HIV LATENCY--MOLECULAR MECHANISM FOR PERSISTENCE

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DESCRIPTION: (Adapted from applicant's abstract) Lymphocytes latently infected with HIV are present in lymph nodes of HIV-infected patients. The ability of HIV to go into latency, therefore, is likely an important mechanism of HIV persistence by rendering the infected cell masked to anti-viral immune response. It also likely explains why HIV re-appears after patients are taken off of protease inhibitors. This project aims to elllucidate viral controlling elements which affect both the rate and the molecular mechanisms of this shutdown. It extends our studies showing that HIV shutdown into latency is the normal outcome following acute replication in T-cell lines and normal PBLs. This shutdown process can be studied kinetically without having to rely on using the established latently-infected clonal lines which are already latent. We found that the rate that HIV goes into latency, as well as the molecular mechanism of shutdown, are both influenced by independent viral sequences. The determinant for the variable rate of shutdown mapped to a single nucleotide(+48) in the LTR. Our ainu are to:(1) Assess the rates and molecular mechanisms of chronic shutdown of different HIV isolates in normal CD4 lymphocytes;(2) Determine the viral genes, and relevant sequences within those genes, which determine the molecular mechanism of chronic shutdown of HIV; (3) Characterize the molecular events involved in the different mechanisms of shutdown; and (4) Determine how NT+48 in TAR affects the rate of shutdown