British Medical Bulletin

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British Medical Bulletin 58:187-203 (2001)
© 2001 Oxford University Press

Immune interventions

The changing face of HIV and AIDS

John Wilkinson and Frances Gotch

Department of Immunology, Imperial College of Science, Technology and Medicine, Chelsea and Westminster Hospital, London, UK

	Abstract

Top Footnotes Abstract The HIV-infected immune system CD4+ T-lymphocytes CD8+ effector cells Immunosuppression and... Long-term survival Anti-retroviral therapy (ART) Immune-based therapies Conclusions Acknowledgements References

 
A better understanding of the immune response to HIV and the deleterious effect that HIV infection may have on the immune system in general, allows us to consider how best to restore protective immune responses to HIV and other opportunistic pathogens in the immunocompromised host. In this chapter, we summarise areas of current innovation and provide an update of the current state of knowledge concerning interventions which could result in the immunocompromised state being reversed. We describe the kinds of immune responses, which are thought to be useful in combating both the human immunodeficiency virus and other pathogenic organisms, and methods which are being considered to stimulate such responses. Lessons which may be learned from other disease states, which lead to immunodeficiency and methods for measuring successful outcome of treatment will be described.

	The HIV-infected immune system

Top Footnotes Abstract The HIV-infected immune system CD4+ T-lymphocytes CD8+ effector cells Immunosuppression and... Long-term survival Anti-retroviral therapy (ART) Immune-based therapies Conclusions Acknowledgements References

 
The immune system is capable of mounting very strong attacks on invading pathogens and is able to eliminate many of them completely. Cellular immune responses are a critical part of the host's defence against viral infections with CD8⁺ T-lymphocytes forming a primary component. Evidence for strong CD8⁺ antiviral pressure can be appreciated by the number and variety of strategies which viruses have evolved to avoid apoptosis and CTL recognition, thus prolonging the life of the virally-infected cell and enabling viral replication and dissemination (reviewed by Meinl et al¹). The importance of CD4⁺ T cell responses should also not be underestimated, providing ‘help’ both to T- and B-cells. Since the original description of CD4⁺ and CD8⁺ T-lymphocytes as ‘helper’ cytokine-producing cells and ‘lytic’ CTLs, respectively, the two have not remained mutually exclusive with CD4⁺ T-lymphocytes demonstrating cytotoxic activity and CD8⁺ T-lymphocytes exhibiting potent cytokine and chemokine-producing activity.

The overall in vivo effect of HIV-1 infection and its interaction with the body's natural response mechanism is of severe damage to the immune system, destroying the means by which the body responds and defends itself against infections. Infection with HIV produces a wide range of qualitative and quantitative immunological changes, the most prominent being the changes that affect the CD4⁺ T-lymphocytes. In normal physiology, the CD4⁺ T-lymphocyte provides regulatory factors that enhance the function of many other cell types. It is widely believed that many of the defects in function in these other cells seen during HIV infection are linked to changes in CD4⁺ T-lymphocyte number and function.

Studies of HIV-specific immunity soon after primary infection show early induction of both CD4⁺ and CD8⁺ cell-mediated immunity. However, in most cases, these immune responses achieve only weak control of viral replication. The mechanisms by which HIV escapes immune control include both immunological and viral factors. The major determinant of the rate of disease progression is the balance between the evolutionary pressures upon HIV from the immune system at large, and the success of the virus population in adapting to these pressures. HIV undergoes a continual process of evolution reflected in the viral load and the CD4⁺ T-lymphocyte count of the individual and in the changes evident in the genotype of the viruses present. During primary infection, viruses utilising the CCR5 co-receptor are likely to predominate. Virus strains able to use the CXCR4 chemokine receptor may predominate with time and are associated with a switch from NSI to SI phenotype and hence a much greater quantitative loss in CD4⁺ T-lymphocytes. This constant evolution helps HIV stay one step ahead of the immune system, which is primed to respond to the previous generation of virus.

	CD4+ T-lymphocytes

Top Footnotes Abstract The HIV-infected immune system CD4+ T-lymphocytes CD8+ effector cells Immunosuppression and... Long-term survival Anti-retroviral therapy (ART) Immune-based therapies Conclusions Acknowledgements References

 
The first cells infected by HIV are likely to be the activated CD4⁺ T-lymphocytes in the lymphoid tissue, and tissue macrophages that are in a differentiated state. CD4⁺ T-lymphocytes either express CD45RA⁺, a cell surface marker which defines the subset of antigen naive cells, or CD45RO⁺, which characterises the memory cell subset. Naive cells originate typically from the thymus and remain in a resting state until they encounter foreign antigen. When antigen and co-stimulatory signals are presented by antigen presenting cells, naive cells become activated and switch to the memory phenotype displaying an effector function and with the ability to respond quickly to antigen. Initial exposure to HIV results in the rapid recruitment of activated memory CD4⁺ T-lymphocytes, which, being the primary targets for HIV infection, are preferentially depleted while in advanced stages of the disease the proportion of naive cells also declines.

Besides the progressive fall in the numbers of peripheral blood CD4⁺ T-lymphocytes in HIV-infected individuals, immunological abnormalities in T-helper cell function occur early in HIV infection, even before the CD4⁺ T-lymphocyte numbers diminish. Reduced proliferative capacity and diminished IL-2 production by peripheral blood mononuclear cells in response to stimulation is one of the hallmarks of HIV disease and these functions decrease progressively with disease. CD4⁺ T cell responses to HIV-specific antigens are difficult to detect even early in the disease process with responses to recall antigens lost as disease progresses and finally a loss of response to mitogens becoming apparent.

CD4⁺ T-lymphocytes in HIV-infected individuals, which recognise antigen in association with class II MHC molecules on the antigen presenting cell, have demonstrated responses to a variety of HIV proteins (env, gag and pol) in early-stage disease. Further, the association between certain MHC HLA class II haplotypes and HIV disease progression suggests a positive role for the host's immune system in determining clinical outcome (reviewed by Westby et al²).

Human CD4⁺ T-lymphocytes can be separated into Th1 and Th2 subsets, secreting cytokines that may play an immunoregulatory role in HIV infection by defining the lymphokine and thus the effector cell profile which can possibly affect progression to AIDS (reviewed by Clerici and Shearer³). Derived from a common precursor (Th0-type) cell capable of expressing a broad range of different cytokines, generally Th1 cells differentially secrete IL-2, IFN-, TGF-ß and IL-12, whilst Th2 cells secrete IL-4, IL-5, IL-6 and IL-10. Studies by Clerici and Shearer³ have suggested that specific humoral immune responses are determined by the cytokines they produce, with a switch during HIV disease progression from Th1 (increasing cellular immunity) to Th2 (enhancing antibody production) type cytokine production. The interaction of the Th1 and Th2 cell subsets is competitive, with over-expression of cytokines by one cell type suppressing the activity of the other, such that the predominance of Th2 cells could be responsible for the decrease in Th1 activity, thus leading to the switch (figure 1).

View larger version (15K): [in this window] [in a new window]   Fig. 1 Model for the differentiation of CD4+ T-lymphocytes with regard to cytokine expression (adapted from Clerici and Shearer3).

 

	CD8+ effector cells

Top Footnotes Abstract The HIV-infected immune system CD4+ T-lymphocytes CD8+ effector cells Immunosuppression and... Long-term survival Anti-retroviral therapy (ART) Immune-based therapies Conclusions Acknowledgements References

 
The contribution of CD8⁺ T-lymphocytes towards cellular immunity has been highlighted in two recent studies which eliminated CD8⁺ T-lymphocytes from SIV-infected rhesus monkeys during primary or chronic infection^4,5. CD8⁺ depletion during primary infection resulted in uncontrolled viraemia with a subsequent inability to generate neutralising antibody responses and rapid progression to disease. Elimination of CD8⁺ cells during chronic infection resulted in a rapid and marked increase in viraemia that was suppressed with the re-appearance of SIV-specific CD8⁺ T cells. Similarly, CD8⁺ T-lymphocytes have been shown to play an important role in controlling HIV infection, either by a direct killing effect on HIV infected cells and/or by the secretion of soluble antiviral factors which suppress HIV replication.

Within the T-lymphocyte compartment, naive (cells which have not encountered antigen), effector (cells with specialised functions such as cytotoxic and suppressor activity) and memory T-lymphocytes can be identified. Memory cells, the progeny of CTLs that escape activation-induced cell death⁶, are an important component of the immune system, responding efficiently to recall antigens, demonstrating less stringent requirements for activation and secreting a broader range of cytokines. Phenotypically, naive, effector and memory cells differ in the expression of several surface antigens, including CD29, LFA-1 and CD45RO, although these markers may just reflect cellular activation. However, in the murine model, various groups have demonstrated that the lymph node homing receptor CD62L is strongly down regulated on CTL compared to naive cells, with memory cells demonstrating heterogeneous expression.

One of the hallmarks of HIV-infection is the dynamic expansion and activation of CD8⁺ T-lymphocytes. During primary HIV infection (PHI), the CD8⁺ cell compartment can increase remarkably in number; a 10-fold expansion was observed in one individual with acute HIV infection who declined anti-retroviral therapy (ART)⁷. Nearly 90% of these CD8⁺ T cells expressed markers of immune activation at seroconversion. An effect of such enormous expansion and activation may be that HIV-specific CD8⁺ T-lymphocytes are eventually deleted through a process of clonal exhaustion.

CD8⁺ cytotoxic T-lymphocytes

CD8⁺ CTL recognise virus-infected cells upon presentation of an 8–10 amino acid peptide epitope by the infected target cell and may be directed against both structural (gag, pol and env) and regulatory (tat, rev and nef) proteins of HIV. Classically, this response is HLA-restricted and requires cell-to-cell contact and appears as early as 5 days following seroconversion, as demonstrated in the SIV model of acute infection. Additionally, the reduction in viraemia in acute HIV infection is associated with the onset of a virus-specific, class I HLA-restricted, CD8⁺ CTL response, which is similar to that which has been observed in acute virus infections in mice (reviewed by Gotch and Hardy⁸).

Precursors of HIV-specific CTL have been detected prior to the appearance of neutralising antibodies, suggesting that HIV-specific cell-mediated immune responses play a major role in down-regulating HIV viraemia following seroconversion. These cells are probably responsible for the destruction of the virus expressing cells, reducing the pool of HIV-producing cells, and leading to the decrease in HIV viraemia at seroconversion. Various studies have demonstrated that in early HIV-1 infection, the induction of memory CTLs, particularly those specific for env, help control viral replication, with this activity associated with slower declines in CD4⁺ T-lymphocyte counts.

CTLs remain in relatively high numbers during the asymptomatic period of HIV infection, but their numbers decline with progression to disease. Direct measurements (using the complementarity-determining region 3 of the T-cell antigen receptor as molecular markers for individual CTL clones) have indicated that the level of CD8⁺ CTL effectors is around 1% of all PBMC in the chronic phase of HIV disease⁹, with antigen-specific CTLs representing > 25% of the total number of circulating CD8⁺ T-lymphocytes during the acute phase¹⁰. Long-term survivors demonstrate high precursor frequencies of CTL (Table 1) and there is evidence that CTL may have a protective role in exposed but uninfected individuals.

View this table: [in this window] [in a new window]   Table 1 Salient features associated with long-term survivors

 
In longitudinal studies, variant HIV species encoding mutated CTL epitopes in regions critical for MHC binding (particularly gag, but nef, tat and pol also) may emerge during the course of infection, with progression to AIDS occurring when new strains of virus are produced that cannot be controlled by the generation of CTL with new specificities. Increasing viral diversity in itself does not correlate with CD4⁺ T-lymphocyte loss and progression to AIDS; in fact, rapid CD4⁺ T-lymphocyte decline has been associated with relatively homogenous viral populations. However, just prior to, or coincident with, a rapid decline in CD4⁺ T-cell numbers, basic amino acid substitutions clustered within and downstream of the gp120 V3 domain can be detected, suggesting that the virus continually accumulates changes in its amino acid sequences well into the time of marked CD4⁺ T cell decline¹¹.

CD8⁺ suppressor cells

The inability to recover virus from asymptomatic HIV-infected individuals unless CD8⁺ T-lymphocytes were first removed led to the discovery of CD8⁺ suppressor responses. When the CD8⁺ effector cells were added back to the assay, virus replication was again suppressed in a dose-dependent manner. Many studies have confirmed the presence of CD8⁺ anti-HIV suppressor activity (CASA) and similar results have been reported in SIV- and HIV-infected non-human primates. CASA demonstrates a broad spectrum of activity against target cells infected with either cytopathic or non-cytopathic strains of HIV-1, HIV-2, and SIV, with autologous CD8⁺ T-lymphocytes demonstrating stronger CASA than allogeneic cells. CASA is not HLA-restricted, does not involve cell killing, and is mediated through a novel soluble factor(s), termed CD8⁺ antiviral factor (CAF).

The degree of CASA and levels of CAF correlate with the patient's clinical state, with CD8⁺ T-lymphocytes from asymptomatic individuals exhibiting the strongest CASA, followed by CD8⁺ T-lymphocytes from symptomatic patients and then AIDS patients who demonstrate the least activity, although, an overlap in the relative anti-HIV suppressor activity exhibited by CD8⁺ T cells from these cohorts has been reported. In addition, CASA in lymphoid tissue has also been observed to correlate with the clinical state of the individual. CASA in the peripheral blood has been detected before neutralising antibodies to HIV, suggesting a positive role for this cellular immune response in controlling viral replication soon after HIV infection (reviewed by Levy et al¹²).

	Immunosuppression and opportunistic infections

Top Footnotes Abstract The HIV-infected immune system CD4+ T-lymphocytes CD8+ effector cells Immunosuppression and... Long-term survival Anti-retroviral therapy (ART) Immune-based therapies Conclusions Acknowledgements References

 
In most patients, chronic HIV infection results in a generalised progressive impairment of cell-mediated immune responses and, as a result, a failure to control the replication of opportunistic pathogens such as cytomegalovirus (CMV), human papilloma virus (HPV), human herpes virus 8 (HHV8), Cryptosporidium and Microsporidium. Opportunistic infections are the clinical manifestations of uncontrolled replication of opportunistic pathogens which usually exist as latent subclinical infections.

	Long-term survival

Top Footnotes Abstract The HIV-infected immune system CD4+ T-lymphocytes CD8+ effector cells Immunosuppression and... Long-term survival Anti-retroviral therapy (ART) Immune-based therapies Conclusions Acknowledgements References

 
Although only a relatively small number of patients fall into this category, the reasons for long-term survival could provide insights into possible therapeutic approaches to HIV. Definitions of long-term survival vary; generally, individuals living with HIV infection for more than 8 years (median duration) with no symptoms and a CD4⁺ T-lymphocyte count above 500 cells/ml are considered long-term survivors. Some consistent features of their infection are outlined in Table 1.

Understanding the immune factors that maintain this natural suppressive response, which may also partly account for the resistance to infection in exposed but uninfected individuals and increased longevity in some HIV-infected individuals, are important when the development of safe and effective immune interventions such as therapeutic or prophylactic vaccines are considered. The stimulation of the cell-mediated immune response with a therapeutic vaccine may be a key factor in the restoration of the immune system following anti-retroviral therapy (ART), where the immune system may be persuaded to assist in the control of continued HIV replication once the viral load has been rendered undetectable. It is important to note that whilst ART may reduce viral load to undetectable levels, viral replication continues within the host. Additionally, with such a high incidence of AIDS in the non-industrialised world, the development of a preventive vaccine that results in vigorous HIV-specific cellular immune responses may be one option for an effective long-term solution to the control of the AIDS pandemic.

	Anti-retroviral therapy (ART)

Top Footnotes Abstract The HIV-infected immune system CD4+ T-lymphocytes CD8+ effector cells Immunosuppression and... Long-term survival Anti-retroviral therapy (ART) Immune-based therapies Conclusions Acknowledgements References

 
The efficacies of current anti-retroviral agents and treatment strategies cannot be simply assessed by quantitation of CD4⁺ T-lymphocytes (a surrogate marker for overall immune function), as alterations in their number does not explain all the effects of therapeutic intervention; but must be assessed by their ability to reconstitute the immune system on a wider scale. There are currently no measures of HIV-specific immunity routinely available in clinical practice. Assays to determine HIV-specific immune function, including neutralising antibody responses, CTL assays and assays for CD4⁺ T cell function are only available in the research laboratory, but may be essential for the clinical monitoring of current ART which incorporates immune based therapies.

Following PHI, the level of viraemia at 4–12 months (the ‘set-point’) correlates with disease progression. Treatment initiated at higher CD4⁺ T-lymphocyte and lower HIV-1 RNA levels, has been associated with greater and more durable immune responses, leading to the possibility of preventing the dissemination of HIV, the preservation of the immune function and the increased likelihood of restoring important components of the HIV-specific immune response¹³ and responses to other important opportunistic pathogens, such as CMV, HSV and HHV8, which have been diminished or lost. In addition, early treatment during PHI, and even at seroconversion, may prevent the stable reservoir of integrated proviral HIV DNA, present in resting CD4⁺ T-lymphocytes both in the peripheral blood and lymph nodes, which persists through ART^14,15.

Highly active anti-retroviral therapy (HAART)

Encouraging results have been observed with a number of combination drug regimens containing various potent antiviral agents which target the HIV enzymes (i) reverse transcriptase, associated with HIV replication, and/or (ii) the protease enzymes, essential for the maturation of the HIV virion. Plasma HIV-1 RNA levels in the peripheral blood in treated patients may be below those seen in long-term survivors. Many studies link the durability of response to HAART with the magnitude of the initial response, with greater initial therapy-induced HIV RNA decreases strongly associated with the reduced risk of progression to AIDS or death (reviewed by DeGruttola et al¹⁶). The advent of combination therapy has led to the partial control of HIV-1 replication in vivo, demonstrated by a decline in AIDS incidence and mortality in the Western world. In addition, HAART has helped revolutionise our understanding of HIV-1 viral kinetics in infected individuals and has given us an opportunity to observe changes in the immune system.

Immune reconstitution with HAART

The decrease in the incidence of mortality and opportunistic diseases observed since the introduction of HAART is compelling clinical evidence of improvements in immune function specific for or ‘directed at’ HIV and for opportunistic pathogens. HAART is associated with decreases in viral burden, which are paralleled by increases in CD4⁺ T-lymphocyte counts and improvements in T-cell function, even in individuals with advanced stages of HIV-1 disease. The extent of immune restoration that can be achieved may be determined by the state of the immune system, in particular by the number of naive T-lymphocytes, prior to the commencement of HAART¹⁷.

Despite the significant increases in CD4⁺ T-lymphocyte numbers with HAART, only a small proportion of individuals demonstrate increases which approach the normal range following 2 years of therapy. In the majority of cases, these increases in T-lymphocytes rarely reach normal levels, and immune reconstitution does not necessarily follow long-term HIV-1 suppression with HAART¹⁸. However, Furrer and co-workers have reported that even a partial restoration of the immune system may protect some individuals against opportunistic infections¹⁹.

In one of the first studies to assess immune reconstitution, Kelleher and co-workers²⁰ noted significant increases in both naive and memory CD4⁺ T-lymphocytes, as well as increased lymphocyte proliferation responses to mitogen, recall antigens and HIV-1-specific proteins in HIV-1 infected individuals treated with ritonavir^®. Similarly, Autran and co-workers reported the appearance of memory CD4⁺ T-lymphocytes during the first 4 months of HAART, followed by increased numbers of functional naive CD4⁺ T-lymphocytes by 12 months¹⁷.

In addition to increases in CD4⁺ T-lymphocytes, increases in CD8⁺ T-lymphocytes are observed with ART, both demonstrating a biphasic response to HAART²¹. Memory CD8⁺ T-lymphocytes expand rapidly within weeks resulting in an overall increase in total CD8⁺ number, but decline again in the subsequent months. The proportion of naive CD8⁺ T-lymphocytes increases slowly maintaining the number of total CD8⁺ T-lymphocytes at an almost constant level^17,20,21.

Infection with HIV-1 leads to the extensive activation of T-lymphocytes resulting in anergy and increased apoptosis. With HIV-1 disease progression the proportion of activated T-lymphocytes increases, which correlates to increases in plasma HIV RNA levels. Initiation of HAART has been reported to rapidly reduce the number of activated CD4⁺ and CD8⁺ T-lymphocytes as measured by the expression of CD38 and HLA-DR cell surface antigens^17,20,22.

In addition to increasing the proliferative responses of CD4⁺ T-lymphocytes to recall antigens and/or to mitogens^17,20,23,24, HAART has resulted in the detection of new DTH responses to recall antigens in a third of those individuals tested²⁴. Proliferative T-lymphocyte responses improve slowly as demonstrated in studies of up to 1.5 years' duration; however, normal levels were still not attained²³. Individuals with a significant improvement in lymphocyte proliferative responses demonstrated a more sustained suppression of plasma HIV RNA, greater CD4⁺ increases and an early increase of memory and naive CD4⁺ T-lymphocytes²⁵. In support of early treatment of individuals with HAART, improved HIV-specific T-helper responses were observed in individuals treated early^23,26,27, but not in those with chronic more advanced HIV-1 disease^17,24.

Despite 12 months of HAART, achieving undetectable viral loads, HIV-1 specific CD4⁺ T cell proliferative responses were not restored in early HIV-1 disease^23,26,27. In some individuals with HAART-associated undetectable viraemia, there is an apparent loss of HIV-1-specific CTL²⁸, a loss of CASA²⁹ and a decline of HIV-1 specific cytotoxic CD4⁺ T-lymphocytes³⁰ probably as a result of reduced HIV antigen levels. Different therapeutic approaches may, therefore, be required to restore fully HIV-1-specific T cell responses lost during early infection. Additional vaccination strategies may be needed to maintain the HIV-1 specific immune response in subjects receiving HAART.

Structured treatment interruptions

Following encouraging reports in PHI treated patients²⁶, a number of groups are studying the effects of transient interruptions of ART in patients with well-controlled viraemia (<50 copies). Such studies are being performed in an attempt to boost HIV-specific immune responses using the viral rebounds that result from treatment interruption as a form of ‘autoimmunisation’. Early success with this approach has been documented by Walker and colleagues, who demonstrated a significant increase in virus-specific CTL responses and a broadening to include more targeted epitopes in patients with PHI following each successive structured treatment interruptions¹³. However, for the majority of individuals, discontinuation of HAART in patients with chronic infection usually results in an increase in the level of viraemia which rapidly (within 4 weeks) returns to pre-HAART levels³¹. The fact that the levels of viraemia usually return to initial levels, and not below, suggest that prolonged effective suppression of virus in these individuals may not result in a significant improvement of the HIV-specific immune response. In addition, interruption of HAART in chronically infected individuals results in a rapid decline of CD4⁺ T-cells³² and structured treatment interruptions may lead to the replenishment of viral reservoirs³³ with the immunological benefits from this approach possibly short-lived³⁴.

The effect of HAART on opportunistic infections

Immune reconstitution, in terms of an increase in T-cell function, can be evidenced clinically by the resolution of opportunistic infections with ART. When HIV replication is controlled, in terms of undetectable viral loads as a result of HAART, a reduction in the incidence of diseases caused by opportunistic pathogens has been observed^19,35. Pathogen-specific immune responses are restored with HAART leading to the resolution of CMV retinitis, HIV-related TB, HPV related cervical disease, Kaposi's sarcoma, cryptosporidiosis and microsporidiosis in many treated patients. A reduction in CMV and HHV8 DNA in the blood of treated patients suggests that replication of these opportunistic pathogens also decline with HAART. This sudden increase in immune function may ironically result in localised inflammation to opportunistic pathogens or ‘immune restoration disease’ (reviewed by French³⁶).

	Immune-based therapies

Top Footnotes Abstract The HIV-infected immune system CD4+ T-lymphocytes CD8+ effector cells Immunosuppression and... Long-term survival Anti-retroviral therapy (ART) Immune-based therapies Conclusions Acknowledgements References

 
It has become apparent that ART alone will not be able to contain fully HIV replication or eradicate virus in most chronically infected individuals. Current estimations suggest that to eradicate the reservoir of infected memory T-cells may take up to 60 years of continuous control of HIV replication with ART³⁷. Therefore, the key to long-term control of HIV replication is likely to be the restoration of the immune system, especially HIV-specific immunity which is lost soon after infection with HIV, in individuals with chronic infection, and to preserve immune competence in those with acute infection. Novel therapeutic approaches are, therefore, required for the treatment of HIV.

Objectives of immune-based strategies have been defined by Pantaleo³⁸ and are summarised in Table 2. A number of immune-based strategies have been investigated in several clinical trials and, with the exception of IL-2 therapy and granulocyte-macrophage colony-stimulating factor (GM-CSF), there has been no clear evidence of clinical benefit or improvement in virological and immunological parameters (reviewed by Emery and Lane³⁹).

View this table: [in this window] [in a new window]   Table 2. Summary of the objectives of immune based strategies

 
IL-2 therapy

IL-2, a cytokine secreted by activated T-cells that regulates lymphoid proliferation and maturation, decreases with HIV disease progression. Various studies with IL-2 as an immune based therapy for HIV have demonstrated increases in CD4⁺ T cell number, but no significant changes in viral load^39,40. However, whether the observed increases in CD4⁺ T-cell number translate into increased immunocompetence remains unclear. Immune recovery may be enhanced by co-administration of IL-2 with HAART, improving both CD4⁺ T-cell number and function. The ESPRIT and SILCAAT trials, looking at IL-2 administration in different cohorts of patients, aim to evaluate immune recovery. Preliminary data suggest IL-2 administration with HAART results in greater increases in CD4⁺ T cell numbers than IL-2 alone⁴¹.

IL-2 may stimulate viral replication in latent viral reservoirs, activating the CD4⁺ T cells and ‘flushing out’ the virus. In the presence of HAART, the virions should not be able to infect new CD4⁺ target cells. In a recent study evaluating the frequency of latently infected CD4⁺ T-cells in patients receiving HAART, with or without IL-2, individuals receiving IL-2 demonstrated a significantly lower number of CD4⁺ T cells containing replication-competent HIV than the patients receiving HAART alone⁴². However, discontinuation of HAART in this group led to an increase in viraemia, suggesting that the latent reservoir had not been abolished.

GM-CSF therapy

Significant increases in CD4⁺ T cell counts have been observed when the cytokine GM-CSF is administered to patients with advanced HIV infection. In addition, significantly fewer changes in ART were necessary and the incidence of an opportunistic infection or death was significantly lower in the GM-CSF group compared to the placebo control. GM-CSF was also shown to augment phagocytosis of Mycobacterium avium complex (MAC) by HIV-infected macrophages in vitro⁴³. In late stage patients receiving HAART, the addition of GM-CSF and IL-2 appeared more effective in inducing both HIV-specific and non-specific proliferative responses⁴⁴, highlighting the positive role of such immunomodulators in the treatment of HIV.

CD8⁺ T-cell re-infusion

The expansion in vitro and re-infusion of HIV-specific CTLs may provide an alternative effective therapeutic approach. Preliminary studies, expanding and re-infusing bulk CD8⁺ T-lymphocytes in the presence or absence of IL-2 demonstrated no changes to CD4⁺ or CD8⁺ T-lymphocyte numbers, nor was there any reduction in HIV viral load. Recent studies have demonstrated the short-term survival of transferred CTL clones. In a study raising and re-infusing gag and pol CTL clones, and monitoring their fate in vivo with the use of a class I tetramer stain, Tan and colleagues observed a rapid rate of apoptosis of the infused cells with over 90% undergoing activation-induced cell death within 48 h⁴⁵.

Therapeutic vaccines

For a therapeutic vaccine to be effective it should induce HIV-1 specific immune responses that have been previously absent. With the reduction in HIV antigen as a result of HAART, HIV-specific immune responses such as T-cell proliferative responses and CD8⁺ CTL and CASA decline. The aim of a therapeutic vaccine is, therefore, to remind the immune system what the viral pathogen ‘looks like’ and elicit an immune response accordingly. The possibility of slowing progression to AIDS by therapeutic immunisation with an HIV vaccine is one such approach currently receiving interest in the literature⁴⁶.

Early trials of therapeutic vaccination yielded disappointing results, but because these vaccines were administered in the pre-HAART era, it is not surprising that the trials failed to show a clinical benefit. Present studies are concentrating on vaccinating with an HIV-1 antigen concurrent with ART, and studies are being conducted as to when such treatment should take place. Results from two randomised trials comparing four envelope vaccine candidates in HIV-infected patients have shown that patients with higher CD4⁺ T-cell counts and lower viral loads may benefit the most from this approach. In addition, a great diversity in immune response between the four vaccination groups was observed, suggesting there is strain specificity to the antigen used⁴⁷.

The HIV-1 Immunogen (Remune^®) is a gp120-depleted inactivated HIV-1 antigen, which has been evaluated in HIV-infected adults since 1987. Remune^® has resulted in increased DTH responses, anti-HIV p24 responses, lymphocyte proliferative responses and increased intensity of antibody bands by Western blot analysis (reviewed by Gotch et al⁴⁸). Patients treated with Remune^® have recently been shown to elicit a strong CD4⁺ T helper cell proliferative response to their own virus as well as demonstrating strong cross-reactive immune response to HIV-1 subtypes B, E and C. Additionally, Remune^® was associated with increased levels of perforin and MIP-1ß, markers of CD8⁺ T-cell activity, and phenotyping of the proliferating cells that were induced by Remune^® has revealed that it is predominantly the CD4⁺ and CD8⁺ memory phenotypes that are induced by the HIV-1 antigen⁴⁹. However, a recent publication⁵⁰ ‘failed to demonstrate that the addition of HIV-1 Immunogen to ART conferred any effect on HIV progression-free survival relative to that achievable by ART alone’.

Several studies of recombinant gp160 (VaxSyn^®) as a therapeutic vaccine have been performed. No advantage in patients receiving VaxSyn^®, in terms of CD4⁺ counts, viral load, time to initiation of ART, incidence of opportunistic infections or death, was observed compared to placebo controls (reviewed by Gotch et al⁴⁸). However, prior to the era of HAART, immunotherapy of patients with recombinant gp160 vaccine demonstrated an increase in T-cell proliferative responses despite suboptimal viral control⁵¹. Such studies will lead to further investigations of new treatment strategies using HAART to produce complete viral suppression in combination with vaccination and/or cytokines, to regenerate the kinds of anti-HIV responses that have been associated with long-term survivors.

	Conclusions

Top Footnotes Abstract The HIV-infected immune system CD4+ T-lymphocytes CD8+ effector cells Immunosuppression and... Long-term survival Anti-retroviral therapy (ART) Immune-based therapies Conclusions Acknowledgements References

 
With more than 30 million people world-wide living with HIV disease, over 90% of whom will not have access to HAART, a prophylactic vaccine to prevent increasing numbers of people becoming infected remains a priority. The ultimate therapeutic goal is that in the era of HAART where the HIV viral load can be reduced to minimal levels, immune responses generated by therapeutic vaccines will eventually be able to control viral replication in the absence of ART^13,52.

It has become clear that viral eradication can not be achieved with the anti-retroviral agents that are currently available. The future of AIDS treatment lies with immune-based therapies that will restore the host immune system into one that is competent, fully functional and able to deliver the appropriate immune response. Studying those individuals who manage to control activation of the latent cell pool and remain with low or undetectable viral loads (long-term survivors) has provided insights into the immune response required for the long-term control of HIV infection. Such insights together with our increasing understanding of the role of the cellular immune system provide a realistic basis for immune-based intervention.

	Acknowledgements

Top Footnotes Abstract The HIV-infected immune system CD4+ T-lymphocytes CD8+ effector cells Immunosuppression and... Long-term survival Anti-retroviral therapy (ART) Immune-based therapies Conclusions Acknowledgements References

 
We would like to thank Nesrina Imami for helpful criticism of this manuscript. JW is funded by MRC grant #G9825083. FG is supported by funding from MRC, Wellcome Trust, NIH and EU.

	Footnotes

Top Footnotes Abstract The HIV-infected immune system CD4+ T-lymphocytes CD8+ effector cells Immunosuppression and... Long-term survival Anti-retroviral therapy (ART) Immune-based therapies Conclusions Acknowledgements References

 
Correspondence to: Dr John Wilkinson, Department of Immunology, Imperial College of Science, Technology and Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK

	References

Top Footnotes Abstract The HIV-infected immune system CD4+ T-lymphocytes CD8+ effector cells Immunosuppression and... Long-term survival Anti-retroviral therapy (ART) Immune-based therapies Conclusions Acknowledgements References

 

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