Understanding the mechanisms by which disease progression occurs is crucial in determining how best to treat HIV infection and prevent AIDS from developing, and so it remains an important focus of scientific research.
Acute infection
The first stage of the process is acute infection (also called primary infection) – the entry of the virus into the body of an uninfected person, usually through mucous membranes such as those found in the rectum, vagina and penis.
Unlike the skin on the surface of the body, which is designed to be impermeable to outside invaders, the mucous membranes are made of a type of damp, thin skin which can absorb and excrete nutrients and other substances. Because of this, they also provide a relatively easy point of entry for bacteria and viruses – many different infectious organisms, from the common cold virus to polio to the Legionella bacterium, enter through mucous membranes which line the gut, the sexual organs, the respiratory system, the throat and so on.
Because the mucous membranes provide such an easy entry to external pathogens, they are covered with special immune system cells, called dendritic cells, which act like a kind of border guard to protect the body from invasion. The dendritic cells capture any invaders (including HIV) and hand them over to another group of immune system cells, the macrophages, which carry them to the lymph nodes. In the lymph nodes, the invader is identified and the immune system swings into action.
It’s at this point that the newly-infected person is likely to experience a seroconversion illness – a combination of ‘flu-like’ symptoms including fever, rash, body aches and pains and fatigue which occurs two to 12 weeks after infection. These symptoms are a sign that the immune system is responding to a threat.
During acute infection, the immune system produces many new CD4 cells in an attempt to control the virus. But because these are the very cells that HIV prefers to infect, rather than controlling the infection the body’s immune response provides an opportunity for the virus to multiply very rapidly. The newly-produced CD4 cells are infected and turned into virus-producing factories, which disables and eventually destroys them.
This combination of factors results in very high viral load during the period immediately after infection. Unchecked by the immune system, the virus multiplies rapidly, leading to astronomical viral loads. One study found that the average viral load about two weeks after infection was greater than 1 million copies/ml. Because higher viral loads are linked to increased infectiousness, this can be the most dangerous time for transmission of HIV to other people.
Also during the acute infection period, HIV can create viral ‘reservoirs’ by infecting CD4 cells which are or subsequently become deactivated, or ‘resting’. If these ‘memory’ cells are infected they are out of reach of antiretroviral drugs. It’s viral reservoirs like these which allow the virus to return even after being suppressed by antiretroviral drugs for many years.
About this point, the body starts producing antibodies to HIV. Antibodies are tiny Y-shaped strings of protein which are custom-designed to attach to the virus and attract other immune cells to attack the invader. It can take between six and 12 weeks before antibodies to HIV are produced, meaning people with recently-acquired HIV infection will not test positive to the HIV antibody test during this window period.
Eventually, the viral load naturally falls to a much lower level. The immune system and the virus fall into a kind of balanced state, called the viral set-point, where the viral load remains more or less the same for several years.
Different set-points have been observed in different people, and people with a higher viral set-point have been shown to progress to later stages of HIV illness more quickly. The time taken before the set-point is reached has also been shown to be related to the time before the virus begins to re-emerge.
Asymptomatic period
Following the acute infection phase, people infected with HIV typically go for many months or years without developing any signs of illness. During this period, there are usually no outward signs of infection, although the lymph glands may remain swollen. The length of this phase varies from individual to individual and can be as long as ten years or as short as a few months.
In the early stages of the HIV epidemic, it was widely believed that HIV must enter a kind of dormant state, however we now know that this is not the case. The virus remains active in the lymph nodes and other areas of the body, reproducing and infecting new CD4 cells.
The viral load remains relatively stable but the CD4 count will slowly decline as more CD4 cells re infected and eventually destroyed by the virus. The average loss of CD4 cells has been measured as 60 cells/mm3 per year, however there is considerable variation in this. Some people, called long-term nonprogressors, may go for many years without treatment and lose relatively little of their immune function, while others, called rapid progressors, go from primary infection to symptomatic in a short period. Most people fall somewhere in between.
It’s during this period that doctors stress the importance of monitoring the CD4 count and viral load, and starting treatment when there is a chance of progression to the next phase. Because the length of the asymptomatic period varies greatly between individuals, it’s necessary to have these blood tests every three or six months.
Symptomatic period
With careful monitoring and by starting treatments at the appropriate time, it’s now possible to keep most people living with HIV in the asymptomatic phase for much longer than would be the case without treatment. We don’t know yet how long the onset of disease can be delayed by current treatments – perhaps indefinitely or at least for many years.
Without treatment, or if treatments fail, eventually the viral load will start to rise again and the infected person will experience increasingly serious symptomatic illness. Traditionally these stages have been called ARC (AIDS-related complex) and AIDS, or they may be called HIV infection category III and category IV. The line between the two stages is somewhat arbitrary, and of course in practice the onset of increasing illness is much more gradual.
During the earlier stages of symptomatic illness, people may experience symptoms such as weight loss, diarrhoea, oral fungal infections and skin conditions. While none of these is usually life-threatening, they are early signs that the body’s ability to fight infection is waning. Eventually, if effective treatment is not commenced, more serious and life-threatening conditions such as PCP (a type of pneumonia), cryptosporidiosis (a serious infection of the gut) and Kaposi’s Sarcoma (a type of cancer) can occur.
It’s a sign of the effectiveness of antiretroviral treatment that these serious and distressing conditions, and the many other AIDS-defining conditions that have been identified, are now relatively rare.
