HIV Life Cycle - Advanced
The HIV virion comprises single-stranded RNA.
It is diploid, because there are two copies of the RNA.
Within the virion, capsid proteins protect the viral RNA.
Surface proteins interact with host cells, which enable attachment and provoke immune responses.
HIV targets CD4+ cells; and exists as a variety of diverse strains.
HIV Strains
We can broadly categorize the strains based on the types of chemokine co-receptors used during host cell invasion:
R5 HIV strains interact with CCR5 co-receptors; these strains predominate early in infection.
X4 strains interact with CXCR4 co-receptors; these strains, which preferentially infect lymphocytes, predominate later in infection.
R5X4 strains can interact with both co-receptor types.
2 copies of single stranded RNA. Nucleocapsid protein 7 is in close association with the RNA and participates in its replication.
Three critical replication enzymes: reverse transcriptase, integrase, and protease.
Capsid comprises protein 24.
Matrix comprises protein 17.
Viral envelope comprises a lipid bilayer; as we'll see, this outer membrane was derived from the host cell's membrane.
The outer surface of the virion is covered by envelope glycoproteins (sometimes referred to as "envelope spikes"):
Gp41 spans the membrane; Gp120 is the proximal tip.
HIV shares structural genes with other retroviruses:
Pol codes for the large protein precursors of reverse transcriptase, integrase, and protease (each of which is cleaved by protease).
Gag codes for matrix, capsid, and nucleocapsid proteins.
Env codes for the envelope proteins that give rise to glycoproteins 41 and 120.
Key Targets of HIV Virion
Recall that HIV most commonly enters the hosts' body via mucosal tissues; not surprisingly, the following cell types are prevalent in mucosa:
Activated CD4+ T cells, which comprise the Helper T cell lineage of the adaptive immune system. Recall that depletion of CD4+ T cells key to the pathogenesis of HIV, as it leads to severe immunosuppression.
CD4+ T cells can have CCR5 or CXCR4 co-receptors.
Though there is great intertextual variation on this point, co-receptor expression and, therefore, susceptibility to R5 or X4 HIV strains may depend on their developmental and/or activation status.
Furthermore, naïve T cells are "protected" by the enzyme APOBEC3G, which inhibits viral replication; however, upon activation, this enzyme is converted and no longer prevents replication.
Unfortunately, protection can be counteracted by Vif (viral infectivity factor), which is an HIV accessory protein that degrades APOBEC3G.
Dendritic cells display CCR5 co-receptors as well as DC-SIGN lectin receptors; not only are some types of dendritic cells susceptible to HIV infection, they also carry HIV transmission to T cells.
Macrophages display CCR5 co-receptors; macrophages may be infected, carry HIV to T cells, or they may serve as viral reservoirs, facilitating HIV's evasion of host immune responses.
We use a CD4+ T cell example. Be aware that we won't be able to cover all the details, here, and that intertextual variation exists.
We draw the T cell and label the cytoplasm and nucleus; we indicate the CD4 protein and co-receptor on the cell surface.
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Attachment
1. Glycoprotein 120 binds the CD4 protein.
2. CD4 binding induces a conformational change in gp120, which allows for co-receptor recognition.
3. Co-receptor binding reveals the fusion protein on glycoprotein 41.
4. This allows gp41 to insert into the host cell's membrane, establishing fusion between the virion and the cell.
Viral Replication
5. The contents of the virion enter the host cell.
6. Reverse transcription of the viral RNA produces double stranded viral DNA. This is mediated by the enzyme reverse transcriptase.
7. Next, the viral DNA is integrated into the host genome (mediated by the enzyme integrase).
8. HIV genome transcription, guided by the tat gene (Transcriptional Activator) and influenced by cytokine activation, produces new copies of viral RNA and the protein precursors.
Under guidance of the rev gene (Regulator of Viral Expression), these components are exported from the nucleus.
9. In the cytoplasm, viral protein synthesis occurs.
Release
10. The viral components are packaged near the surface of the T cell, and budding with new envelope formation begins.
11. Finally, a new virion is released, and can infect other CD4+ cells.
We show a new HIV virion as it buds from the surface of an infected cell: notice that budding begins as a swelling on the cell surface, then begins to pinch off; once free, it can infect new host cells.
HIV virion budding EM
Two Important Points:
- After integration into the host genome, the proviral DNA may wait for years to complete the process and produce new free virions.
- In an untreated individual, several billion new virions can be produced every day.
Because HIV constantly evolves and can remain latent in cellular reservoirs, a cure remains elusive.
However, antiretroviral drugs that interrupt HIV replication and reduce the viral load have proven effective, particularly when used in combination.
HAART: Highly Active Antiretroviral Therapy
Aka, combination antiretroviral therapy
Comprises administration of 3 or more of the following drugs:
Co-receptor antagonists, such as
Maraviroc; these drugs block HIV from binding with the CCR5 co-receptor, preventing attachment to the host cell.
Fusion inhibitors, such as
Enfuvirtide; these drugs inhibit gp41 insertion and fusion with the host's cell membrane, blocking entry.
Reverse transcriptase inhibitors, which, as their name suggests, inhibit reverse transcription:
Includes Nucleoside and Nucleotide Reverse Transcriptase Inhibitors, as well as Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI).
Integrase inhibitors, such as
Raltegravir, inhibit integration of proviral DNA into host DNA.
Protease inhibitors, such as
Saquinavir, inhibit viral protein synthesis (which is mediated by protease).
When used in combination, these drugs can reduce viral load, which, over time, may allow CD4+ cell counts to rise to normal.
However, be aware that each of these drugs has its drawbacks.
If treatment is stopped, viral replication resumes.
Learn more:
HIV Treatments
Two Important Points: