Role of HIV-1 capsid in innate sensing of viral nucleic acids

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Abstract Despite the development of dozens of drugs since the start of the HIV/AIDS epidemic, the emergence of drug resistance and lack of a vaccine or cure necessitate the development of new antiretroviral compounds. The HIV-1 capsid (CA) protein plays essential roles throughout the viral replication cycle. After an immature HIV-1 virion buds from a host cell, the structural Gag polyprotein undergoes proteolytic cleavage and rearrangement. The retroviral core is formed when rings of CA, held together by intra- and inter-subunit interactions, arrange into a conical lattice around the viral genomic RNA (gRNA) and enzymes. Since many CA-CA interactions are required to form a stable lattice, CA is genetically fragile and a favorable drug target. In fact, compounds that successfully target CA assembly and stability have recently been developed as part of long-acting drug regimens and show great promise clinically. Following their release into the cytoplasm of target cells, HIV-1 cores undergo an uncoating process in which CA subunits are shed from the core. It is now evident that proper uncoating is crucial for subsequent steps in virus replication, including reverse transcription, nuclear entry, and integration. We have recently demonstrated that destabilization of the CA lattice through mutations and CA-targeting compounds increases the propensity to form aberrant virus particles. In these particles, the gRNA and enzymes are localized between the CA lattice and viral envelope. Interestingly, this phenotype has striking similarities with the eccentric virions that are generated by inhibition of integrase (IN)-gRNA interactions. We have shown that the lack of protection by the CA lattice in both circumstances results in premature loss of gRNA and IN in a proteasome-independent manner. However, the mechanism by which IN and gRNA are degraded upon loss of CA protection remains unclear. Furthermore, recent studies have implicated that CA may shield viral nucleic acids from the host sensor proteins that initiate antiviral responses. I hypothesize that tampering with the stability of the HIV-1 CA lattice will result in premature exposure and sensing of viral nucleic acids in infected cells. Here, I propose to determine how prematurely exposed viral ribonucleoprotein complexes (vRNPs) are degraded in target cells (Aim 1). I plan to determine if altered CA stability elicits a more robust innate immune response against HIV-1 and the mechanism by which viral nucleic acids are sensed (Aim 2). Together, the results of these experiments will contribute to a better understanding of the proposed role of CA in virus replication and evasion of innate immune sensing.