HIV - Virus-Host Cell Interactions

HIV - VIRUS–HOST CELL INTERACTIONS

HIV is an enveloped virus with a cone-shaped nucleo-capsid containing two copies of a positive-sense ss RNA molecule and the enzyme reverse transcriptase. The viral genome encodes for the following genes: env, envelope proteins; gag, capsid proteins; pol, enzymes involved in viral multiplication; and tat, enzymes regulating host metabolism. Seventy glycoprotein spikes (gp120) project from the envelope and interact specifically with the CD4 protein receptor on the T-lymphocyte. The HIV core penetrates the cell cytoplasm following membrane fusion and is uncoated releasing the two RNA molecules and the reverse transcriptase into the cytoplasm. The RNA is copied by reverse transcriptase into ss DNA, which is then duplicated to form a ds DNA copy of the original viral RNA genome. This DNA moves into the host cell nucleus where it is integrated as a provirus into a host cell chromosome.

The provirus can lie dormant in the cell or can be expressed, producing viral mRNA and proteins and resuming the multiplication cycle producing virions. The viral mRNA is polycistronic, producing polyproteins that need to be cleaved by a specific virus-encoded protease. Following the assembly of viral proteins and viral RNA, the virions bud off the infected cells.

At present there is no prospect of any drugs that can be developed to eliminate proviruses from infected cells. Current therapy has evolved around maintaining a high count of T4 helper lymphocytes by regulating the viral load produced by infected cells (up to 10 ¹⁰ viral particles produced continuously per day). Indeed, the ultimate decrease in T4 helper cells (below 200/ml of blood) seriously compromises the host immune system and allows infection by a range of opportunist pathogens including fungi, protozoa, bacteria and other viruses. Currently, antiviral treatments (highly active antiretroviral therapy—HAART) combining a protease inhibitor and two reverse transcriptase inhibitors, reduce the number of HIV particles and slow the progression of the disease by restoring and maintaining the number of T4 helper lymphocytes. However, this triple therapy does not eliminate the virus completely. Patients who stop using the drugs experience a rapid rebound in levels of the virus in the blood and progression of the disease. The inability to eliminate the virus completely calls for lifelong therapy that is prohibitively expensive for countries with very limited health budgets.