The Amazing Mr HIV

HIV infects the CD4 T cells. But how does it enter those cells? It has two envelope glycoproteins called gp 120 and gp 41. These are translated from a single unspliced mRNA, which itself is transcribed from the env gene that forms part of the 9-gene HIV genome. The virus relies on a host protease to split the two envelope proteins. However, it needs its own protease to split apart another monolithic protein (called polyprotein), that comprises the viral core protein and another that includes vital enzymes like reverse transciptase, integrase and the protease itself (mRNA transcribed from two genes called gag and pol)- this viral protease is a target for therapeutic protease inhibitors that form a cornerstone of HAART (highly active anti-retroviral therapy).

Gp 120 binds to the CD4 molecule itself, but also to a chemokine receptor on the surface of CD4 T cells, called CCR5. CCR5 is normally a ligand for chemokines called CCL3, CCL4 and CCL5 and serves a vital function in normal T-cell physiology. After gp 120 has anchored the virus to its target CD4 T-cell, the second envelope protein- gp 41- causes fusion of the viral coat with the cell membrane of the T-cell, thus allowing the virus to enter its victim.

As you can expect, CCR5 is vital for virus replication. This has been starkly brought out by a small number of subjects of Caucasian origin, who are completely resistant to HIV infection, despite repeated exposure. As it happens, these individuals are homozygous for a mutated CCR5 exon, which has a 30 base pair deletion resulting in a frameshift mutation and a truncated CCR5 peptide chain, termed delta 30. The defective protein blocks entry for HIV into the CD4 T cell. Currently, there is intense research into developing a pharmacological CCR5 binding molecule that would block entry of HIV into CD4 T-cells.

Curiously, there is another portal for entry for HIV into the CD4 T-cell. This is a receptor called CXCR4 (The 2 Cs stand for cysteine residues, joined to each other by another amino acid, designated X). It is thought that CCR5 acts as the entry point for the virus early in infection, while CXCR4 becomes important much later in the course of infection, around the time that the infected individual develops clinical AIDS. HIV virus that uses the CCR5 co-receptor for entry is also called R5 virus, while virus subgroups that use CXCR4 are called X4 viruses.