Investigation of in vitro Vpu function across major HIV-1 group M subtypes

Investigation of in vitro Vpu function across major HIV-1 group M subtypes

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Since the beginning of the epidemic, 78 million people have become infected with HIV and 35 million people died from AIDS-related illness. Although the number of new HIV infections has been reduced considerably since 1990 due to prevention interventions such as condom use and the increased availability of combination antiretroviral therapy (cART), the global HIV epidemic is still alarming. Despite tremendous biomedical research efforts, an effective vaccine or cure for HIV has not been developed.

A notable feature of HIV-1 is its extensive global genetic diversity. Isolates of the HIV-1 group M "pandemic" strain can be classified into nine subtypes, and inter-subtype recombinant forms emerge continually. The human immunodeficiency virus type 1 (HIV)-1 genome contains a number of "accessory" genes that are non-essential for viral replication in vitro, but critical to enhance viral pathogenesis in vivo. One of these genes is Vpu which encodes a multifunctional ~16kDa transmembrane protein. Vpu represents one of HIV-1's most genetically diverse regions; it increases viral replication and facilitates immune evasion. Vpu's best-characterized functions are its abilities to downregulate the HIV entry receptor CD4 and the antiviral protein tetherin from the surface of infected cells.  Together, these functions of Vpu help infected cells evade detection by innate and adaptive immune responses and also promote viral egress.

In this study, Umviligihozo analyses the function of the vpu isolates from samples collected from cART-naïve chronic HIV-infected patients from geographical areas with different predominant HIV-1 subtypes. To assess this, vpu clones are isolated and their function is assessed in vitro using a panel of genetically diverse vpu sequences representing HIV-1 subtypes A, B, C, and D from chronic virus-infected participants located in Canada, Uganda, and South Africa. The resulting data will be used to examine differences in these functions among natural Vpu isolates, specifically between subtypes, and to identify specific Vpu polymorphisms that are associated with reduced function.

This study will provide a comprehensive analysis of Vpu function in HIV-1 subtypes, including subtype C, which accounts for the majority of global infections. Results will improve our understanding of vpu sequence diversity and its consequences for protein function, which may inform the design of novel HIV-1 interventions, including vaccine and possible cure strategies.