How does HAART lead to the resolution of Kaposi’s sarcoma?

Justin Stebbing*, Simon Portsmouth and Brian Gazzard

Department of Immunology, The Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK

Keywords: HIV, immunology, HAART

As highly active antiretroviral therapy (HAART) is available for less than one million individuals worldwide, Kaposi’s sarcoma (KS) remains a common complication of infection with the human immunodeficiency virus (HIV). Use of HAART has reduced the incidence of KS and, in affected individuals, HAART alone can lead to KS resolution. Possible mechanisms include general improvements in immune function including the specific generation of anti-KS responses, the inhibition of HIV-1 cofactors that are thought to be important in tumour development and inhibitory effects on angiogenic growth factors and cytokines that promote KS formation. The relative contributions of these mechanisms will be discussed.

Infection with HIV-1 is associated with a significant and increased risk of developing KS, a tumour that remains a significant cause of morbidity and mortality.13 Its aetiologic agent is Kaposi’s sarcoma-associated herpesvirus (KSHV),4 a {gamma}-herpesvirus that is widely prevalent in immunosuppressed populations, associated with all the clinico-epidemiological forms of KS and levels of which appear predictive of its development.3 The introduction of HAART with combinations of nucleoside analogue reverse transcriptase inhibitors and protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) has altered survival associated with HIV5 and there is increasing evidence that the incidence of KS in the HIV-seropositive population is declining;6 this fall coincides with the increasing use of HAART.2 The epidemiological evidence is supplemented by observations that individual KS lesions resolve with HAART7 and KSHV loads decrease during this resolution.8

The lower incidence and regression of KS observed with HAART may result from a variety of effects. These include one or more of the following: (i) immune reconstitution following initiation of HAART; (ii) the inhibition of HIV-1 replication and the resultant decrease in its ‘angiogenic’ Tat protein; and (iii) the reduction in intracellular cytokine production, which triggers the production of angiogenic factors and KSHV reactivation, and, related to this, direct anti-angiogenic effects of HAART on KS. The potential role of each of these is discussed below.


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The importance of the immune system in the pathogenesis of KS is demonstrated by its more frequent occurrence in immunosuppressed individuals, including persons with AIDS2 and allograft transplant recipients. In the latter group of patients, a reduction in the immunosuppressive therapy prescribed to prevent organ rejection may lead to regression of the KS.9,10 Furthermore, early in the AIDS epidemic, it was recognized through anecdotal reports that regression of KS occasionally occurred during monotherapy with the nucleoside analogue zidovudine.11 There are increasing data to suggest roles for both the adaptive and innate immune systems.

It is well known that adaptive, cellular immune responses are a critical defence against chronic viral infections and cytotoxic T lymphocyte (CTL) activity has been detected against KSHV lytic and latent proteins.1215 The early lytic gene K1 has a remarkable preponderance of amino acid-altering mutations (more so than that observed with HIV even though it lacks an error-prone reverse transcriptase) and there is a suggestion that these mutations serve to facilitate recognition by the host immune system.16 It is possible here that continual immune surveillance, even in the context of HIV-1 infection, helps to identify cells reactivating from latency, which limits viral dissemination, thus preserving the host and therefore the virus. However, increases in anti-KSHV responses during HAART are modest, particularly when compared with anti-HIV CTL responses.17 A study of innate, natural killer (NK) cells showed that cells latently infected by KSHV are efficiently lysed by NK cells from individuals with normal immune parameters.18 However, NK-mediated immunity was found to be significantly reduced in AIDS patients with progressing KS compared with both HIV-negative patients with indolent classic KS or normal blood donors. This NK-mediated immunity was restored after treatment with HAART only in those AIDS-KS patients that showed regression and not in others who progressed. This suggests a key role for the innate immune system in the control of viral infections and tumour development.


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HIV-1 Tat (transactivating protein), released by infected cells, transactivates HIV genes and activates host regulatory pathways. As Tat induces the growth of KS spindle cells in vitro,19 protects KSHV-positive cell lines from chemotherapy- induced apoptosis,20 is angiogenic in transgenic mice21 and contains arginine-lysine rich sequences with homology to human angiogenic factors,22 it has been proposed that decreases in its levels are associated with KS resolution. However, baboons infected with HIV-2, whose Tat lacks these ‘angiogenic’ amino acids, can develop ‘KS-like lesions’.23 It has also been recently shown that Tat is unable to directly activate lytic KSHV replication,24 contradicting previous suggestions that it can.25 Furthermore, HIV-negative cases of KS are well known and we now observe KS developing and progressing in HIV-1-seropositive individuals with suppressed HIV-1 viral loads.


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Tumour growth is dependent on the formation of new blood vessels, and angiogenesis in carcinomas often correlates with survival. This has led to studies of the anti-angiogenic effects of HAART.26 Systemic administration of the protease inhibitors saquinavir and indinavir to nude mice was found to block the development of, and induce regression of, angioproliferative KS-like lesions promoted by primary human KS cells, basic fibroblast growth factor (bFGF), or bFGF and vascular endothelial growth factor (VEGF) combined. These drugs were also found to block bFGF or VEGF-induced angiogenesis in the chorioallantoic membrane assay with a potency similar to paclitaxel, which is also used to treat KS. Their effects were found to be mediated by the inhibition of endothelial- and KS-cell invasion, and by inhibition of matrix metalloproteinase-2 proteolytic activation by protease inhibitors at concentrations present in plasma of treated individuals. As these drugs inhibited the in vivo growth and invasion of an angiogenic tumour-cell line, these data indicate that protease inhibitors are potent anti-angiogenic and anti-tumour molecules that might also be used in treating non-HIV KS and in other HIV- and non-HIV-associated tumours. This work did not however include non-PI antiretrovirals, which are also known to lead to KS resolution, and similar data had also been previously observed in the same models with the anti-oxidant N-acetyl cysteine.27

At the Chelsea and Westminster Hospital, we have previously shown that the median time to treatment failure for KS from the start of HAART is 1.7 years.6 This was statistically longer than the equivalent time for the same cohort of patients before they started HAART (log rank {chi}2 = 16.5, P < 0.0001). We therefore wished to compare antiretrovirals to determine whether their anti-KS effects were largely confined to PIs.28 Multi-variate logistic regression analyses of 1204 cases of AIDS-KS seen between 1986 and 2002, found that the incidence decreased from 30 cases per 1000 patient years (PY) before 1995 to 7.6 immediately thereafter. This was clearly coincident with treatment using dual nucleoside analogue reverse transcriptase inhibitors. More recently, the incidence has fallen dramatically to 0.03 cases per 1000 patient years, although to our surprise patients receiving non-PI-based therapies had a statistically significant difference in their incidence of KS when compared with those treated with PIs: 0.2 cases per 1000 patient years (95% CI 0.02–0.12) versus 1.1 cases per 1000 patient years (95% CI 0.15–0.38), respectively (P = 0.002). This study, the first showing a decreased incidence of an AIDS defining illness with NNRTI-based therapy, demonstrates that non-PI-based regimens are at least as effective as PI-based HAART in terms of protection against KS.

There are now anecdotal reports in the literature describing complete remission of visceral KS with non-PI-based triple therapy.29 Similarly, studies that we have undertaken in KS patients of angiogenic growth factors and cytokines have not revealed significant reductions in those who respond to therapy.

Because of increased awareness of the activity and toxicity of current drugs, the threshold for initiation of therapy has shifted to a later time in the course of HIV disease. In addition, NNRTI-based regimens are now being increasingly used in order to reduce the complexity of therapy and reduce long-term toxicities. These data should provide reassurance for clinicians when advising of therapeutic options.

The cytokine milieu observed both in KS and as a response to HIV-1 infection probably contributes in some way to the development and progression of this tumour.30 HAART may help reverse this process and possible mechanisms include direct anti-angiogenic effects and immune reconstitution; new studies are now addressing the role of the innate immune system in this process. Decreases in HIV-1 Tat appear to play a lesser role. The direct effects of HAART on KSHV replication may be a further consideration although in vitro work has not been able to show inhibitory effects. Whereas the anti-herpetic agents cidofovir, foscarnet and high concentrations of aciclovir may have a role in decreasing KSHV replication,31 this is not the mechanism by which HAART has led to a decreased incidence of KS and resolution of individual lesions. Use of anti-herpetic agents may be useful in the treatment and prophylaxis of individuals with KS, and cidofovir in particular has been shown in vivo to decrease KSHV32,33 load although its cost and requirement for intravenous administration may limit its widespread use.

An improved understanding of the functions of the KSHV genes, the identification of novel immune-evasion strategies and the analysis of the KS micro-environment in the context of a viral infection, should lead to a better understanding of angiogenesis, the immune system and the interaction of viruses with their hosts. This will help us to design safer strategies to treat virus-induced pathology. As many cases of KS do not resolve with HAART and require treatment with cytotoxic chemotherapy, it is important to reveal the underlying mechanisms involved in the response to treatment.


    Footnotes
 
* Corresponding author. Tel: +44-20-8746-8251; Fax: +44-20-8746-5997; E-mail: j.stebbing{at}ic.ac.uk Back


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