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overview
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The research in our lab focuses on delineating the interactions between HIV-1 and host, as well as HIV-1 and other human microbes with the effort on finding a solution to inhibit HIV-1 replication. We have following three ongoing projects.
1. Mucosal surfaces serve as the predominant point of transmission for human immunodeficiency virus (HIV-1). However, it is well-documented that the transmission/acquisition of HIV-1 through oro-genital contact is rare. The risk associated with the vaginal acquisition of HIV-1 after sexual contact with a HIV-1 positive individual is 0.03% to 0.2%, while the risk of oral acquisition is estimated to be 20 times less. This indicates that the protection provided by the innate and adaptive immune system of the host is robust, but varies according to the mucosal site. APOBEC3G (A3G) is a potent host restriction factor of HIV-1. It has been shown that A3G blocks HIV-1 replication or transmission when its expression is up-regulated. Streptococcus Cristatus CC5A is a non-pathogenic oral bacterial. We found that a small molecule of Streptococcus cristatus CC5A (S. cristatus CC5A) was able to up-regulate APOBEC3G expression and inhibit HIV replication. Now we are working on developing a novel, efficient anti-HIV/AIDS strategy using this molecule.
2. GB virus type C (GBV-C, also called hepatitis G virus) is a single, positive strand RNA virus in the Flaviviridae family. It has not been conclusively associated with any known disease, although it is a very common infection in humans. Most of the cohort studies about the interaction of GBV-C and HIV-1 showed that GBV-C infection could prolong AIDS patient survival. Since GBV-C shares the same transmission pathway with HIV-1 and replicates in CD4+ T cells, it could be a very promising candidate for establishing novel anti-AIDS therapy strategies and gene therapy vectors which specifically deliver anti-HIV genes to CD4+ T cells. In our study, we found that when one of GBV-C structural protein E2 was co-expressed with the HIV-1 proviral construct, HIV-1 Gag processing was dramatically inhibited resulting less virus has been released. This may shed light on developing GBV-C as novel anti-HIV/AIDS strategy. We are working on elucidating the mechanism of GBV-C’s anti-HIV/AIDS effect and testing whether we could develop a novel anti-HIV/AIDS drug based on this discovery.
3. We are trying to understand the interaction between HIV-1 Vif and APOBEC3G (A3G). A3G is a host restriction factor of HIV-1. HIV encodes Vif to overcome A3G antiviral effect. It is well-established that Vif counteracts A3G via proteasome-mediated A3G degradation and repression of A3G translation. Such a mechanism is essential for the production of infectious virions because inclusion of A3G in Vif-deficient virions has been shown to result in non-infectious particles. However, clinical and laboratory evidence, including that of our group, has shown that A3G is detectable in Vif competent HIV-1 viral particles without affecting their infectivity. How HIV solves this conundrum remains unclear. We have been addressing the above paradox by examining A3G activities in the presence of Vif. We showed that besides depleting A3G, Vif directly inhibits A3G cytidine deaminase activity, which is necessary for G-to-A hypermutation in an exogenous protein expression system. As a result, the presence of functional Vif significantly reduces the rate of G-to-A hypermutations generated by A3G to promote HIV replication. Right now we are further evaluating this phenotype under physiologically relevant condition and working on the identification of the specific interaction domains which play a role in inhibiting A3G cytidine deaminase activity. Understanding details of the interaction between APOBEC and HIV-1 Vif will shed light on anti-HIV/AIDS drug design.
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