The human immunodeficiency virus (HIV) relies on a protective shell, the capsid, to shield its genetic blueprint. This internal structure encases the viral RNA and several enzymes, safeguarding them as the virus travels between cells. The capsid is fundamental for the virus’s ability to establish and maintain an infection. Without this barrier, the virus cannot complete its life cycle.
The HIV Capsid’s Architecture
The HIV capsid presents a unique, elongated conical structure within the mature virus particle. This distinctive shape forms from the precise assembly of thousands of identical p24 protein units. These p24 proteins self-assemble to create a stable, symmetrical container.
This architecture protects the virus’s genetic material (single-stranded RNA) and enzymes like reverse transcriptase, integrase, and protease. Its stability is maintained by interactions between p24 units. This arrangement ensures the viral core’s integrity, allowing it to withstand environmental stresses until it reaches a host cell.
How the Capsid Functions in HIV Infection
The HIV capsid plays dynamic roles throughout the viral life cycle, starting when the virus enters a host cell. Upon entry, the capsid remains intact, shielding viral contents from cellular defenses. This allows the virus to navigate the cellular environment until it reaches the appropriate location for replication. The capsid then undergoes a precise disassembly process, known as uncoating, releasing its viral RNA and enzymes into the host cell cytoplasm.
The timing and location of this uncoating are tightly regulated, ensuring the viral genetic material is exposed only when and where it can be effectively used by the host cell machinery. Following uncoating, partially intact capsid components guide the newly synthesized viral DNA towards the nucleus. This facilitates transport of the pre-integration complex across the nuclear pore, a necessary step for viral DNA to integrate into the host genome.
In the later stages of the viral life cycle, new p24 proteins are synthesized within infected cells. These proteins assemble into immature, spherical capsid structures as new virus particles bud from the cell. After budding, a viral enzyme called protease cleaves precursor proteins, allowing the immature capsid to undergo a final rearrangement. This maturation transforms the spherical structure into the infectious, conical shape of mature HIV particles, preparing them to infect new cells.
Why the Capsid is a Drug Target
The HIV capsid is an appealing target for antiretroviral drugs due to its multifunctional roles. Its involvement in viral entry, uncoating, nuclear import, assembly, and maturation means interfering with its function can halt viral replication. The capsid’s structure is also unique to the virus, offering potential for drugs that specifically target HIV without affecting host cellular processes.
Drugs can interfere with capsid function in several ways, such as by stabilizing the capsid to prevent uncoating, thereby trapping the viral contents. Alternatively, some compounds can destabilize the capsid, leading to premature uncoating and degradation of the viral genome. Other drug candidates might disrupt the assembly process of new capsids, preventing the formation of infectious viral particles. Lenacapavir is an example of a capsid inhibitor drug that works by interfering with multiple steps of the HIV life cycle. It prevents the proper assembly of new capsids and also causes premature uncoating of the viral core in newly infected cells, thereby blocking the virus’s ability to replicate and spread.
Lenacapavir is a first-in-class HIV-1 capsid inhibitor that binds to p24 protein subunits. This binding interferes with multiple stages of the viral replication cycle, including nuclear uptake of HIV-1 proviral DNA and virus assembly. The drug works by altering the structure and stability of the assembled capsid, leading to premature breakage before the virus can fully convert its RNA into DNA. This disruption prevents successful infection.