Viral Entry and Pathogenesis

Principal Investigator:

The common goal of our research is to gain an understanding of the cellular and molecular processes that govern the initial interactions between the human immunodeficiency virus (HIV) and the cell surface and how these processes affect cytopathicity, and pathogenicity both in cell culture models and in vivo.

Three branches of research stem from this primary objective:

1. We began our work by trying to understand the mechanism of action of anti-HIV agents that block the early steps of the virus life cycle. HIV must interact with cellular receptors at the cells surface and this, in turn, may be used as a target to intervene viral replication. Attachment of HIV to the cell surface, receptor and coreceptor interaction and virus-cell fusion are mechanisms that are driven by the virus glycoprotein complex gp120/gp41. A lot can be learnt by studying the antiviral properties of agents designed to block these mechanisms. A notable aspect of our work has been the development of HIV variants that are resistant to agents that block virus-cell binding, virus interaction with chemokine receptors, and to inhibitors of gp41-dependent fusion. Development of HIV-resistance has shed light into the mechanism of action of these inhibitors. We now know the molecular determinants that confer drug resistance, the molecular targets of early inhibitors and clarified how HIV resistance to the drugs alters the replication capacity of HIV, its pathogenicity and tropism to distinct cell types. Our work with early inhibitors of HIV life cycle has allowed us to begin, in collaboration with local and international groups, a modest but expanding drug screening program for the evaluation and development of new anti-HIV agents.

2. The envelope glycoprotein complex gp120/gp41 (env) is a determinant factor in the pathogenicity of HIV. CD4+ and CD8+ cells die through direct and indirect mechanisms some of which may be induced by the envelope glycoproteins through intracellular signals that either predispose the cell for productive infection but that, at the same time, may trigger defence mechanisms that lead to cell death We attempt to identify those mechanisms that promote virus replication and cell death though the use of RNA interference and cell culture of primary cells susceptible to HIV infection.

3. Viral evolution is rapid and involves the adaptation of HIV to its host and eventually, the emergence of virus strains with increased replication capacity, expanded tropism and greater pathogenicity. However, many of these phenomena appear to remain silent during the clinical latency of the infection and are triggered by yet unknown mechanisms. The third branch of our work attempts to identify those factors in the host that maintain HIV pathogenicity and cell tropism at bay for long periods of time and the events that trigger the evolution of HIV into more pathogenic, malignant variants. Crossectional, longitudinal and clinical trials are currently ongoing to evaluate coreceptor expression, cytokine and chemokine levels in HIV+ individuals and HIV-induced cells death and pathogenicity in patients under antiretroviral therapy with current, approved drugs or experimental treatments that target virus-cell fusion.

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