(306b) Mechanistic Insights into Differential Coreceptor Usage By HIV to Inform the Design of Novel Vaccine-Candidate Antigens

Human Immunodeficiency Virus (HIV) has caused an ongoing global epidemic since 1981, and 38 million people are currently living with the disease worldwide¹. HIV’s envelope glycoprotein, Env, is a heterotrimer composed of subunits gp120 and gp41. To infect cells, gp120 first binds human host cell receptor CD4, which induces a conformational change in gp120 that allows it to then bind a second coreceptor. In early HIV infection, which is typically initiated by a single transmitter/founder (T/F) viral strain, the second coreceptor of choice for gp120 is usually CCR5. In approximately 50% of HIV-positive individuals, gp120 evolves to utilize another host coreceptor, CXCR4, which is associated with a faster progression to AIDS³. Which coreceptor gp120 utilizes describes that strain’s tropism—R5 tropic, X4-tropic, or R5/X4-tropic (able to utilize CCR5, CXCR4, or both, respectively). A multitude of evidence suggests mutations in the V3 loop of gp120 play a key role in mediating HIV tropism switching⁴. However, the underlying molecular mechanisms remain unclear. Elucidating these mechanisms is crucial to understanding why tropism switching occurs in only a subset of HIV-infected individuals, and how immunotherapies might be designed to prevent this switch from occurring, thus slowing or even preventing the progression to chronic disease.

We hypothesized that despite the highly diverse set of mutations that can arise in the V3 loop of gp120 to enable this switch in coreceptor usage, conserved molecular mechanisms nonetheless exist to facilitate improved gp120 binding to CXCR4. To elucidate these mechanisms, we introduced mutations associated with X4-tropism into the structure of the V3 loop of a T/F, R5-tropic strain of gp120 bound to both CCR5 and CXCR4 embedded in a lipid bilayer. We simulated these systems with molecular dynamics for 100 nanoseconds each. Our results show that introducing diverse X4-tropic mutations into CCR5-bound gp120 consistently leads to reduced binding to CCR5 and increased binding to CXCR4. Further, these increases in binding arise via conserved mechanisms that revolve around the extracellular loop 2 and N-terminal tail of CXCR4, supporting our hypothesis. Overall, this study contributes new molecular-level insights into differential coreceptor usage by HIV, which may inform future efforts to design vaccine-candidate HIV-based antigens with certain mutations to control tropism switching and prevent chronic infection.

References:

[1] HIV.gov, Global Statistics, The Global HIV/AIDS Epidemic. (2022).

[2] Rawson et. al, HIV-1 and HIV-2 exhibit similar mutation frequencies and spectra in the absence of G-to-A hypermutation. Retrovirology, 12, 60. (2015).

[3] Coetzer et. al, Genetic characteristics of the V3 region associated with CXCR4 usage in HIV-1 subtype C isolates. Virology, (356): 95–105. (2006).

[4] Jacquemard et. al, Modeling of CCR5 recognition by HIV-1 gp120: How the viral protein exploits the conformational plasticity of the coreceptor. Viruses, 13, 1395. (2021).