Human Immunodeficiency Virus (HIV-1) Envelope glycoprotein (Env) sequentially binds the CD4 receptor and the CCR5 coreceptor for entry into CD4+ T-cells. Structural information from the unliganded Env trimer and the CD4-bound gp120 core, in addition to previous research on the molecular dynamics of CD4-gp120 binding, provides information about the transition between unliganded and CD4-bound conformations during viral entry. However, knowledge about the transition from the CD4-bound Env trimer to the fusion-active conformation, which includes the CCR5-bound Env conformation, is limited. This project attempts to fill this gap by investigating the effect of limiting CCR5 availability on viral entry by adapting CCR5-tropic HIV-1 to cells expressing low levels of CCR5. We will assess the role of these acquired adaptations on the entry process using available genetic, biochemical, and structural tools as well as assessing the effect of these changes within the context of an in vivo infection. Data on the transition between the CD4-bound and fusion-active Envs as triggered by CCR5 binding will provide insights into an integral step in HIV-1 biology.
The data gathered from the Research Strategy will be integral to the understanding of HIV-1 entry, viral resistance to CCR5 inhibitors, and the structural conformations of HIV-1 Envelope glycoprotein which could be targets of small molecule inhibitors and antibodies. Implications of this work are a better understanding of HIV-1 infection in humans and the elucidation of new methods to treat or prevent future infections.