Intrinsic immune response to viral replication in primates

Description

The host immune defense against viruses includes innate, adaptive and intrinsic mediators. Humans vary in their susceptibility to human immunodeficiency virus type 1 (HIV-1) acquisition and in the level of HIV-1 replication following infection. The objective of this dissertation was to define genetic mechanisms underlying the variable intrinsic susceptibility of primate species to virus infection. Through an analysis of the differential permissivity of rhesus monkeys for simian immunodeficiency virus (SIV) replication, we identified a dominant, capsid specific antiviral factor that limited early reverse transcription of SIV in a subset of animals. Through candidate gene sequencing, we identified a causal relationship between rhesus monkey susceptibility to SIV replication, in vitro and in vivo, and polymorphims of the cytoplasmic tripartite motif protein 5alpha (TRIM5alpha) protein. TRIM5alpha has been shown to restrict the replication of a broad range of retroviruses in a species-specific manner. We present data that the B30.2 domain of TRIM5alpha is a key determinant of SIV susceptibility in rhesus monkeys. We extended our observations to the examination of the role of the human intrinsic immune response for controlling HIV-I replication. Through genomewide association analysis of the susceptibility of a large cohort of human Blymphoblastoid cell lines (B-LCLs) for VSV-G pseudotyped HIV-GFP infection, we found no evidence of common gene variants that significantly impact intrinsic susceptibility of human cells to HIV-1 replication. Lastly, through the examination of monkey B-LCL susceptibility for virus replication, we have described a novel molecular mechanism for differential susceptibility of rhesus monkeys for herpesvirus infection. We examined the role of rhesus monkey TRIM5alpha alleles on the control of endemic non-retroviral pathogen replication in vitro and in vivo in rhesus monkey populations. We found a significant restriction of rhLCV and rhCMV by a subset of rhesus TRIM5alpha alleles. Moreover, expression of these rhTRIM5alpha alleles restricts rhLCV replication in transduced TRIM null cell lines. Finally, these TRIM5alpha alleles are associated with reduced antirhLCV and anti-rhCMV IgG titers in rhesus monkeys. We hypothesize that balancing evolutionary selection forces could be responsible for maintaining primate TRIM5alpha alleles which have reduced lentivirus affinity and enhanced herpesvirus affinity.

Subjects

Series Statement

• Collections of the Harvard University Archives