The most commonly used immune boosting therapy in HIV infection is antiretroviral therapy. If antiretroviral therapy can suppress virus replication, the immune system has the chance to recover and becomes able to control opportunistic infections.

In the past, single- or dual-drug therapy had only modest effects on CD4 cell counts. It is now known that this is related, at least in part, to its modest antiretroviral effects. Current antiretroviral therapy combining at least three drugs has had spectacular effects on the immune systems of many people.

Immune system recovery is a gradual process which varies a great deal between individuals. Despite its benefits, most experts currently believe that immune restoration resulting from antiretroviral therapy will not result in complete restoration and normalisation of immune function. Factors which may influence immune restoration are discussed below.

Immune cell recovery during antiretroviral therapy

Researchers have looked in detail at the CD4 cell count increases seen among people taking antiretroviral therapy. The most common pattern is for people to experience dramatic increases in their CD4 cell count in the first few months of treatment, followed by a more gradual increase during the following months and years.

The current consensus is that the initial rapid increase contains few newly produced CD4 T-cells. Instead, the majority of the 'new' cells in the blood are thought to be ones that were previously in the lymph nodes, where most of the HIV in the body is found. Once viral load is strongly suppressed by antiretroviral therapy, the CD4 T-cells regain their ability to travel from the lymph nodes and into the bloodstream. Most of these cells appear to be memory CD4 T-cells. This phenomenon is sometimes called 'redistribution'.

The later, more gradual increase in CD4 cell count contains new CD4 T-cells - of both the naive and memory variety. Some seem to come from the clonal expansion of pre-existing naive and memory CD4 T-cells. People with low CD4 cell counts often have extremely few naive cells left, so it is likely to take them a long time to rebuild their stocks of naﶥ cells in this way. Even among people who have no measurable naive cells when they start treatment, naive cells may start to appear after several months of antiretroviral therapy (Autran 1997, 1999; Hengel 1999; Li 1998). One possibility is that these people did have a very small number of naive cells that was too low to be detected, but these few cells are clonally expanded. Another theory, discussed below, attributes the rise in naive cells to production of new cells by the thymus.

The range of different antigens that CD4 T-cells can recognise is gradually restored in people who sustain undetectable viral loads for a long period. The response to 'recall' antigens such as tuberculosis and cytomegalovirus (CMV) has been noted within twelve weeks of commencing therapy, although it eventually reaches a plateau (Autran 1998).

Another study found that immune responses to Candida and mumps improved following antiretroviral treatment during chronic infection but that responses to HIV and tetanus remained depressed for one year of treatment (Connick 2000). Instances of opportunistic infections in people on treatment with CD4 cell counts above 200 cells/mm³, who previously had very low counts, indicate that in some individuals the full repertoire of immune responses does not return in the short to medium term. Early treatment has been associated with improved specific immune responses to HIV, as well as to Candida and tetanus (Malhotra 2000).

Although the bulk of any increase in CD4 cell count appears to occur during the first year of therapy, the balance of evidence suggests that CD4 cell counts continue to rise during each year of treatment, and do not tend to plateau.

Although several studies have suggested that a plateau is reached in the third year of treatment (Felipe 2003; Kaufman 2002), a Californian study found that people in their fourth year of antiretroviral therapy with viral loads below 1000 copies/ml were still experiencing CD4 cell count increases (Hunt 2003). This study showed that CD4 cell count increases beyond the third year averaged around 85 cells/mm³ in people with baseline CD4 cell counts below 350 cells/mm³.

Similarly, five-year follow-up of 48 French patients with undetectable viral load showed that the greatest CD4 cell count increase occurred during the first 18 months of treatment (Viard 2004). The researchers questioned the benefit of extending therapy beyond the 18-month point if patients had achieved a CD4 cell count above 400 cells/mm³. In the French APROCO study involving over 1280 patients a plateau in CD4 cell count increases was seen after three years, possibly due to a homeostatic mechanism that sets T-cell counts at a pre-determined limit (Le Moing 2005).

Six-year follow-up of 20 individuals who had participated in ACTG 315 found 55% of the participants experienced declines in CD4 cell counts after five years, coupled with increases in markers of immune activation from years 3 to 6. However, there was no correlation between viral load and immune activation, and the researchers suggest that it may be due to increased CD4 cell counts in the presence of ongoing HIV replication (Smith 2004).

After long-term suppression of HIV by antiretroviral therapy, 15 to 35% of people show HIV-specific activity of CD4 T-cells which is rarely apparent in untreated people (Deeks 2000). This phenomenon is discussed in more detail in Restoring HIV-specific immunity in Anti-HIV therapy: Restoring the immune system.

Different types of CD4 T-cells

There is more than one type of CD4 cell, but the standard CD4 count test performed in clinics is a relatively crude measurement that simply tells you how many CD4 cells of all types are present in a blood sample. In research studies, scientists have been looking more closely at which types of CD4 cells are returning during anti-viral therapy, and where they are coming from.

CD4 T-cells can be divided into naive cells (also known as CD45RA cells) and memory cells (CD45RO cells). When a naive cell encounters a 'foreign' antigen it becomes activated and produces many copies of itself which stimulate immune responses against the antigen. Afterwards, some of these CD4 T-cells become dormant, resting' memory CD4 T-cells, ready to respond rapidly if they encounter their particular antigen again in the future.

When the CD4 cell count falls in someone with untreated HIV infection, both naive and memory cells are being lost. The loss of naive cells reduces the body's ability to respond to new antigens, while the loss of memory cells leaves 'gaps' in the immune system where it can no longer respond to antigens it has encountered in the past.

HIV can enter both naive and memory CD4 T-cells. However, new evidence suggests that when HIV enters a resting memory CD4 T-cell, it cannot merge its genetic material into the cell's DNA and thus cannot reproduce itself. It is only when the cell later encounters its antigen, and becomes activated again, that HIV can start to reproduce in the cell - and only then is the virus susceptible to anti-HIV drugs. Thus, resting memory cells may provide HIV with an important hiding place within the body, where it can lurk for months or years unaffected by even the most potent of today's therapies.

Where do CD4 T-cells come from?

The conventional view is that new CD4 T-cells can come from two different sources.

Firstly, existing CD4 T-cells can reproduce themselves through a process known as 'clonal expansion'. Naive cells reproducing in this way produce new memory cells, and memory cells produce further new memory cells.

Secondly, entirely new cells may be generated in the bone marrow and travel to an organ in the upper chest called the thymus, from which they emerge as mature, naive CD4 T-cells. New naive cells continue to be produced into old age, but the capacity of the thymus to generate new naive cells begins to decline gradually during adulthood.

Once released into the body, naive CD4 cells circulate until they encounter an antigen, at which point they orchestrate immune responses and become memory CD4 cells. The generation of naive cells during antiretroviral therapy is desirable, because these cells are able to replace holes in the immunological repertoire created by HIV.

The thymus and immune recovery

There is now good evidence that naive cells which emerge during antiretroviral therapy may be newly produced, manufactured in the bone marrow and matured in the thymus. Recent research has proven that the thymus continues to produce new naive CD4 T-cells until a person is over 50 years old. It was thought that the thymus was less active in adults than in children, but researchers from the University of California have found that the thymus has similar activity in children and middle-aged adults.

When a person starts antiretroviral therapy, restoration of naive CD4 and CD8 T-cells begins. Some research suggests this is linked to improved thymic function, as demonstrated by increased thymic size. Other research suggests that naive cells which had been trapped in the HIV-rich lymphoid tissue begin to circulate around the body when anti-HIV treatment is commenced (Nokta 2002). According to Dutch researchers, even if HIV impacts on naive T-cell production, this impact is small or rapidly reversible following antiretroviral treatment (Cohen Stuart 2002).

A larger thymus seems to be an important factor in the extent of naive cell immune restoration. Researchers from San Francisco have studied thymic size in people on antiretroviral therapy using computed tomography (CT) scans. They found that over a period of 48 weeks, those with more thymic tissue were most likely to see the greatest increases in T-cell production. Younger patients were also found to experience greater increases in thymic size (Komanduri 1999). In a study comparing people with weak or strong CD4 T-cell responses after a median of 130 weeks on treatment, markers of recent naive T-cell emigration from the thymus were lower in those with a poor CD4 response (Teixera 2001). Lower levels of T-cell emigration were correlated with a smaller thymus and with age, and the authors concluded that reduced thymus capacity was the cause of the poor CD4 T-cell response to therapy. Another study also found that thymus size was associated with the degree of CD4 cell count response and the overall completeness of the immune repertoire (Kolte 2002).

The thymus can continue to generate new CD4 T-cells even in people with long-term treatment failure and rising viral load. A Spanish study in 32 individuals with a median of seven years prior antiretroviral therapy found that whilst the group's CD4 cell counts had fallen by a median of 24 cells/mm³ in the previous year, those who had the smallest declines in CD4 cell count were those who had the greatest level of naive cell production from the thymus (Delgado 2002). These findings support the view that drug-resistant viruses not only have less replicative capacity, but are also less damaging, both to naive CD4 T-cells and to cells within the thymus.

Thymus size has been observed to increase soon after commencing antiretroviral therapy in treatment-naive adults. Spanish researchers looked at twelve individuals who started a protease inhibitor-containing regimen and found substantial thymic regeneration after twelve weeks on treatment. This was the case even in two individuals over 50 years of age with undetectable thymus activity before commencing treatment (Franco 2002). Another Spanish study of 21 HIV-infected adults found that thymic size increased significantly in people who had a CD4 cell count rise of at least 100 cells/mm³ six months after starting treatment (Rubio 2002).

Further evidence that the thymus plays an important role in the production of naive T-cells in people on antiretroviral therapy comes from a study in which five adults received recombinant human growth hormone treatment. All experienced significant increases in thymic mass and increases in naive CD4 T-cell numbers when compared with historical controls receiving antiretroviral therapy alone. Thymus size decreased to pre-growth hormone levels in two individuals after discontinuing growth hormone therapy. However, the authors concluded that their findings did not support the wider use of growth hormone for immune reconstitution purposes (Napolitano 2002). Growth hormone has also been shown to improve HIV-specific lymphocyte responses when dosed daily (Imami 2002).

While most research suggests a link between viral suppression, increased thymic output of naive cells and greater thymic size, not all studies have established this connection (Chavan 2001; Marchietti 2000; Sekaly 2000; Sommerville 2000). It should also be noted that researchers have detected new CD4 T-cells in response to antiretroviral therapy among HIV-infected people whose thymuses have been surgically removed for unrelated reasons, proving that the thymus is not essential for CD4 T-cell replenishment.

Another study reported that abundant thymic size was associated with a greater initial CD4 cell count increase in response to antiretroviral therapy, but that after 48 weeks of treatment, individuals with more thymic tissue had a greater chance of viral rebound than those with minimal tissue. Those individuals who had the largest CD4 cell count increase at week 4 were most likely to maintain undetectable viral load. The same research team also found no difference between HIV-negative and HIV-positive individuals in thymus size (Smith 2004).

Two studies analysing the effect of age on response to antiretroviral therapy have shown that people over 50 years old do not have a poorer response to treatment, suggesting that any age-related restriction of the thymic output of CD4 T-cells is relatively marginal (Perez 2003; Tumabarello 2003).

Bone marrow and immune recovery

CD4 T-cell production during HIV infection is probably restricted because HIV affects T-cell progenitor production in the bone marrow. However, antiretroviral therapy is also associated with a rapid improvement in T-cell progenitor production (Dam Neilsen 1998). See Why do CD4 T-cells disappear in HIV infection? in The immune system and HIV: How HIV damages the immune system for further discussion of this topic.

Factors influencing CD4 cell count recovery - viral load

The major factors determining the extent of CD4 T-cell recovery remain the topic of ongoing research. There is contradictory evidence concerning the impact of low baseline CD4 cell counts on the extent of immune restoration.

An international study published in 1999 found that prolonged suppression of HIV viral load is the key to CD4 T-cell replenishment, rather than baseline CD4 cell count. This study provided confirmation that even people with severely damaged immune systems can benefit from antiretroviral therapy, and led researchers to speculate that full immune restoration may be possible if HIV replication is suppressed in the long term. There is also evidence that the greater the initial suppression of viral load, the greater the CD4 cell count increase (Phillips 1999).

However, as discussed in Discordant CD4 cell count and viral load responses in Anti-HIV therapy: Restoring the immune system, some people have substantial CD4 cell count responses without sustained or full suppression of viral load.

An American study of 34 people also failed to confirm the importance of undetectable viral load. Achieving undetectable viral load was not associated with a greater CD4 cell count increase nor an improved antigen-specific immune response. This result should be treated with caution, as the authors acknowledged that the study was not designed to compare the effects of partial and complete HIV suppression. The magnitude of viral suppression did correlate with the magnitude of CD4 cell count increase, but it did not correlate with functional immune reconstitution. The authors suggested that re-exposure to antigen during antiretroviral therapy may play a crucial role in the renewal of specific immune responses (Connick 2000).

Factors influencing CD4 cell count recovery - immune function

Until relatively recently, some scientists were concerned that immune recovery may only be possible among people whose immune damage had not reached a 'point of no return', although no-one was clear precisely where that point might lie.

There are now many studies showing that even people with extremely low CD4 cell counts can experience very substantial increases in their CD4 cell counts, comprising both memory and naive T-cells during antiretroviral therapy. Both the quantity and the quality of the CD4 T-cells improve, and they start responding properly to common infectious antigens. Numerous studies have demonstrated that people with sustained immune recovery can safely discontinue secondary prophylaxis for opportunistic infections, demonstrating the body's capacity to regain immune function during antiretroviral therapy. See Prophylaxis and immune recovery in Anti-HIV therapy: Restoring the immune system for more information on stopping prophylaxis.

Nevertheless, some studies have found that people with more damaged immune function have a poorer response to treatment. For instance, long-term follow-up of the INCAS study of AZT (zidovudine, Retrovir), ddI (didanosine, Videx / VidexEC) and nevirapine (Viramune) showed that only those with higher baseline CD4 cell counts and undetectable viral loads for two years had significant re-population of naive CD4 cells (Pakker 1999). A study of 19 individuals who started therapy with AZT, 3TC (lamivudine, Epiviv) and ritonavir (Norvir) found that the baseline naive CD4 T-cell population was the best predictor of overall CD4 cell count increases after 72 weeks on treatment (Notermans 1999). People with the lowest baseline level of naive CD4 T-cells had lower total CD4 cell count increases than participants with more naive CD4 T-cells at baseline.

Despite normalisation of CD4 cell counts on antiretroviral therapy, people who start treatment with more advanced HIV disease may have impaired responses to some common infectious agents. To assess the health or impairment of the immune system, researchers measure T-cell proliferation in response to 'recall antigens'. If memory cells are still present in sufficient number, the responses should be robust. Some findings of 'recall antigen' studies are summarised below:

• In the COLA3003 study, which tested a protease inhibitor-containing regimen in treatment-naive individuals, responses to recall antigens were found to be weaker in people who started treatment with CD4 cell counts below 500 cells/mm³ (Al-Harthi 2002).

A study of eleven patients who received antiretroviral therapy found that people who had experienced more than two years with a CD4 cell count below 400 cells/mm³ were less likely to respond to common antigens than people who started therapy with higher CD4 cell counts or shorter periods of low CD4 cell count (Sieg 2002).

• A study of 29 HIV-positive people who received common vaccinations found that proliferative responses to the vaccine antigens were significantly stronger in those who had never had a CD4 cell count below 250 cells/mm³. All participants had CD4 cell counts above 450 cells/mm³ at the time of vaccination, suggesting that past immune deficiency continues to affect the immune response even after apparently successful immune response (Lange 2002).

• Responses to antigens were also impaired in 199 patients who began antiretroviral therapy with CD4 cell counts below 50 cells/mm³. By the time of sampling the median CD4 cell count had risen to a median of 226 cells/mm³. However the study did not find any difference in the rate of opportunistic infections according to whether patients responded to challenge antigens or not (Lederman 2004).

Another factor which contributes to a poor immune response to therapy is the level of ongoing immune activation. People with greater CD4 and CD8 T-cell activation have smaller increases in CD4 cell counts when they start treatment (Hunt 2003). Factors associated with ongoing T-cell activation included hepatitis C co-infection, frequent low-level detectable HIV viral load (between 50 and 1000 copies/ml and a lower nadir CD4 cell count. Ongoing T-cell activation could be the result of the inflammatory effect of HIV infection, draining the pool of both resting and memory CD4 T-cells. Immune modulators may offer means of combating T-cell activation.

Factors influencing CD4 cell count recovery - adherence

The Highly active antiretroviral therapy Observational Medical Evaluation and Research (HOMER) study found that adherence, rather than baseline CD4 cell count, predicted the degree of CD4 T-cell gain after starting treatment. In this study, individuals who were at least 95% adherent were most likely to achieve a CD4 cell count gain of 50 cells/mm³ or more than those who were less adherent. Other factors that predicted CD4 cell count gain in included age, baseline viral load and being male (Wood 2004).

Adherence of 95% or more has been associated with the best long-term viral load outcomes in several more recent studies.

Other factors influencing CD4 cell count recovery

It is unclear whether specific drugs lead to greater CD4 cell count increases. Protease inhibitor (PI) and NNRTI-based regimens appear to be equally able to bring about immune reconstitution in people who start treatment early, even though Spanish research has shown that PI-based regimens achieve greater reductions in viral load and increases in the number of CD4 T-cells.

This study compared the PI indinavir (Crixivan) with nevirapine, both combined with d4T (stavudine, Zerit) and ddI. After twelve months the PI group had achieved a better reduction in viral load, with 71% experiencing a drop in viral load to below 50 copies/ml, compared to 45% respectively for the NNRTI group. CD4 percentages in the PI group increased significantly from 35% to 52%, whilst remaining at baseline in those treated with nevirapine at approximately 44%. However, detailed analysis of the immune profiles of both treatment groups suggested that their immune systems had experienced comparable reconstitution (Plana 2002).

Another study compared viral suppression and immune reconstitution in 24 patients between those taking a PI-based treatment regimen, to those taking a PI-sparing regimen. Overall they noticed few differences in immune reconstitution between the two groups, although they did notice that the PI group had lower levels of immune activation (Smith 2002).

Similarly, a comparison of 44 individuals receiving ritonavir-boosted lopinavir (Kaletra) with nevirapine or d4T, 3TC, abacavir (Zerit) and nevirapine found that immune restoration, as measured by CD4 cell count changes and other changes in immune cell populations, did not differ between the PI-containing and the PI-sparing groups (Landay 2002).

Another study did not find PI-containing regimens superior to other combinations. A review of 55 French patients who achieved viral load below 200 copies/ml after one year of treatment showed no difference in responses to cytomegalovirus (CMV), tuberculosis or tetanus antigens between those who received a PI-containing regimen and those who received three nucleoside reverse transcriptase inhibitors (NRTIs), suggesting that PI treatment may not be essential for immune restoration (Carcelain 2001).

Other factors that have been linked to a poor CD4 cell count increase on antiretroviral therapy include fewer naive CD4 T-cells and greater immune activation, more cells primed to commit suicide or apoptosis, poorer response to CMV antigen and lack of thymus enlargement (Teixieira 2001). Steroid treatment of people with advanced HIV infection may interfere with the thymic contribution to immune restoration (Pido-Lopez 2002).

Impact on CD8 T-cells

After starting of antiviral therapy, the number of activated CD8 T-cells decreases, and the number of memory CD8 T-cells increases. With ongoing suppression of HIV replication, the number of HIV-specific memory CD8 T-cells declines. If viral load increases during this time, so does the activity of HIV-specific CD8 T-cells, indicating a dynamic equilibrium between viral load and immune response (Kalams 1999).

Fewer target cells

Antiretroviral therapy is also reported to be associated with reduced expression of the chemokine receptors CCR5 and CXCR4. These receptors are essential co-receptors for HIV to gain entry to CD4 T-cells. Reduced expression of these co-receptors may be a response to falling levels of virus production, but it also has the effect of reducing the number of target cells for HIV infection (Tortajada 2000).

The restoration of T-helper 1 immunity

One theory about how HIV affects the immune system has suggested that in people with HIV there is gradual loss of balance between different parts of the immune system.

There are at least two different types of CD4 T-cells, known as T-helper 1 (Th1) and T-helper 2 (Th2) cells. Th1 cells are associated with cell-mediated immunity, triggering the CD8 T-cells to attack invading organisms directly. Th2 cells are associated with humoral immunity, triggering the production of antibodies. Various studies have suggested that as viral load increases there is a gradual shift from a Th1 to a Th2 immune response. People who maintain a Th1 response may have a better prognosis and longer survival. In some individuals, a strong Th1 response may also prevent infection and seroconversion despite exposure. However, critics of this theory say that the apparent switch from cellular to humoral immunity is simply a reflection of the gradual depletion of immune cells such as CD4 T-cells, so that antibodies are left dominant.

Recent research has demonstrated that initiation of antiretroviral therapy is accompanied by a return towards Th1 responses. Researchers at the Chelsea and Westminster Hospital in London studied nine individuals before and after starting antiretroviral therapy and noted increased production of the Th1 cytokines interleukin-2 (IL-2) and interferon gamma and reduced production of the Th2 cytokines IL-4 and IL-10. IL-4 and IL-10 often became undetectable on antiretroviral therapy (Imami 1999).

Age and immune recovery

A review of participants in the EuroSIDA cohort found that older age was associated with a smaller CD4 cell count, less likelihood of gaining more than 200 cells/mm³ and a longer time to achieving a CD4 cell increase of more than 100 or 200 cells/mm³. In this group of individuals, the median age was 37 years, with one quarter of patients below 32.7 years of age, and one quarter above the age of 44.5 years. The differences were most significant between those below 32 and above 44 years of age (Viard 2001).

The investigators suggest that the decline of the activity of the thymus with age may reduce the capacity of the thymus to produce naive CD4 T-cells during the second phase of immune reconstitution. A Dutch team reported that older people on antiretroviral therapy have a slower rate of regeneration of naive T-cells but they found little evidence that HIV infection itself affects naive cell production (Cohen Stuart 2002).

Another study has also found a link between age and immune recovery. Of 71 people on antiretroviral therapy, CD4 cell count recovery was greatest soon after beginning treatment in people who had very high viral loads. In contrast, during the second phase of immune recovery, younger people had greater CD4 cell count increases (Lederman 2003).

However a retrospective analysis of 52 patients found no difference in immune reconstitution in those above and below 50 years of age. There was no significant difference with regard to the development of opportunistic infections or drug related side-effects. The number of hospitalisations was also similar. Both groups experienced comparable increases in CD4 cell count and falls in viral load. Although the mortality rate was higher in the over 50s, it was found that the majority of these were caused by factors unrelated to HIV and that there was no significant difference in AIDS-related deaths between the groups.

These findings suggest that any differences in laboratory measures of immune reconstitution do not translate into functional differences in immunity (Grimes 2002). Similar conclusions were reached by an Italian group, which reviewed immune reconstitution in 58 HIV-positive patients aged 50 or above and 116 patients aged between 20 and 35. At baseline, the over 50s had an average CD4 cell count significantly lower than that of the younger patients, although viral loads were comparable (Tumaberello 2003).

Immune restoration in children

Children on antiretroviral therapy have the potential for faster and better immune reconstitution than adults. This is due, in part, to the thymus, which may be more active in children than in adults. One study which measured immune recovery in children found a steep increase in the total number of CD4 T-cells, particularly in the number of naive cells (Gibb 2000). Measurement of thymic tissue showed that the return of naive CD4 T-cells correlated with the increase in thymic tissue. Thymus growth and CD4 cell count increases are often greater in younger children during anti-HIV treatment (Chavan 2001; Vigano 2000). CD4 cell count restoration may be pronounced in children on treatment even when viral load reduction is minimal.

A Dutch study of 71 children who received at least 96 weeks of antiretroviral therapy found no difference in naive T-cell production according to age, or in immune reconstitution according to virological response. This led the authors to suggest that CD4 cell count restoration in children occurs faster and more fully in children than in adults (van Rossum 2001). Similarly, a Belgian team who studied 19 children found rapid increases in memory and naive cells during the first three months of antiretroviral therapy. Younger children had a faster increase in naive cells but after twelve months of treatment, age was not associated with a better naive cell response (Hainaut 2003).

CD4 percentage at the beginning of treatment may be a more useful predictor of immune reconstitution, regardless of viral load. Treatment tends to have a greater effect in children with more advanced immunosuppression, irrespective of the viral load reduction achieved by treatment (Nikolic-Djokic 2002).

Lymph node repair

The latest studies are also optimistic about lymph node damage. In a healthy person, the lymph nodes are known to play a key role in the interaction between various immune cells.

Lymph nodes contain 'follicular dendritic cells' that trap foreign organisms and 'present' them to CD4 T-cells. This then kick-starts other immune responses. Among people with untreated HIV infection, the structure of the lymph nodes is often damaged, and it had been unclear whether they could be rebuilt even if HIV is suppressed.

Recent investigations have shown clear signs that the lymph nodes begin to regain their normal structure among people receiving antiretroviral therapy. For example, a Spanish group found evidence that some patients were beginning to restore structures that had been severely damaged by long-term HIV infection after 48 weeks of treatment (Macias 2001). Examination of the follicular dendritic cell network, which is largely destroyed by long-term HIV infection, has also shown that it is restored after 48 weeks or more of antiretroviral therapy (Zhang 1999).

However, follicular dendritic cells often continue to display the p24 antigen after more than a year of suppressive treatment. It has been theorised that the persistence of HIV antigen in lymph tissue during antiretroviral therapy may explain continuous CD4 T-cell activation despite plasma viral loads being below 50 copies/ml (Cohen-Stuart 1999). This study found no evidence of HIV in patients with follicular dendritic cells displaying HIV antigen, suggesting that antigen trapped prior to the initiation of antiretroviral therapy may be responsible for ongoing immune activation.

Restoration of other immune function

As well as destroying CD4 T-cells, HIV damages other immune cells called neutrophils, monocytes and phagocytes. These cells are involved in two important functions: chemotaxis and phagocytosis. Chemotaxis is the ability of a cell to receive immune signalling and move where directed by that signal to fight infection. Phagocytosis refers to the ingestion and destruction of an infected cell or micro-organism. A study of 18 HIV-infected people found significant improvement in chemotaxis after nine months treatment with antiretroviral therapy. Phagocytosis did not improve to the same extent as chemotaxis (Mastroianni 1999).

HIV also damages the DNA of white blood cells. This affects the number of particular cells, as well as high levels of activation markers such as CD38. Sustained suppression of HIV led to only modest improvement in these immune indices in one study, suggesting that very low levels of HIV are enough to cause immune dysregulation (Patki 1999).

French research has also found that CD4 T-cell production of IL-2 normalises following nine months of antiretroviral therapy (Weiss 1999).

Mismatch between virologic and immunologic responses

See Discordant CD4 cell count and viral load responses in Anti-HIV therapy: Restoring the immune system for further discussion of this topic.

References

Al-Harthi L et al. Evaluation of immune restoration parameters in antiretroviral-naﶥ patients: role of the thymus in naﶥ T-cell rise (COLA3003). Fourteenth International AIDS Conference, Barcelona, abstract ThPpA2129, 2002.

Autran B et al. Positive effects of combined anti-retroviral therapy on CD4+ T-cell homeostasis and function in advanced HIV disease. Science 277: 112-116, 1997.

Autran B et al. Restoration of the immune system with anti-retroviral therapy. Immunol Lett 66: 207-211, 1999.

Carcelain G et al. Reconstitution of CD4+ T lymphocytes in HIV-infected individuals following antiretroviral therapy. Curr Opin Immunol 13: 483-488, 2001.

Chavan S et al. Evaluation of T cell receptor gene rearrangement excision circles after antiretroviral therapy in children infected with human immunodeficiency virus. J Infect Dis 183: 1445-1454, 2001.

Clark DR et al. T-cell progenitor function during progressive human immunodeficiency virus-1 infection and after antiretroviral therapy. Blood 96: 242-249, 2000.

Cohen-Stuart JWT et al. Persistence of HIV antigens in lymphoid tissue despite 18 months of HAART may explain the slow delay of activated CD4 cells. Antivir Ther 4: S107, 1999.

Cohen Stuart J et al. Reconstitution of naive T cells during antiretroviral treatment of HIV-infected adults is dependent on age. AIDS 16: 2263-2266, 2002.

Connick E et al. Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response. J Infect Dis 181: 358-363, 2000.

Dam Nielsen S et al. Highly active antiretroviral therapy normalizes the function of progenitor cells in human immunodeficiency virus-infected patients. J Infect Dis 178: 1299-1305, 1998.

Deeks SG al. Sustained CD4+ T cell response after virologic failure of protease inhibitor based regimens in patients with human immunodeficiency virus infection. J Infect Dis 181: 946-953, 2000.

Delgado J et al. Evidence of thymic function in heavily antiretroviral-treated human immunodeficiency virus type 1-infected adults with long-term virologic treatment failure. J Infect Dis 186: 410-414, 2002.

Felipe G et al. Long-term CD4+ T-cells response to highly active antiretroviral therapy according to baseline CD4+ T cell count and age. Second International AIDS Society Conference on HIV Treatment and Pathogenesis, Paris, abstract 433, 2003.

Florence E et al. Factors associated with a reduced CD4 lymphocyte count response to HAART despite full viral suppression in the EuroSIDA study. HIV Med 4: 255-262, 2003.

Franco JM et al. T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy. Blood 99: 3702-3706, 2002.

Gatell J et al. Lack of T-cell proliferative response to HIV-1 antigens after 1 year of highly active antiretroviral treatment in early HIV-1 disease. Lancet 352: 1194-1195, 1998.

Gibb DM et al. Immune repopulation after HAART in previously untreated HIV-1-infected children. Lancet 355: 1331-1332, 2000.

Grimes M et al. Clinical experience with human immunodeficiency virus infected older patients in the era of effective antiretroviral therapy. Clin Infect Dis 34: 15301533, 2002.

Hainaut M et al. Age-related immune reconstitution during highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children. Pediatr Infect Dis J 22: 62-69, 2003.

Hengel RL et al. Lymphocyte kinetics and precursor frequency-dependent recovery of CD4(+)CD45RA(+)CD62L(+) naive T cells following triple-drug therapy for HIV type 1 infection. AIDS Res Hum Retroviruses 15: 435-443, 1999.

Hunt PW et al. Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy. AIDS 17: 1907-1915, 2003

Hunt PW et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiecny virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis 187: 1534-1543, 2003.

Imami N et al. Assessment of type 1 and type 2 cytokines in HIV type 1-infected individuals: impact of highly active antiretroviral therapy. AIDS Res Hum Retroviruses 15: 1499-1508, 1999.

Imami N et al. Growth hormone therapy induces HIV-1 specific CD4 and CD8 T cell responses in HAART treated patients. XIV International AIDS Conference, Barcelona, abstract ThPeA7090, 2002.

Jamieson BD et al. Generation of functional thymocytes in the human adult. Immunity 10: 569-575, 1999.

Kalams SA et al. Levels of human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy. J Virol 73: 6721-6728, 1999.

Kaufmann G et al. The extent of HIV-1-related immunodeficiency and age predict the long-term CD4 T lymphocyte response to potent antiretroviral therapy. AIDS 16: 359-367, 2002.

Komanduri K. Second Meeting of the Research Institute for Genetic and Human Therapy (RIGHT), Washington, 1999.

Kolte L et al. Association between larger thymic size and higher thymic output in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy. J Infect Dis 185: 1578-1585, 2002.

Kost R et al. Partial immunological recovery after 13 months of potent antiretroviral therapy. International Workshop on Drug Resistance, Treatment Strategies and Eradication, Florida, abstract 123, 1997.

Landay AL et al. First phase immune restoration is comparable in antiretroviral-naive subjects receiving a protease inhibitor or triple-NRTI-based ARV regimen. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 481, 2002.

Lange C et al. Immune reconstitution with antiretroviral therapies in chronic HIV-1 infection. J Antimicrob Chemother 51: 1-4, 2003.

Lederman MM et al. Cellular restoration in HIV infected persons treated with abacavir and a protease inhibitor: age inversely predicts naive CD4 cell count increase. AIDS 14: 2635-2642, 2000.

Lederman HM et al. Incomplete immune reconstitution after the initiation of highly active antiretroviral therapy in HIV-infected patients with severe CD4 cell count depletion. J Infect Dis 188: 1794-1803, 2003.

Li TS et al. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 351: 1682-1686, 1998.

Macias J et al. Structural normalization of the lymphoid tissue in asymptomatic HIV-infected patients after 48 weeks of potent antiretroviral therapy. AIDS 15: 2371-2378, 2001.

Mackall C et al. Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy. Immunol Rev 157: 61-72, 1997.

Malhotra U et al. Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection. J Infect Dis 181: 121-131, 2000.

Marchietti G et al. Evidence for enhanced thymic output, measured by T cell receptor excision circles (TRECs), after HAART. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 328, 2000.

Mastroianni CM et al. Improvement in neutrophil and monocycte function during highly active antiretroviral treatment of HIV-1-infected patients. AIDS 13: 883-890, 1999.

Napolitano LA et al. Increased thymic mass and circulating naive CD4 T cells in HIV-1-infected adults treated with growth hormone. AIDS 16: 1103-1111, 2002.

Nikolic-Djokic D et al. Immunoreconstitution in children receiving highly active antiretroviral therapy depends on the CD4 cell percentage at baseline. J Infect Dis 185: 290-298, 2002.

Nokta MA et al. Entrapment of recent thymic emigrants in lymphoid tissues from HIV-infected patients: association with HIV cellular viral load. AIDS 16: 2119-2127, 2002.

Noterdams DW et al. Immune reconstitution after 2 years of successful potent antiretroviral therapy in previously untreated human immunodeficiency virus type-1 infected adults. J Infect Dis 180: 1050-1056, 1999.

Oxenius A et al. Residual HIV-specific CD4 and CD8 T cell frequencies after prolonged antiretroviral therapy reflect pretreatment plasma virus load. AIDS 16: 2317-2322, 2002.

Pakker NG et al. Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. AIDS 13: 203-212, 1999.

Patki AH et al. HIV infection perturbs DNA content of lymphoid cells: partial correction after 'suppression' of virus replication. AIDS 13: 1177-1185, 1999.

Perez JL et al. Greater effect of highly active antiretroviral therapy on survival in people aged 50 and above compared with younger people in an urban observational cohort. Clin Infect Dis 36: 212-218, 2003.

Pido-Lopez J et al. Thymic activity in late-stage HIV-1 infected individuals receiving highly active antiretroviral therapy: potential effect of steroid therapy. HIV Med 3: 56-61, 2002.

Plana M et al. Immunologic reconstitution after 1 year of highly active antiretroviral therapy, with or without protease inhibitors. J Acquir Immune Defic Syndr 29: 429-434, 2002.

Rubio A et al. Changes in thymus volume in adult HIV-infected patients under HAART: correlation with the T-cell repopulation. Clin Exp Immunol 130: 121-126, 2002.

Sekaly RP et al. Primary HIV infection results in a potent thymic rebound. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 329, 2000.

Sieg SF et al. Close link between CD4+ and CD8+ T cell proliferation defects in patients with human immunodeficiency virus disease and relationship to extended periods of CD4+ lymphopenia. J Infect Dis 185: 1401-1416, 2002.

Smith KY et al. Thymic size and lymphocyte restoration in patients with human immunodeficiency virus infection after 48 weeks of zidovudine, lamivudine and ritonavir therapy. J Infect Dis 181: 141-147, 2000.

Smith KY et al. Immune reconstitution after successful treatment with protease inhibitor-based and protease inhibitor-sparing antiretroviral regimens. J Acquir Immune Defic Syndr 29: 544-545, 2002.

Smith K et al. Long-term changes in circulated CD4 T lymphocytes in virologically suppressed patients after 6 years of high active antiretroviral therapy. AIDS 18: 1953-1956, 2004.

Sommerville-King D et al. Reconstitution of the T cell pool in treated, HIV-infected children correlates with response to antiretroviral therapy. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 322, 2000.

Staszewski S et al. Determinants of sustainable CD4 lymphocyte count increases in response to antiretroviral therapy. AIDS 13: 951-956, 1999.

Teixiera L et al. Poor CD4+ T cell restoration after suppression of HIV replication may reflect lower thymic function. AIDS 15: 1749-1756, 2001.

Tortajada C et al. Comparison of T-cell subsets' reconstitution after 12 months of highly active antiretroviral therapy initiated during early versus advanced states of HIV disease. J Acquir Immune Defic Syndr 25: 296-305, 2000.

Tumbarello M et al. Older HIV-positive patients in the era of highly active antiretroviral therapy: changing of a scenario. AIDS 17: 129-131, 2003.

van Rossum AM et al. Therapeutic immune reconstitution in HIV-1-infected children is independent of their age and pretreatment immune status. AIDS 15: 2267-2275, 2001.

Viard JP et al. Influence of age on CD4+ cell recovery in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy: evidence from the Eurosida study. J Infect Dis 183: 1290-1294, 2001.

Viard J-P et al. Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level. AIDS 18: 45-49, 2004.

Vigano A et al. Early immune reconstitution after potent antiretroviral therapy in HIV-infected children correlates with the increase in thymus volume. AIDS 14: 251-261, 2000.

Weiss L et al. Restoration of normal interleukin-2 production by CD4+ T cells of human immunodeficiency virus-infected patients after 9 months of highly active antiretroviral therapy. J Infect Dis 180: 1057-1063, 1999.

Wood E et al. The impact of adherence on CD4 cell count responses among HIV-infected patients. J Acquir Immune Defic Syndr 35: 261-268, 2004.

Zhang ZQ et al. Reversibility of the pathological changes in the follicular dendritic cell network with treatment of HIV-1 infection. Proceedings of the National Academy of Sciences U S A 96: 5169-5172, 1999.