Fold Recognition and Flexibility of the HIV-1 V3-Loop Crown Structure during the Course of Adaptation to a Host

Human immunodeficiency virus type 1 (HIV-1) has a principal neutralizing determinant (PND) located in the external envelope protein, gp120. The PND is part of the third hypervariable region (V3), which is a surface-accessible loop of gp120. Many aspects of HIV-1 viral infectivity are integrated into the V3 region. The PND sequence contains a GPG motif that is usually conserved between different HIV-1 isolates and amino acids at flanking residues around the motif differ from isolate to isolate. Sequence variation in the V3 region has been linked to changes in several different phenotypes: cell tropism, the ability to induce syncytia, and progression from an initial infection to AIDS. These phenotypes were often found to be associated with the differential use of chemokine receptors. Viruses that use the chemokine receptor CCR5, CXCR4, or both are termed R5, X4, and R5X4, respectively. Intra-host populations of HIV-1 show considerable genetic diversity due to high rates of mutation. A key point on viral evolution is coreceptor switching from CCR5 to CXCR4, and patterns of molecular evolution consistent with the coreceptor usage have been analyzed within single patients [2]. The V3 sequence is likely influenced by coreceptor usage. To understand the genetic basis of viral adaptation, we examined the dynamics of structural flexibility and fold recognition of the V3 region within a single host. Using the existing structural information obtained by X-ray crystallography and NMR spectroscopy [3], we were able to define the “universe” (full spectrum) of V3-loop structures. For each sequence, the structural distribution in the universe was estimated by the inverse folding approach. The strength of sequence-structure fitness (SSF) was also calculated, taking into account the uncertainty of the structure, and it was found that toward the end of the asymptomatic period, the SSF had weakened. The results of analysis of viral sequences within patients implied that the structural flexibility depended on the patient. We discuss possible sources of these structural features of the V3-loop.