HIV is not able to enter through most of the surface linings of the body. However, it can enter through some wet mucous membranes such as in the rectum, the female genital tract, the skin at the tip of the penis (particularly in uncircumcised men) and the urethra, the tube that carries urine. Blood and genital secretions in men and women are the infectious fluids for people with HIV infection.

It is not clear whether HIV is infectious as free virus outside cells or as HIV within CD4 T-cells passing to another person. The first cells to become infected with HIV are usually dendritic cells in the linings of the rectum and sexual organs. There is good evidence that other sexually transmitted diseases can increase the risk of HIV transmission, by increasing the number of immune cells in genital secretions or by causing ulceration.

HIV is trapped in the tissue of the rectum or sexual organs by dendritic cells and macrophages and carried to the lymph nodes where it is presented to and recognised by a few T- and B-cells. Under T-cell control the B-cells produce clones of plasma cells which can release antibodies that specifically attack HIV in the bloodstream. The appearance of these antibodies against HIV antigens in the blood is called seroconversion. HIV viruses outside cells can become coated with antibodies and may then be attacked and destroyed by phagocytic cells. However, HIV makes small errors when it reproduces itself, resulting in a large amount of variability in the 'envelope antigens' on its coat. This variability enables the HIV variants to escape recognition by specific antibodies and persist in the body.

Early detection of HIV

Several different tests can be used to establish whether a person is in the early stages of HIV infection.

The most sensitive test which can be used is HIV polymerase chain reaction (PCR) testing, which is the same as the viral load test. This test may be able to detect HIV within 48 hours of infection in some cases. However, caution should be exercised in interpreting the results of such tests when the viral load measurement appears below 5000 copies/ml, as these may be false positive results (Hecht 2002; Rich 1999).

Some laboratories may offer a proviral DNA test which is a highly sensitive and specific test for early HIV infection. An Australian clinic reported that 14 cases of HIV seroconversion were correctly identified by both the proviral DNA test and HIV RNA test. Viral loads were above 15,000 copies/ml in all these cases (Medland 2003).

Another method called p24 antigen testing may also be used to determine early infection. This looks for the presence of a viral protein called the capsid protein. However, this method has been superceded by PCR testing.

Antibody testing, which is used to diagnose HIV infection under normal circumstances is unlikely to detect HIV antibodies until at least six weeks after infection in the majority of cases. Less than 1% take up to six months to develop antibodies. The HIV antibody test is known as an enzyme-linked immunosorbent assay (ELISA) test.

A comparative study of diagnostic methods in people with seroconversion illness found that the p24 antigen and ELISA methods together detected only 79% cases of seroconversion. In contrast, the PCR test detected HIV in every infected person. The third generation ELISA antibody test, designed to detect antibodies earlier than standard tests, was only as accurate as the p24 antigen test.

The authors recommended that patients with suspected primary infection should be tested with a third generation ELISA test and a PCR test, with repeat PCR testing if the ELISA test is negative. If viral load remains higher than 5000 copies/ml while the ELISA result is negative, HIV infection should be presumed. However, ELISA testing should be continued on a regular basis until the presence of antibodies is confirmed (Hecht 2002).

Other experts have advocated the use of the PCR test in conjunction with the proviral DNA test and routine antibody testing as the most reliable and accurate way of establishing the presence of HIV infection shortly after exposure or when seroconversion illness is suspected (Medland 2003).

Seroconversion illness

Seroconversion typically occurs two to twelve weeks after infection and may be associated with a flu-like illness. The most commonly reported symptoms include:

• Fever.

• Rash.

• Aches and pains.

• Oral ulcers.

• Sore throat.

• Weight loss of more than 2.6kg.

• Fatigue.

• Nausea.

Fever and rash together, as well as loss of weight and appetite are the most strongly predictive symptoms of HIV seroconversion illness, according to a study carried in San Francisco (Hecht 2002; Vanhems 1999). It is unclear if the presence of a larger number of these symptoms is a stronger predictor of HIV seroconversion. The duration of the illness and the severity of the symptoms are associated with a higher viral load during and just after seroconversion (Lavreys 2002).

It is thought that somewhere between 50 and 80% of newly infected people will experience most or all of these symptoms. A smaller proportion may develop diarrhoea, ulceration of the mouth, throat or genitals, anorexia or swollen lymph nodes (Clark 1991). Weight loss, abdominal pain, loss of appetite, oral thrush and neurological abnormalities have also been reported as symptoms of seroconversion (Vanhems 1999).

A study of seroconverters in Zambia has suggested a slightly different profile for seroconversion illness. Influenza, rash and sore throat were not linked to HIV seroconversion. Instead, malaria, diarrhoea, swollen glands, inflammation, night sweats and weakness were associated with HIV seroconversion (Fideli 2003). A study of women in Uganda and Zambia has also shown that women with acute or early HIV infection are more likely to have fever, severe headaches, abdominal pain, pelvic tenderness, fatigue, abnormal vaginal discharge and itching and abnormalities of the vagina and cervix than HIV-negative women, along with an increased incidence of vaginal infections (Morrison 2004). These studies may point to regional or ethnic differences in the nature of seroconversion illness.

There is some evidence that people who experience symptoms during primary infection tend to have a more rapid rate of disease progression than people who have few or no symptoms upon initial infection with HIV. See Viral load, CD4 cell counts and other tests: Other markers for further discussion of the prognostic significance of seroconversion illness.

Until recently it was thought that HIV remains concentrated in the lymph nodes during early infection, replicating in very large numbers and infecting more CD4 T-cells. While this is partly true, recent studies have shown that after the first six days of infection the virus spreads to infect huge numbers of T-cells in the lining of the bowel. Here as many as 60 to 80% of memory CD4 T-cells may be destroyed in the first 17 days of infection (Johnson 2005; Mattapallil 2005). However during this earliest stage of infection and for the first months or years afterwards swollen lymph nodes are often the only clinical feature seen in a person with HIV infection.

Immune response during primary infection

The presence of high levels of HIV in the body stimulates the immune system, and huge numbers of HIV-specific CD4 T-cells are produced in an attempt to contain the virus. However, these activated CD4 T-cells are also prime targets for the virus. Therefore, rather than controlling the infection, they are rapidly infected and destroyed, leaving the body with only weak anti-HIV immune responses. Long-term non-progressors, on the other hand, tend to have strong immune responses such as high levels of HIV-specific CD4 T-cells, and HIV-specific CD8 T-cells which effectively control HIV replication and keep viral loads low.

HIV-specific CD8 T-cells are the only immune parameter which has a significant association with the fall in viral load seen during primary infection, suggesting that these cells play a key role in controlling viral replication (Routy 2000). Recently however, researchers in London found that antibodies which neutralise HIV may also be detected at this same time, if they are measured together with the immune factor called complement, which helps antibodies kill viruses and bacteria (Aasa-Chapman 2005).

For further information on the immune response with anti-HIV treatment during primary infection, see Treatment during primary infection in Anti-HIV therapy: When to start treatment.

Viral dynamics during primary infection

During the first few days of infection, HIV replicates without being checked by the immune system. This allows levels of HIV in the blood to rise to very high levels. For example, one study reported that individuals had an average viral load above 1,000,000 copies/ml 13 days after infection (Kaufmann 2000).

It is thought that the ability of an individual to infect another person increases with viral load, so infectiousness may be very high soon after infection. A Ugandan study investigated the role of the stage of HIV infection in virus transmission between monogamous partners. This study found that the risk of virus transmission was twelve times higher during the first two and a half months of infection and again about two years before the infected partner's death. This is likely to be a result of higher viral loads at these times (Wawer 2005).

During the initial period of infection, HIV establishes viral reservoirs by infecting a range of different cells. Some of these cells become resting memory cells which harbour HIVs genetic material within the cells' DNA, thus holding the potential to produce more virus in the future. Anti-HIV drugs are unable to affect these reservoirs.

Follicular dendritic cells in the lymphoid tissue are known to be a major site of HIV trapping. It seems that HIV rapidly accumulates in lymphatic tissue following infection (Schacker 2000).

When the bodys anti-HIV immune response begins, symptoms of seroconversion may develop and viral load falls. One study found a relationship between viral load levels during primary infection, the severity of symptoms during primary infection and the level at which viral load subsequently stabilised, or the 'set-point'. A higher set-point has been found to predict the speed of progression to AIDS, as has the speed with which a patient reaches the set point: patients who reach their set point more quickly have a slower progression to AIDS (Blattner 2004; Pedersen 1997).

Key research

Blattner (2004) identified 22 patients with primary HIV infection from the Trinidad Seroconverter Cohort and followed them for 7 years. All those with viral load set points above the median of 25,000 copies/ml progressed to AIDS within 4.5 years, but half of those with set points below this value had not progressed to AIDS after 7 years. The 11 patients with a viral load decline after acute infection slower than the median of 0.63 log₁₀ per month had progressed to AIDS within 5 years, but a quarter of those with faster declines had progressed to AIDS within 7 years. Fast initial clearance of HIV and maintaining a set point for over 20 months was associated with a 10-fold lower chance of progressing to AIDS, and having a set-point over 25,000 copies/ml was associated with a 6.5-fold increased chance.

Hecht reported a survey of 258 people screened for potential primary HIV infection (newly exposed individuals). The study was carried out by Positive Health Program at San Francisco General Hospital, which advertised in the community for people with suspected high risk exposures such as unprotected sex or needle sharing with an HIV-positive partner, and/or suspected symptoms of HIV seroconversion. Individuals were tested for HIV using a variety of methods, and the researchers assessed which symptoms occurred more frequently in people who were subsequently found to have HIV infection. The significant predictors were: Fever and rash together ( OR 8.4); fever ( OR 5.2); rash (OR 4.8); oral ulcers (OR 3.1); joint pain (OR 2.6); sore throat ( OR 2.6); loss of appetite (OR 2.5); weight loss of greater than 5lbs (2.5kg) (OR 2.8); muscle pain (OR 2.1); fatigue (OR 2.2); nausea (OR 1.9). Other previously reported symptoms, such as headaches, night sweats, diarrhoea, ulcers on the genitals and vomiting were just as likely to occur in people who did not have infection. The study was not able to identify whether the presence of a greater number of these symptoms had stronger predictive power, due to the relatively small number of people who were diagnosed with primary HIV infection (40 out of 258). There was no difference in the length of time that key symptoms lasted between people with HIV infection and people without. On average, symptoms lasted for ten days or less. The only exception was genital ulcers, which lasted significantly longer in patients with HIV infection (27 days vs 9.5 days).

Lavreys identified 74 women who seroconverted and for whom viral load measurements were available. Women were tested for HIV on a regular basis after being recruited to the cohort study, which enrolled a total of 1295 women. Fever, vomiting, headache, fatigue, arthralgia, myalgia, sore throat, skin rash and being too sick to work were associated with a significantly higher viral load. Asymptomatic women had a median viral load of 216 copies/ml (a level that would be regarded as a potential false positive result in at-risk individuals seen in everyday clinical practice). In women with one symptom, the median viral load was 32,111 copies/ml, compared with approximately 4 million copies/ml in women with five or more symptoms.

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