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Reader in Immunology
Professor of Immunology/Head of Department
Department of Immunology
Imperial College London
Chelsea and Westminster Hospital
Our understanding of the pathogenic effects of HIV-1 and the potentially protective immune responses that may be specifically elicited by the virus have increased almost exponentially in the past 20 years.(1,2) However, tens of millions of people in the world have become infected with HIV-1, and treatments to alleviate the effects of the infection are still limited.(3) Highly active antiretroviral therapy (HAART), a great success since its introduction in 1996, has revolutionised the way that the developed world thinks about HIV-1. However, there are many drawbacks as HAART does not eradicate latent HIV-1 in the host, and emergence of virus resistant to the effects of drugs is common. This is slowly leading to fewer treatment options in the infected population.(4) The drugs have unacceptable toxicities and induce unpleasant side-effects in some individuals and, until very recently, have been unaffordable or unobtainable for the majority of HIV-1(+) patients in the developing world. It should nevertheless be noted that, in the majority of individuals receiving HAART, plasma viral loads drop, CD4 T-cell counts rise and potentially life-threatening opportunistic infections do not occur. However, low levels of viraemia always persist, and high levels of virus immediately reappear if HAART is suspended.(5) Treatments to induce long-term nonprogressor (LTNP) status in the absence of drugs (or even to rid the host of virus and cure the infection) seem to be a distant dream. However, it appears that HAART, with all its imperfections, may allow a window of opportunity to manipulate the immune system to the patient’s advantage.
The long-term nonprogressor (LTNP)
The clinical hallmarks of LTNPs are that, in the absence of HAART, there is no sign of immuno‑suppression, CD4 T-cell counts remain high, viraemia is low/undetectable with no escape from CD8 cytotoxic T lymphocyte (CTL) responses, and no opportunistic infections emerge. From an immunological point of view, LTNPs possess large numbers of broadly reactive, HIV-1-specific CTL, fully functional CD4 T-cells that proliferate and produce cytokines in response to HIV-1 and other stimuli, low levels of neutralising antibodies, good thymic output with no thymic or lymph node destruction, and no observable defects in antigen-presenting cell function.(6)
When considering the potential of therapeutic vaccination and other forms of immune-based therapy (IBT) for HIV-1(+) patients, it is important to consider why long-term use of HAART during chronic HIV-1 infection may allow partial restoration of immune responses to some opportunistic pathogens, but does not apparently allow regeneration of HIV-1-specific immune responses that have the potential to keep the virus under control. In the vast majority of cases (the exception perhaps being when HAART is administered extremely early after initial infection),(7) HAART alone does not allow establishment of LTNP status – that is, allow reconstitution or regeneration of potentially protective HIV-1-specific immune responses that keep viraemia under control and protect CD4 T-helper (Th) cells from infection and destruction – thus eventually allowing discontinuation of HAART. It has been felt that much of the early damage is irreparable; however, we now believe that, rather than being deleted, some HIV-1-specific CD4 T-cell clones are anergised and thus fail to provide help to critical CD8(+) CTL. This implies a potentially reversible process.(8)
The aim of IBT must therefore be to induce LTNP status and to augment, establish or re-establish the kind of cellular and humoral immune responses seen in LTNPs, which have the potential to control viraemia and opportunistic infections in the absence of HAART. Qualitative and quantitative defects in immune responses must be reversed, and the emergence of drug-resistant virus must be delayed. Ideally, viral reservoirs should be depleted. The burden of disease must be reduced and the patient’s quality of life improved.
Therapeutic immunisation, cytokine-and hormone-based therapies
Therapeutic vaccines used in the context of HAART-induced aviraemia may have the potential to activate selectively the immune system against specific viral proteins. By presenting viral proteins in different, novel ways with or without specific adjuvants, or by presenting proteins that are somewhat different to those already present in vivo, specific beneficial memory responses may be augmented and anergy may be reversed. Cytokines such as interleukin-2 (IL-2), interferon and granulocyte macrophage colony-stimulating factor (GM-CSF), as well as hormones such as recombinant human growth hormone (rhGH) and thymosine-α1, have the potential to expand useful subsets of immunoregulatory cells in vivo. Over the past few years, several small phase I therapeutic trials of vaccines, passive infusions of neutralising antibodies and/or immunotherapy with cytokines or other immunomodulators have been conducted.(9,10) All appear to work better if administered when viral load is low (in the context of HAART). Transient HIV-1-specific responses have been induced in many cases, but these do not persist. Parallel transient reductions of viral load have been observed, together with increases in viral load-doubling times following treatment interruptions and lower viral set-points. Some clinical benefits such as delayed virological failure and decreased mortality have been reported.(11)
There seems little doubt that immunotherapy has optimal chance of success if HAART is started very early after infection, and the conundrum that we now face is the possibility that such therapy may work well only at this early disease stage, before inevitable damage has been inflicted on the immune system. Current BHIVA (British HIV Association) guidelines suggest that HAART should be initiated in asymptomatic individuals when their CD4 T-cell counts drop to between 200 and 350 cells/μl blood.(12) In asymptomatic patients with CD4 T-cell counts >350, therapy should be considered if viral load is above 100,000copies/ml. Therefore, trials of IBT in chronically infected patients (the majority of whom start HAART relatively late in the disease) and attempts to reverse the damage that will have already occurred in chronic and late-stage disease are warranted, and some such investigations have recently been conducted by our group. These include:
In the trials outlined above, some potentially beneficial immunological effects, which may translate into clinical benefit, have been observed. Others have seen similar benefit in similar trials performed elsewhere.(5,18–20)
In many cases, potentially beneficial transient
HIV-1-specific responses that may translate into clinical benefit have been induced by IBT in chronic HIV infection in the context of HAART, but these do not persist.
Future studies, where novel immunogens and other immunotherapeutic agents are further defined and optimised, where therapeutic regimens are carefully and rationally designed and where patients are followed for protracted periods of time to observe clinical benefit, are warranted.
Funded by the MRC (Grant number G0501957), AVIP EU Programme (Grant number LSHP-CT-2004-503487), Wellcome Trust (Grant number 058700) and St Stephen’s Trust