HIV Replication: From Entry to Maturation in Host Cells

Human Immunodeficiency Virus (HIV) is a retrovirus responsible for Acquired Immunodeficiency Syndrome (AIDS). Understanding its replication process within host cells is essential for developing treatments and preventive strategies. The virus’s ability to hijack cellular machinery allows it to persist in the body, making eradication challenging.

The journey from viral entry to maturation involves several key steps, each offering potential targets for therapeutic intervention.

Viral Entry

The initial step in the HIV replication cycle is the virus’s entry into a host cell, typically a CD4+ T lymphocyte. The viral envelope glycoprotein, gp120, binds to the CD4 receptor on the host cell surface. This binding triggers conformational changes in gp120, allowing interaction with a co-receptor, usually CCR5 or CXCR4. The choice of co-receptor is influenced by the viral strain and can affect the virus’s pathogenicity and disease progression.

Once gp120 engages both the CD4 receptor and a co-receptor, another viral protein, gp41, facilitates the fusion of the viral envelope with the host cell membrane, releasing the viral core into the cytoplasm. This fusion process is a target for antiretroviral drugs like enfuvirtide, which inhibit gp41 and prevent the virus from entering the cell.

Reverse Transcription

After the viral core enters the host cell’s cytoplasm, reverse transcription begins. This process is orchestrated by the enzyme reverse transcriptase, which is carried within the viral core. Unlike most cellular enzymes, reverse transcriptase is error-prone, leading to mutations within the viral genome and rapid genetic diversity. This diversity poses a challenge for vaccine development, as it allows the virus to adapt to immune pressures and antiretroviral drugs.

Reverse transcription involves converting the viral RNA genome into DNA. Initially, the enzyme synthesizes a complementary DNA strand (cDNA) from the RNA template, followed by the degradation of the RNA strand, leaving a single-stranded cDNA. The enzyme then constructs a second DNA strand, resulting in a double-stranded DNA molecule known as the provirus, primed for integration into the host’s genomic DNA.

Integration into Genome

Following the synthesis of the proviral DNA, integration into the host genome occurs. This process is mediated by the enzyme integrase, which facilitates the insertion of the proviral DNA into the host’s chromosomal DNA. The virus tends to favor transcriptionally active regions of the host genome, ensuring efficient transcription of viral genes.

The integration site selection is influenced by factors such as chromatin structure and specific host proteins. This strategic positioning allows the virus to remain latent, evading immune detection and antiretroviral drugs. Latency is a barrier to eradicating HIV, as the integrated provirus can persist in a dormant state, reactivating when conditions are favorable.

Transcription and Translation

Once integrated into the host’s genome, the provirus undergoes transcription and translation, transforming genetic information into viral proteins. Transcription initiates when the host’s RNA polymerase II binds to the long terminal repeat (LTR) sequences of the proviral DNA, resulting in the synthesis of viral mRNA. This mRNA is processed and exported from the nucleus to the cytoplasm, serving as a template for protein synthesis and as genomic RNA for new virions.

In the cytoplasm, the viral mRNA is translated into structural and regulatory proteins. The translation involves host ribosomes and cellular factors, producing key proteins like Gag, Pol, and Env, crucial for assembling new viral particles. The Gag-Pol polyprotein undergoes proteolytic cleavage by the viral protease, producing functional enzymes such as reverse transcriptase, integrase, and protease itself.

Assembly of Components

Once the viral proteins are synthesized, the assembly of new virions begins. The Gag protein, crucial for assembling the viral core, accumulates at the inner surface of the cell membrane, orchestrating the packaging of the viral RNA genome and associated proteins. As Gag multimerizes, it recruits other viral proteins and two copies of the viral RNA, forming an immature viral particle.

The Env proteins, including gp120 and gp41, are synthesized in the rough endoplasmic reticulum and transported to the cell membrane via the Golgi apparatus. These proteins become embedded in the host cell membrane, positioning themselves to be incorporated into the budding virion.

Budding and Maturation

As assembly nears completion, the budding process begins, allowing the nascent virion to exit the host cell. The immature viral particle pushes against the host cell membrane, which envelops it, eventually pinching off to release the virion into the extracellular space. The budding process is mediated by host cell machinery, particularly the ESCRT system, which assists in membrane scission.

Following budding, the virion undergoes maturation, vital for its infectivity. Maturation involves the proteolytic cleavage of the Gag and Gag-Pol polyproteins by the viral protease, resulting in the formation of a mature viral core. This restructuring is crucial for converting immature, non-infectious particles into fully infectious virions. Protease inhibitors, a class of antiretroviral drugs, target this step, highlighting the therapeutic potential of disrupting viral maturation.