Genetic variation in the envelope gene of HIV-1 results in biological changes in the virus. Globally, HIV-1 has been classified into eleven distinct viral clades, designated A-J, and O, based on phylogenetic properties of envelope genes. The best characterized viral clade, clade B, is the dominant HIV-1 subtype found in the Americas and Europe. Over 60 percent of infections with HIV-1, however, occur in sub-Saharan Africa. Multiple clades are found in African populations, including clades A, C, and D and the highly divergent clade O. Infections with clade A are most common throughout western, central and east Africa. Because the envelope gene contributes important features to viral phenotype, it is likely that clade-specific properties exist. The paradigm for HIV-1 pathogenesis and the strategies for therapeutic intervention are, however, based on HIV-1 clade B viruses. Models of early infection dynamics presuppose that an infection is initiated by a single viral variant that diversifies over time in response to selection pressures in the new host. As the virus diversifies, variants emerge which are phenotypically different than the founder population. This pattern of events may be more complex in African women because multiple variants are present in many individuals at seroconversion. The extent of diversity (2-5.5 percent) found in women are seroconversion is generally not achieved in an individual infected with a single variant until several years after infection. Because more than 50 percent of HIV-1 infections in Africa involve women, it will be important to characterize variants found at the time that infection is detected in African women to determine if properties of individual variants, or interaction among variants, may influence pathogenic potential of the viral population. The proposed experiments will test the hypothesis that (1) distinct genetic variants identified at seroconversion in clade A infected women will have different biological potentials (2) and that interaction between variants may lead to an evolutionary course that differs from that defined by studies of individual variants.
AIMS : (1). Viruses will be constructed and characterized that contain envelope genes from the heterogeneous seroconversion population of clade A HIV-1 infected women. (2) The ability of monoclonal antibodies to gp120 to recognize clade A variants will be determined, and the affect of antibodies on replication kinetics of the viruses will be assessed. (3) The genetic and phenotypic features of viruses that evolve in individual and in mixed cultures under antibody selection will be determined. (4) Structural models of clade A seroconversion envelope glycoproteins will be determined by homology modeling.
| Poss, Mary; Holley, David C; Biek, Roman et al. (2004) Development of a homology model for clade A human immunodeficiency virus type 1 gp120 to localize temporal substitutions arising in recently infected women. J Gen Virol 85:1479-84 |
| Painter, Sally L; Biek, Roman; Holley, David C et al. (2003) Envelope variants from women recently infected with clade A human immunodeficiency virus type 1 confer distinct phenotypes that are discerned by competition and neutralization experiments. J Virol 77:8448-61 |
