energy Landscape Exploration (PELE), a Monte Carlo stochastic approach. Our results clearly indicate that the binding profiles of sensitive and resistant strains to a bNAb behave differently, showing the latter's weaker binding profiles, that can be exploited for predicting antibody neutralization efficacy in hypermutated HIV-1 strains.

An emerging realization of infectious disease is that pathogens can cause a high incidence of genetic instability within the host as a result of infection-induced DNA lesions. These often lead to classical hallmarks of cancer, one of which is the ability to evade apoptosis despite the presence of numerous genetic mutations that should be otherwise lethal. The Human Immunodeficiency Virus type 1 (HIV-1) is one such pathogen as it induces apoptosis in CD4+ T cells but is largely non-cytopathic in macrophages. As a consequence there is long-term dissemination of the pathogen specifically by these infected yet surviving host cells. Apoptosis is triggered by double-strand breaks (DSBs), such as those induced by integrating retroviruses like HIV-1, and is coordinated by the p53-regulated long noncoding RNA lincRNA-p21. As is typical for a long noncoding RNA, lincRNA-p21 mediates its activities in a complex with one of its two protein binding partners, namely HuR and hnRNP-K. In this work, we monitor the cellular response to infection to determine how HIV-1 induces DSBs in macrophages yet evades apoptosis in these cells. We show that the virus does so by securing the pro-survival MAP2K1/ERK2 cascade early upon entry, in a gp120-dependent manner, to orchestrate a complex dysregulation of lincRNA-p21. By sequestering the lincRNA-p21 partner HuR in the nucleus, HIV-1 enables lincRNA-p21 degradation. Simultaneously, the virus permits transcription of pro-survival genes by sequestering lincRNA-p21's other protein partner hnRNP-K in the cytoplasm via the MAP2K1/ERK2 pathway. Of particular note, this MAP2K1/ERK2 pro-survival cascade is switched off during T cell maturation and is thus unavailable for similar viral manipulation in mature CD4(+) T cells. We show that the introduction of MAP2K1, ERK2, or HDM2 inhibitors in HIV-infected macrophages results in apoptosis, providing strong evidence that the viral-mediated apoptotic block can be released, specifically by restoring the nuclear interaction of lincRNA-p21 and its apoptosis protein partner hnRNP-K. Together, these results reveal a unique example of pathogenic control over mammalian apoptosis and DNA damage via a host long noncoding RNA, and present MAP2K1/ERK2 inhibitors as a novel therapeutic intervention strategy for HIV-1 infection in macrophages.