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Abstract
BackgroundNumerous studies have shown that viral quasi-species with genetically diverse envelope proteins (Env) replicate simultaneously in patients infected with the human immunodeficiency virus type 1 (HIV-1). Less information is available concerning the extent that envelope sequence diversity translates into a diversity of phenotypic properties, including infectivity and resistance to entry inhibitors.MethodsTo study these questions, we isolated genetically distinct contemporaneous clonal viral populations from the plasma of 5 HIV-1 infected individuals (n = 70), and evaluated the infectivity of recombinant viruses expressing Env proteins from the clonal viruses in several target cells. The sensitivity to entry inhibitors (enfuvirtide, TAK-799), soluble CD4 and monoclonal antibodies (2G12, 48d, 2F5) was also evaluated for a subset of the recombinant viruses (n = 20).ResultsEven when comparisons were restricted to viruses with similar tropism, the infectivity for a given target cell of viruses carrying different Env proteins from the same patient varied over an approximately 10-fold range, and differences in their relative ability to infect different target cells were also observed. Variable region haplotypes associated with high and low infectivity could be identified for one patient. In addition, clones carrying unique mutations in V3 often displayed low infectivity. No correlation was observed between viral infectivity and sensitivity to inhibition by any of the six entry inhibitors evaluated, indicating that these properties can be dissociated. Significant inter-patient differences, independent of infectivity, were observed for the sensitivity of Env proteins to several entry inhibitors and their ability to infect different target cells.ConclusionThese findings demonstrate the marked functional heterogeneity of HIV-1 Env proteins expressed by contemporaneous circulating viruses, and underscore the advantage of clonal analyses in characterizing the spectrum of functional properties of the genetically diverse viral populations present in a given patient.
Highlights
Numerous studies have shown that viral quasi-species with genetically diverse envelope proteins (Env) replicate simultaneously in patients infected with the human immunodeficiency virus type 1 (HIV-1)
Diversity of envelope sequences Phylogenetic analysis indicated that env sequences (C1-V2 region) for all clones from each patient clustered together along with the consensus sequence obtained for bulk envelope sequences amplified directly from plasma by reverse transcriptase (RT)-PCR (Fig. 1)
Viral isolates obtained from different individuals can differ in their sensitivity to inhibition by chemokines [26,27,28,29,30], entry inhibitors [3137], certain monoclonal antibodies [32,38], and autologous serum [26,39], but the extent that different viruses obtained from the same individual show similar sensitivity to a given entry inhibitor has not been extensively evaluated
Summary
Numerous studies have shown that viral quasi-species with genetically diverse envelope proteins (Env) replicate simultaneously in patients infected with the human immunodeficiency virus type 1 (HIV-1). In the evolution of infection, viruses expressing extremely homeogeneous env sequences become dominant, presumably reflecting the selection of viruses that are best adapted for replication in available target cells, and/or resistant to the nascent host immune response [1,2,3,7]. This initial homogenization is followed by a period often lasting many years, in which both the diversity of the env sequences and the evolutionary distance from the initially dominant strain increase linearly by approximately 1% per year [5,817]. The extent of viral diversity begins to plateau and, in the late stages of disease, a decline in viral diversity can be observed [8,11,12,18]
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