Many studies have shown that the immune system's ability to recognise and respond to common antigens improves after effective anti-HIV therapy is started. But paradoxically, the one exception to this rule may be immune responses against HIV itself.

The body's own cellular immune response to HIV plays a pivotal role in disease progression. Experts have established that HIV-specific immune cells are present in the early days of HIV infection, and play an important role in controlling HIV during primary infection and determining the viral set-point. In most people who become infected with HIV, these HIV-specific immune cells are either impaired during primary infection or gradually lost during chronic infection.

HIV-specific CD4 T-cells orchestrate the response of CD8 T-cells. These control HIV by direct killing of infected cells and by the release of chemokines such as RANTES, MIP-1 alpha and beta, which act against CCR5-tropic viruses. When CD8 T-cell levels decline, HIV levels rise.

These findings have led researchers to explore ways of stimulating the bodys own HIV-specific immune response to slow or stop the immune damage caused by HIV. Continuous treatment with antiretroviral therapy, intermittent treatment and treatment during the earliest phase of infection have all been explored as strategies to strengthen HIV-specific immune responses.

HIV-specific responses in long-term non-progressors

See Immune responses to HIV in The immune system and HIV: How HIV damages the immune system for further information on the immune responses that appear to be protective against disease progression.

HIV-specific immune cells and antiretroviral therapy

Several studies have found that anti-HIV immune responses do not usually improve during treatment of chronically infected people, and may in fact decline (Carcelain 2001; Ghanekar 2001; Pitcher 1999). Untreated people have relatively high levels of HIV antigens in their bodies, prompting the immune system to produce antibodies and other immune responses.

One study found HIV-specific immune responses were not improved after one year's treatment with antiretroviral therapy (Gatell 1998), while another found no improvement after 68 weeks (Rinaldo 1999). Furthermore, a Dutch group found that six of ten individuals had an increase in HIV-specific immune cell precursors during early treatment, but this level either plateaued or decreased in the long-term. The only person with increasing HIV-specific immune responses failed to sustain HIV suppression (Pontesilli 1999).

A non-randomised study of 41 people receiving ritonavir (Norvir)-boosted saquinavir (Invirase / Fortovase) found that after 96 weeks, 44% of individuals had HIV-specific responses, compared with 5% at baseline. Treatment interruptions and viral load blips were associated with a loss of responses to HIV. The authors suggested that the lack of use of nucleoside reverse transcriptase inhibitors in this study, particularly AZT (zidovudine, Retrovir), may be the reason for the good HIV-specific responses seen in these patients. However, they also noted that ritonavir or saquinavir down-regulated interleukin-2 (IL-2) production in white blood cells from HIV-negative subjects, a finding consistent with the transient increase in IL-2 production seen during the first 48 weeks of the study, followed by a decline back to baseline (Angel 2001).

A group of American researchers reported that HIV-specific memory CD4 T-cells are present in people with chronic HIV infection, albeit at levels lower than those seen in long-term non-progressors. However, levels were seen to decrease in people who were treated with antiretroviral therapy, with more prolonged viral suppression leading to a greater the loss of HIV-specific CD4 T-cells (Pitcher 1999). This supports the suggestion that antiretroviral therapy alone will not be enough to restore HIV-specific CD4 T-cells among people with chronic infection.

In contrast to these results, one study has found some evidence of HIV-specific CD4 T-cell activity after long-term antiretroviral therapy. One study found that 15 to 35% of patients with long-term viral suppression had detectable HIV-specific CD4 T-cell responses to HIV (Deeks 2000).

Despite this finding, the current weight of evidence suggests that most people do not have a substantial HIV-specific CD4 T-cell immune response while on anti-HIV drugs, even after long-term viral suppression.

The observation that antiretroviral therapy may reduce the bodys anti-HIV responses in the long term may be due to the suppression of HIV replication and the reduction in the number of HIV antigens for the immune system to recognise. From the immune system's perspective it looks as though the virus has mostly gone away, so it starts to shut down its anti-HIV immune responses. It is unclear whether or not this is a bad thing. The immune system may simply be reducing its anti-HIV activity because the need for it is no longer so great. HIV-specific memory cells do exist, so if viral replication increases again the immune system should quickly be able to scale up its responses again.

Researchers are looking at ways of maintaining strong anti-HIV responses during antiretroviral therapy, such as giving people a vaccine consisting of HIV proteins alongside their anti-HIV therapy. The idea is that the vaccine will trick the immune system into believing that high levels of HIV remain in the body, so anti-HIV immune responses will be sustained.

Research into viral blips has given some clues as to what responses need to be primed.

A comparison of people with viral suppression below 50 copies/ml and those with intermittent or persistent viral loads between 50 and 1000 copies/ml found that CD4 and CD8 T-cell activation was greater among those with detectable viral load, and the risk of viral rebound was greatest in those with the narrowest range of responses to HIV-specific CD8+ epitopes (Karlsson 2002)

Early treatment and HIV-specific immunity

As discussed above, HIV-specific responses are present in most people with chronic HIV infection. However, in most patients, this response is weak. Strong HIV-specific immune responses do naturally occur in long-term non-progressors. There is also evidence that a strong HIV-specific immune response may emerge and persist in some people if they begin antiretroviral therapy during primary infection.

Much of the research in this area has been carried out by Bruce Walkers team from the Harvard Medical School and Massachusetts General Hospital. The Harvard team initially reported evidence of HIV-specific CD4 T-cell responses to core proteins of the virus in 13 of 17 individuals treated during seroconversion. Five individuals followed for more than one year all have evidence of HIV-specific CD4 T-cell responses.

However, the Harvard team has reported that HIV-specific CD8 T-cell responses prior to full seroconversion are generally poor and decline while individuals are on antiretroviral therapy. The group is now investigating whether structured treatment interruptions will enhance HIV-specific CD8 T-cell responses among individuals treated during primary infection. Initial findings have been encouraging. Five participants who interrupted treatment at least twice have shown improved CD8 T-cell responses. Four months after the second interruption, two individuals had viral loads below 5000 copies/ml while the other three had recommenced treatment although two had not reached a viral load of 5000 copies/ml. Comparative work has shown that structured treatment interruption increased the range and magnitude of HIV-specific immune cells amongst seroconverters (Altfeld 2002; Rosenburg 1999).

A further study on patients at Harvard Medical School reported a relationship between the maturation of HIV-specific CD8 T-cells and the ability to control viral replication (Hess 2004). It is thought that part of the reason CD8 T-cell responses to HIV do not work very well in people who develop progressive disease is because they fail to mature to a fully functional state. Patients with acute HIV infection in this study had undergone structured treatment interruptions following antiretroviral therapy. Those individuals who controlled viral load during treatment interruptions had significantly greater levels of fully matured HIV-specific CD8 T cells than those who did not control virus.

Another study of 41 seroconverters found that treatment within four months of infection was associated with HIV-specific immune responses. In contrast, individuals treated during the chronic phase of infection did not have HIV-specific immune responses. The HIV-specific immune responses were durable at one year, although levels did not rise much above levels attained at twelve weeks, and these responses were relatively weak. HIV-specific cytotoxic CD8 T-cells were maintained or developed in all but one of the treated patients (Mulhotra 2000).

An important comparative study of structured treatment interruption versus continuous treatment in macaques found that those treated during primary infection had reduced viral levels during each subsequent interruption, as well as evidence of improved immune response, compared to macaques treated during chronic infection (Lori 2000d).

However, other research has found that treatment during primary infection does not always stimulate HIV-specific immune responses (Plana 2002).

For more detailed discussion, see Treatment during primary infection in Anti-HIV therapy: When to start treatment. For further discussion of structured treatment interruption and induction of HIV-specific immune responses, see Anti-HIV therapy: Structured treatment interruption.

The role of memory CD8 T-cells

A fully functioning HIV-specific CD8 T-cell response may be the key to avoiding HIV disease progression, although no-one knows how to ensure such a functional CD8 T-cell response. At the present time, researchers are trying to understand the role of CD8 T-cells in HIV infection.

It is currently known that CD8 T-cells, or cytotoxic lymphocytes, identify cells infected by viruses and then proliferate in vast numbers to kill infected cells. CD4 helper T-cells are needed to aid proper functioning of CD8 T-cells. The population of CD8 T-cells expands enormously during early HIV infection, and HIV-specific CD8 T-cells may form 50% of all circulating CD8 T-cells during this period.

As the immune system gets HIV replication under control, the level of activated CD8 T-cells will fall, leaving a small reservoir of HIV-specific memory cells. These memory cells appear to form the backbone of immune control of HIV. At present, it is not understood why some people continue to exhibit effective CD8 T-cell responses and do not experience disease progression. See Immune responses to HIV and Immune disruption in The immune system and HIV: How HIV damages the immune system for more information on CD8 T-cells.

One theory, known as 'viral escape', proposes that viral variants emerge which cannot be recognised as easily by CD8 T-cells, although this theory has become less certain following a report that CD8 T-cells can adapt to viral variations. A further consequence of increasing viral production is an increase in levels of viral proteins which can interfere with the functioning of CD8 T-cells. Both of these trends will swing the balance in favour of HIV. It has also been suggested that CD8 T-cells may be reduced during the course of HIV infection.

Other research groups have found evidence that symptomatic HIV infection is characterised by a high and stable proportion of activated CD8 T-cells that specifically target HIV antigens. These researchers have suggested that rapid HIV disease progression is due to problems with activation and proliferation of HIV-specific cytotoxic CD8 T-cells, rather than with a lack of these cells.

This group also found that there is an inverse correlation between the maturation state of HIV-specific CD8 T-cells and control of viral load after the interruption of antiretroviral therapy, as described above. Long-term non-progressors also display high levels of mature, fully differentiated CD8 T-cells, suggesting to the researchers that maturation of virus-specific CD8 T-cells might be linked to the preservation of HIV-specific CD4 T-cell function (Hess 2004).

Stimulating HIV-specific responses

Despite this controversy, research is proceeding along a number of avenues to try to find out whether HIV-specific immune responses can be stimulated, and whether these responses will ultimately be sufficient to control HIV infection without the need for antiretroviral therapy.

These approaches include:

• Using interleukin-2 and other cytokines or interferons to stimulate CD8 and CD4 T-cell production and responses.

• Using therapeutic vaccines to stimulate HIV-specific CD4 and CD8 T-cell responses.

• Cell transfer techniques.

See Interleukin-2 and immune restoration, Therapeutic vaccines, Cytokines and Cell transfer techniques in Anti-HIV therapy: Restoring the immune system for details.

Genetic factors in the HIV-specific response

A recent analysis of viral load responses in individuals who began treatment soon after seroconversion has revealed that people with particular cell surface markers called 'human leukocyte antigen (HLA) haplotypes', are more likely to develop HIV-specific immune responses to a particular region of HIV, and to retain undetectable viral load whilst on treatment.

The study compared 21 people who began treatment in primary infection with 18 HIV-infected long term non-progressors who had been infected for at least ten years without a CD4 cell count decline below 500 cells/mm³. A strong response to antiretroviral therapy and a strong HIV-specific lymphocyte response were associated with the DRB1*13-DQB1*06 haplotype, which has not previously been associated with HIV disease progression in epidemiological studies (Malhotra 2001).

The study also found that particular HIV peptides from the Gag region 30 of the virus elicit a strong HIV-specific CD4 T-cell reaction. This suggests that this specific region may be implicated in the immune control of HIV, and that it should be included in the sequences used in therapeutic vaccines.

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