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AIDS

AIDS stands for Acquired Immune Deficiency Syndrome.

It represents the late stages of infection by a retrovirus called Human Immunodeficiency Virus (HIV).

The immune deficiency is caused by the loss of the CD4+ T cells that are essential for both cell-mediated immunity and antibody-mediated immunity.

General discussion of CD4+ T cells and
more on their significance in AIDS.

HIV — Human Immunodeficiency Viruses

There are two of them: They are retroviruses.

Infection

HIV can only enter cells that express

The virion binds to both CD4 and either coreceptor by means of molecules on its surface called glycoprotein 120 (gp120). The virion then is swept into the cell by receptor-mediated endocytosis. Fusion of the lipid membranes of the virion and the endosome ("Endocytic vesicle" — see figure at left.) releases the contents of the virion into the cytosol. The fusion is mediated by gp41.

When HIV infects a cell

Disease Transmission

HIV is present in body fluids

Breaks or abrasions in mucous membranes and skin allow the virus in.

In North America, transmission occurs primarily

Disease Progression

Infection by HIV produces three phases of disease:

Treatment

In affluent countries, the progression of HIV disease has been markedly slowed by the use of HAART (= Highly Active AntiRetroviral Therapy).

This refers to combined therapy with three or more drugs, e.g., two that target the reverse transcriptase and one that targets the viral protease.

Reverse Transcriptase Inhibitors

Protease Inhibitors

These block the viral protease so that the proteins needed for assembly of new viruses cannot be cleaved from the large protein precursor. Examples:

Fusion Inhibitors

Fusion of the virion membrane with the endosome membrane [View] involves noncovalent binding between two segments of the gp41 molecule designated HR1 and HR2.

Enfuvirtide (Fuzeon®), a synthetic polypeptide containing 36 of the amino acids present in the HR2 segment, interferes with this process. It probably acts as a kind of competitive inhibitor, binding to HR1 thus preventing HR2 from binding HR1.

Integrase Inhibitors

Raltegravir (Isentress®), a drug that inhibits the HIV-1 integrase, has slowed disease progression in patients for whom other drugs were losing their effectiveness.

Inhibiting Coreceptor Binding

Several drugs — as well as some monoclonal antibodies — that block the binding of HIV to the coreceptors CCR5 and CXCR4 are being tested for safety and efficacy. Maraviroc®, a drug that binds to CCR5, has performed so well that it received FDA approval in 2007.

People who have a mutation in their CCR5 gene are resistant to infection. Early clinical trials of gene therapy in which a patient's normal CCR5 gene is deliberately disrupted have shown promise. [More]

Problems with drug treatment

Despite the great advances in drug therapy has many drawbacks.

Genetic Variability of HIV

Reverse transcription (RNA → DNA) lacks the proofreading capabilities of DNA replication or of normal transcription (DNA → RNA). Therefore errors, i.e., mutations, are frequent. Because of these,

Origin of HIV

Genome sequencing of different isolates of HIV-1 and HIV-2 shows that each is related to retroviruses that occur in primates in Africa. These are designated simian immunodeficiency viruses (SIV) although they do not cause immune deficiency (or any disease) in their natural host. However, on those occasions when a SIV accidentally infects a primate of a different species, it does cause disease in the new host. The human epidemic is one example. Genome analysis also permits the construction of phylogenetic trees which reveal different clades of HIV just as such analysis reveals evolutionary relationship between species.
Link to discussion of phylogenetic trees and cladistics.

The picture so far:

Just as with other evolutionary trees, one can also estimate from genome sequences the time of divergence of two branches. This evidence indicates that the Group M clade of HIV-1 invaded humans sometime very early in the 20th century.

But the worldwide epidemic of AIDS did not get its start until the 1980s.

What took so long? An answer to that requires an appreciation of the way in which contagious diseases spread. Their rate of spread depends on: So diseases like HIV only smolder in isolated populations because they lack the density of susceptible contacts. In crowded populations, the equation changes. (There has been a dramatic population shift from rural to urban areas in sub-Saharan Africa since 1950.) In the case of STDs, the availability of multiple sexual contacts — perhaps accompanied by changing sexual mores — tips the scales. In any case, the major factor today in the spread of HIV is promiscuity, whether homosexual or heterosexual.

Prevention of AIDS

Vaccines

Many once-feared infectious diseases have been reduced or eliminated by the development of a vaccine to prevent the disease.
Discussion and examples

Over two dozen experimental anti-HIV vaccines have been developed and clinical trials of some of these have been — and are presently being — undertaken.

So far, the results have been disappointing. There are probably several reasons.

Some of the vaccines attempt to induce antibodies, e.g., against the outer portion of the envelope protein (called gp120). But antibody-mediated immunity may not give adequate protection. So other vaccines have been designed to favor the development of cell-mediated immunity; e.g., cytotoxic T cells.

Many of these are DNA vaccines, for example,

It is hoped that expression of these genes within the cells (e.g., muscle) of the subject will induce a protective immune response, but to date there has been no success [Link].

Behavior

Because HIV transmission is so difficult, changing behavior could go a long way toward stopping the epidemic. In the words of Anthony S. Fauci, Director of the National Institute of Allergy and Infectious Diseases,
"Unlike microbial scourges, such as malaria and tuberculosis (among many others), for which there is very little that people can do to prevent infection, HIV infection in adults is entirely preventable by behavior modification" [emphasis added].
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22 October 2014