Most people infected with HIV will mount an effective immune response to the virus during the first few months of infection. However, over time this response will prove ineffective.

The response comes in two forms: cellular and humoral. The cellular response refers to the activity of the CD4 and CD8 T-cells, while the humoral response refers to antibody production and activity.

Cellular immune responses

In the first few weeks after infection, the number of CD8 T-cells increases to up to 20-fold above the normal range, whilst CD4 T-cell numbers fall sharply.

There is a decline in the immune functions which are governed by CD4 T-cells, sometimes leading to the appearance of infections such as Candida (thrush), herpes and Pneumocystis pneumonia (PCP) during seroconversion illness. Six months after infection, CD4 T-cell function improves except in relation to HIV-specific antigen (Musey 1999). The few people who maintain strong HIV-specific CD4 T-cell responses have lower viral loads than people with poor responses. Importantly those people who maintain HIV-specific CD4 T-cells which can respond by producing the cytokines interferon gamma and interleukin-2, appear to be able to control viral loads. In contrast most other peoples HIV-specific CD4-T cells are thought not to be functioning correctly as they can only produce interferon gamma, and this is associated with a lack of viral control (Boaz 2002; Palmer 2004).

It seems that HIV can disrupt the function of CD4 T cells, even without infecting them, and this has knock-on effects on other cells of the immune system. For more detail on CD4 T-cell decline following HIV infection see Mechanisms of CD4 T-cell destruction in The immune system and HIV: How HIV damages the immune system.

CD8 T-cells in HIV infection

CD8 T-cells play a crucial role in controlling HIV replication during the early phase of infection. HIV-specific CD8 T-cells are targeted at the dominant viral variant and their emergence is associated with a rapid fall in viral load, before the development of an antibody response. Most of the CD8 T-cells generated during primary infection die within a few weeks, leaving a reservoir of HIV-specific CD8 memory T-cells which will persist regardless of the presence of an antigen or CD4 helper T-cells.

CD8 T-cells appear to act against HIV in two ways during primary infection: by killing HIV-infected cells and by secreting chemokines. HIV-specific CD8 T-cells recognise a specific genetic sequence of HIV and are primed to copy themselves if this sequence is encountered again in the future.

Many studies indicate that CD8 T cells are a critical component of the immune response which can control HIV. Recently researchers at Harvard University found that people with HIV-specific CD8 T-cells that mature fully into 'effector memory' T-cells are able to control viral load after stopping anti-HIV treatment (Hess 2004). It is not fully understood why some people continue to exhibit strong HIV-specific CD8 T-cell responses that control viral load.

Several theories have attempted to account for the gradual failure of CD8 T-cells to control HIV replication. The 'viral escape' theory states that the cells begin to lose the ability to recognise HIVs genetic sequences due to the high level of viral turnover and mutation. A second theory is that HIV may actually kill off some of the CD8 T-cell repertoire.

In support of the viral escape theory, one study found that CD8 T-cells lose their ability to recognise and kill viral variants, even though they may be responsive to normal 'wild type' viruses. The researchers compared CD8 cytotoxic T-cells from HIV-infected asymptomatic individuals with those from symptomatic AIDS patients. They found that CD8 T-cells from asymptomatic individuals can recognise and kill both types of target cells. In contrast, the CD8 T-cells from symptomatic patients, while still able to recognise and eliminate the laboratory strain targets, no longer killed target cells that were infected with their own virus.

While there may still be high numbers of CD8 cytotoxic T-cells late in HIV disease, the researchers found that they are likely to be programmed only to kill wild type HIV. As HIV mutates in the body due to several factors, including pressure from antiretroviral medications, these CD8 T-cells become increasingly irrelevant. Without helper T-cells, which slowly disappear during HIV disease, the CD8 T-cells are unable to keep up with the increasingly diverse population of HIV inside the body.

Another theory is that rapid progression and death may be linked to a defect in the activation and proliferation of HIV-specific CD8 T-cells. Studies have found that HIV-specific CD8 T-cells do recognise viral variants, calling into question the viral escape theory outlined above. Further evidence to support this theory has come from German researchers who reported CD8 T-cells which specifically target 3TC (lamivudine, Epivir)-resistant virus in individuals with 3TC resistance, indicating the body's ability to adapt to viral variation even during advanced HIV disease (Schmitt 2000). A poor immune response to HIV may not therefore be due to a lack of HIV-specific CD8 T-cells, but to a lack of activity by these cells.

This lack of activity by HIV-specific CD8 T-cells is possibly due to lack of help signals from CD4 T-cells which are directly disrupted by HIV. Strong CD8 T-cells responses which proliferate in response to HIV are associated with IL-2-producing HIV-specific CD4 T-cells which only seem to be present in people who can control viral load such as long-term non-progressors (Boaz 2002; Hess 2004).

A subset of CD8 T-cells called CD8 / CD28 T-cells seem to be the most important cytotoxic cells, but their number decreases during HIV infection. Very rarely, an efficient CD8 T-cell response can occur before HIV has started to replicate in CD4 T-cells or macrophages. This can prevent HIV infection before the production of HIV antibodies. This may occur more frequently in newborn babies than in adults.

A study of seven long-term non-progressors has found that they had relatively low levels of HIV-1-specific CD8 T-cells targeting HIV's Gag and Env proteins, but high levels of CD8 precursor cells. Three of six long-term non-progressors had high HIV-1 p24-specific CD8 T-cell responses (Greenough 2000).

More recently, research with a group of long-term non-progressors has identified that the CD8 T-cells of non-progressors could divide and proliferate more readily when called upon to fight infection. In addition, they also produced higher levels of a molecule called perforin which assists in the destruction of HIV-infected cells (Migueles 2002).

Another group has identified another set of proteins, called alpha-defensins, which are secreted by CD8 T-cells. However, when alpha-defensins were isolated from the CD8 T-cells of long-term non-progressors, investigators found that the HIV-inhibiting properties of these proteins were minimal (Zhang 2002).

CD8 T-cells and activation markers

Researchers from the University of California have published work which confirms that CD8 T-cells are crucial in determining the speed of HIV disease progression. Comparing ten long-term non-progressors and eleven progressors who were matched for age, race, sex and time of seroconversion, the researchers found that long-term non-progressors had a low viral load, as well as significantly lower levels of the CD38-positive subset of CD8 T-cells. These differences were unrelated to viral type, variations in the CCR5 receptor or antibodies (Barker 1998; Mackewicz 1998).

Similarly, a study of men with advanced HIV disease found that high levels of the CD38 activation marker on CD4 and CD8 T-cells was associated with shorter survival time. In contrast, people with high levels of the human leukocyte antigen (HLA)-DR activation marker on their CD8 T-cells had a longer survival time. Other factors such as high viral load, naive cell numbers and co-receptor usage did not impact on survival time (Giorgi 1999). Another group reported that the activation marker C1.7 Ag exhibited on activated CD8 T-cells was associated with disease progression (Peritt 1999).

Chemokine responses

CD8 cytotoxic T-cells appear to produce a cytokine called CD8 antiviral factor (CAF) that inhibits HIV replication, and may or may not directly kill CD4 T-cells. While some researchers believe that CAF is composed of the RANTES, MIP-1alpha and MIP-1beta chemokines that are thought to block the CCR5 receptor, when these cytokines are blocked with monoclonal antibodies, another HIV-suppressive factor still appears to be at work.

There is conflicting evidence about the impact of chemokine activity on HIV disease progression. Some research has suggested that chemokines suppress HIV replication, and that high levels of certain chemokines are associated with delayed HIV disease progression (Garzino-Demo 1999). However, one group of researchers has found either no consistent relationship between beta-chemokine production and HIV replication or an unexpected correlation between high beta-chemokine levels and high-level virus replication (Greco 1998).

Chemokine activity appears to decline during the course of HIV infection. The only test of an artificial chemokine as a therapy so far found no anti-viral efficacy, and researchers are now looking at whether they need to give higher doses or to administer chemokines in a different way.

Chemokine receptor genotype also affects the response to antiretroviral treatment. An analysis of 272 individuals in the ACTG 343 study of indinavir (Crixivan)-based triple therapy found that those with the genotype CCR5+/+, CCR2+/+ and CCR5-59029 A/A were 2.5 times less likely to sustain undetectable viral load than patients with other genotypes. Furthermore, mean viral load reduction was 2.12 log₁₀ for this group compared with 2.64 log₁₀ for all other groups combined (OBrien 2000).

Antibody responses

Antibody responses begin to develop four to eight weeks after infection. Antibodies are chiefly targeted against free-floating virions, although some antibodies may destroy HIV-infected cells. Most antibodies cannot prevent the transmission of HIV from one cell to another. While some antibodies can neutralise HIV, this effectiveness is short lived for each antibody. The antibodies are primed to recognise particular genetic sequences of HIV, but the gradual mutation of the virus enables evasion of antibodies with each new generation of altered virus. It is unclear how much evolutionary pressure antibodies place upon the virus.

A very small number of people infected with HIV do not develop antibodies to the virus. A study of six HIV-infected people found that the absence of antibodies was due to individual immune dysfunction (Ellenberger 1999).

Intracellular responses

A vital step in the infection of a human cell with HIV is the removal, or uncoating, of the protective shell surrounding the viruss genetic material. This coat, called the capsid, must be removed before HIV can insert its genetic material into a human cell and make copies of itself.

In early 2004, scientists announced the discovery of an intracellular immune protein which blocks this process in monkeys, and to a lesser extent in humans (Goff 2004; Stremlau 2004). This molecule, called TRIM5-alpha in humans, specifically targets HIVs capsid. In humans the protein has some ability to block HIV, and investigators are speculating that it could help to explain why some people infected with HIV do not experience disease progression.

Investigators believe that TRIM5-aplha chops up HIVs capsid, preventing the orderly uncoating the virus must undergo before it replicates. TRIM5-alpha is one of a number of intracellular proteins with anti-HIV effects that may be expressed more or less strongly according to genetic inheritance.

References

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