Influence of cellular proteins incorporate in HIV-a virions in modulating viral infectivity

Resumen

A B S T R A C T More than 30 years after the discovery of HIV-1, AIDS still represents a pandemic emergency. The implementation of antiretroviral ther- apy (ART) has been a milestone in the treatment of HIV-1 infected individuals, nevertheless the spread of drug-resistant strains and the long-term side effects arising in patients on ART, call for the character- ization of new therapeutic targets. A number of host proteins are selectively incorporated into the HIV-1 envelope when the virus buds from the cell membrane and several studies attest the contribution of these virally acquired cell proteins in virus infectivity. The aim of this thesis was to explore the role of HLA-C and gelsolin in the viral life cycle in order to generate knowl- edge exploitable for the design of new therapeutic strategies in the near future. In a past work performed by our lab, HLA-C molecules incorpo- rated within the HIV-1 envelopes have been shown to bind to the envelope glycoprotein gp120 and to enhance viral infectivity. In this thesis we looked for further informations about this association and show for the first time the subcellular distribution of these two interact- ing proteins into the cell. By using a particular model system lacking b2-microglobulin, we provide evidence that the HLA-C /Env complex involves free heavy chains of HLA-C, devoid of b2-microglobulin, and we show that the propensity of Env to associate with HLA-C is a unique capacity of HIV-1 Env, which is not displayed by other viral envelopes nor other HIV-1 proteins. In view of these results and taking into account that MHC molecules have been yet shown to participate in the translocation of viral proteins, we speculate that HLA-C may act as a chaperon of Env during the budding process. Several groups have reported that the reorganization of cortical actin is fundamental to promote efficient viral entry. This process increases the probability of HIV-1 to interact with the viral receptors which mediate its entry into the cell. Here, we provide the first evidence that, by severing cortical actin, gelsolin provokes changes in actin reorganization and drives the receptors implicated in viral infection to one pole of the cell. Altering gelsolin activity perturbs this actin reorganization and the redistribution of viral receptors, severely re- stricting early HIV-1 entry. Thus, we propose that gelsolin is a new factor that can limit HIV-1 infection and accordingly, cell-signals that regulate gelsolin expression and/or its actin-severing may be crucial to combat HIV-1 infection.