HIV genetic flexibility and evolution
A main feature of the human immunodeficiency virus (HIV) is its remarkable genetic flexibility, which appears to be the key to adaptation to the immune response from the host and to escape antiviral treatments. This flexibility is not unlimited, though, and understanding its constraints at the molecular level is central for identifying the inter- and intra-gene interactions that define the epistatic network essential for protein and genome functionality. Interfering with this network can impair viral replication.
Our laboratory has been interested in the study of genetic variability since several years. We have highlighted the central role played by viral genomic RNA structures in the generation of recombinant forms of HIV in the envelope gene (figure 1).
In particular, we have been interested in the mechanisms of generation and selection of recombinant forms, starting from primary isolates of HIV-1 group M. Two types of HIV have been identified (HIV-1 and HIV-2). While HIV-2 is restricted to defined geographical regions in Africa, HIV-1 is present worldwide. HIV-1 is subdivided in four groups M, N, O, and recently, P. Group M, which is responsible for most infections in the pandemics, is further subdivided in subtypes, called with letters from A to K (with letters E and I not used). This large diversity is further amplified by the occurrence of recombination among these different types and subtypes. This generates what are known as recombinant forms, which carry a mosaic genome. These recombinant strains might undergo a relevant epidemiological success and are, consequently, defined as circulating recombinant forms, or CRF (figure 2).
Some of these forms constitute predominant HIV strains in the pandemics. Which mechanisms are responsible for the establishment of these forms at the level of the pandemics remains largely unknown.
Crossing natural HIV isolates through recombination provides a remarkable tool to probe the existence of coevolution networks and epistatic interactions (figure 3).
In fact, by bringing together, in a single infectious cycle, large portions of genomes of divergent phylogenetic origin, recombination can perturb these networks in the recombinant progeny, decreasing its fitness. Projects developed in the laboratory are aimed at revealing epistatic interactions that constrain the variability of viral proteins. Among the several HIV genes we are interested in, the HIV envelope is the most intensively studied. For the HIV envelope, in particular, there appears to be a clear lack of information about the spatial rearrangements that gp120 (the outer portion of the envelope) undergoes to ensure the achievement of its various tasks for efficient viral entry into the target cell. Understanding the rules that govern the dynamic of HIV envelope evolution in the pandemics could be precious not only for understanding how HIV manages to balance the competing requirements for the maintenance of functionality and antigenic variation, but also to pinpoint vulnerable aspects of Env functionality.
To address these issues, we rely on the use of original genetic approaches based on cell culture assays and the laboratory has several well-established international collaborations for developing complementary approaches, as phylogenetic and structural studies.
- David Roberston (Manchester, UK)
- Darren Martin (Cape Town, South Africa)
- Jeff DeStefano (College Park, MD, USA)
- Rafael Sanjuan, Moya Laboratory (Valencia, Spain)
- Cecilia Graziosi, (Lausanne, Switzerland)
- Andrés Finzi, (Boston, MA, USA)
- Vincenzo Di Bartolo, (Paris, France)
- Kevin Weeks (Chapel Hill, NC, USA)
- Eric Arts (Cleveland, OH, USA)