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Our Research

Dr Serra-MorenoThe Serra-Moreno lab studies the mechanisms by which Human Immunodeficiency Virus (HIV) and its close relative Simian Immunodeficiency Virus (SIV) circumvent the barriers of the innate immunity in their respective hosts and cause Acquired Immunodeficiency Syndrome (AIDS). Current projects in the lab are investigating the interplay between HIV/SIV and the cellular factors Tetherin/BST2, BCA2 and autophagy. 

Tetherin is an integral membrane protein that traps nascent virions to the plasma membrane, thereby, impeding their release and spread. Our previous studies demonstrated that while pandemic HIV-1 use Vpu and HIV-2 use Env, most SIVs use the Nef accessory protein to overcome restriction by non-human primate Tetherin. Nef achieves this by targeting a five amino-acid motif that is present in simian Tetherin but not in the human ortholog of this protein, which may explain why HIV-1 and HIV-2 needed to evolve alternative mechanisms (Vpu, Env) after their cross-species transmissions from non-human primates to humans (Jia and Serra-Moreno et al., PLoS Pathog. 2009; Serra-Moreno et al., Cell Host & Microbe 2011; Serra-Moreno et al., PloS Pathog. 2013). These observations highlight the extraordinary plasticity of the primate lentiviruses to counteract this restriction factor and suggest that Tetherin constitutes a significant obstacle for infectivity and cross-species transmission. 

BCA2 (Breast-Cancer Associated gene 2) is a co-factor in the restriction imposed by Tetherin on HIV. By interacting with Tetherin, BCA2 promotes the internalization and degradation of “tethered” virions. However, we found that BCA2 also exhibits Tetherin-independent antiviral activity. Specifically, BCA2 promotes the lysosomal degradation of the HIV protein Gag. Gag is the major driver of virion assembly and release. Therefore, the BCA2-mediated depletion of Gag significantly reduces virion production (Nityanadam and Serra-Moreno, PLoS Pathog. 2014). In addition to this effect, we recently uncovered that BCA2 is intimately connected with the innate immune system, since it modulates the transcription factor NF-κB. NF-κB is normally activated in response to infections and other insults. However, HIV takes advantage of the activation of this pathway, and uses NF-κB to enhance the expression of its viral genes. BCA2, on the other hand, potently shuts down NF-κB signaling, significantly impairing virus gene expression and replication (Colomer-Lluch and Serra-Moreno, J. Virol. 2017). Therefore, these observations provide additional mechanisms by which BCA2 represents a promising factor for antiretroviral therapy against HIV. In fact, we are currently investigating the potential of encapsulating BCA2 as a strategy to reduce active HIV replication and enforce a permanent state of transcriptional inactivity.

Autophagy is a highly conserved cellular response against stress such as viral infections. The role of autophagy in HIV infection has remained controversial in the last decade. Some reports state that HIV activates autophagy to enhance its infectivity, while others claim that HIV blocks specific steps in the autophagy machinery to prevent viral degradation. We recently found that autophagy poses a hurdle for HIV by targeting Gag for elimination. However, the virus uses Nef to circumvent this barrier. In particular, Nef enhances the association between the autophagy initiator BECN1 and its natural inhibitor BCL2, consequently impairing autophagosome biogenesis and restoring Gag levels. Nef achieves this by recruiting the cellular E3 ligase Parkin and facilitating the mono-ubiquitination of BCL2, a post-translational modification that renders BCL2 more stable and enhances in turn its inhibitory effect over BECN1. Phylogenetic analyses of closely related lentiviral species revealed that Nef’s ability to inhibit autophagy initiation is primarily observed among the most widely distributed pandemic clades of HIV-1 and their direct ancestors SIVcpz, which suggests that autophagy antagonism might have facilitated the spread of pandemic HIV-1 viruses in the human population (Castro-Gonzalez et al., Autophagy, accepted for publication). We are currently investigating the role of autophagy antagonism in HIV pathogenesis.