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, Kaposis 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 Kaposis sarcoma-associated herpesvirus (KSHV),4 a -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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Immune reconstitution |
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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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Decreases in HIV-1 on HAART |
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Anti-angiogenic and anti-cytokine effects |
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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 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 0.020.12) versus 1.1 cases per 1000 patient years (95% CI 0.150.38), 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.
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Footnotes |
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References |
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2
.
International Collaboration on HIV and Cancer. (2000). Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. Journal of the National Cancer Institute 92, 182330.
3 . Stebbing, J., Portsmouth, S. & Bower, M. (2003). Insights into the molecular biology and sero-epidemiology of Kaposis sarcoma. Current Opinion in Infectious Diseases 16, 2531.[ISI][Medline]
4 . Chang, Y., Cesarman, E., Pessin, M. S., Lee, F., Culpepper, J., Knowles, D. M. et al. (1994). Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposis sarcoma. Science 266, 18659.[ISI][Medline]
5
.
Palella, F. J., Jr, Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A. et al. (1998). Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. New England Journal of Medicine 338, 85360.
6 . Bower, M., Fox, P., Fife, K., Gill, J., Nelson, M. & Gazzard, B. (1999). Highly active anti-retroviral therapy (HAART) prolongs time to treatment failure in Kaposis sarcoma. AIDS 13, 210511.[CrossRef][ISI][Medline]
7 . Lebbe, C., Blum, L., Pellet, C., Blanchard, G., Verola, O., Morel, P. et al. (1998). Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV-related Kaposis sarcoma. AIDS 12, F459.
8 . Gill, J., Bourboulia, D., Wilkinson, J., Hayes, P., Cope, A., Marcelin, A. G. et al. (2002). Prospective study of the effects of antiretroviral therapy on Kaposi sarcoma-associated herpesvirus infection in patients with and without Kaposi sarcoma. Journal of Acquired Immune Deficiency Syndromes 31, 38490.[Medline]
9 . Andreoni, M., Goletti, D., Pezzotti, P., Pozzetto, A., Monini, P., Sarmati, L. et al. (2001). Prevalence, incidence and correlates of HHV-8/KSHV infection and Kaposis sarcoma in renal and liver transplant recipients. Journal of Infection 43, 1959.[CrossRef][ISI][Medline]
10
.
Emond, J. P., Marcelin, A. G., Dorent, R., Milliancourt, C., Dupin, N., Frances, C. et al. (2002). Kaposis sarcoma associated with previous human herpesvirus 8 infection in heart transplant recipients. Journal of Clinical Microbiology 40, 22179.
11 . Langford, A., Ruf, B., Kunze, R., Pohle, H. D. & Reichart, P. (1989). Regression of oral Kaposis sarcoma in a case of AIDS on zidovudine (AZT). British Journal of Dermatology 120, 70913.[ISI][Medline]
12 . Wang, Q. J., Jenkins, F. J., Jacobson, L. P., Meng, Y. X., Pellett, P. E., Kingsley, L. A. et al. (2000). CD8+ cytotoxic T lymphocyte responses to lytic proteins of human herpes virus 8 in human immunodeficiency virus type 1-infected and -uninfected individuals. Journal of Infectious Diseases 182, 92832.[CrossRef][ISI][Medline]
13
.
Wang, Q. J., Jenkins, F. J., Jacobson, L. P., Kingsley, L. A., Day, R. D., Zhang, Z. W. et al. (2001). Primary human herpesvirus 8 infection generates a broadly specific CD8(+) T-cell response to viral lytic cycle proteins. Blood 97, 236673.
14
.
Wang, Q. J., Huang, X.-L., Rappocciolo, G., Jenkins, F. J., Hildebrand, W. H., Fan, Z. et al. (2002). Identification of an HLA A*0201-restricted CD8+ T-cell epitope for the glycoprotein B homolog of human herpesvirus 8. Blood 99, 33606.
15 . Micheletti, F., Monini, P., Fortini, C., Rimessi, P., Bazzaro, M., Andreoni, M. et al. (2002). Identification of cytotoxic T lymphocyte epitopes of human herpesvirus 8. Immunology 106, 395403.[CrossRef][ISI][Medline]
16
.
Stebbing, J., Bourloulia, D., Johnson, M., Henderson, S., Williams, I., Wilder, N. et al. (2003). KSHV specific CTLs recognize and target Darwinian positively selected autologous K1 epitopes. Journal of Virology 77 430614.
17
.
Wilkinson, J., Cope, A., Gill, J., Bourboulia, D., Hayes, P., Imami, N. et al. (2002). Identification of Kaposis sarcoma-associated herpesvirus (KSHV)-specific cytotoxic T-lymphocyte epitopes and evaluation of reconstitution of KSHV-specific responses in human immunodeficiency virus type 1-infected patients receiving highly active antiretroviral therapy. Journal of Virology 76, 263440.
18 . Sirianni, M. C., Vincenzi, L., Topino, S., Giovannetti, A., Mazzetta, F., Libi, F. et al. (2002). NK cell activity controls human herpesvirus 8 latent infection and is restored upon highly active antiretroviral therapy in AIDS patients with regressing Kaposis sarcoma. European Journal of Immunology 32, 271120.[CrossRef][ISI][Medline]
19 . Albini, A., Soldi, R., Giunciuglio, D., Giraudo, E., Benelli, R., Primo, L. et al. (1996). The angiogenesis induced by HIV-1 tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells. Nature Medicine 2, 13715.[ISI][Medline]
20
.
Deregibus, M. C., Cantaluppi, V., Doublier, S., Brizzi, M. F., Deambrosis, I., Albini, A. et al. (2002). HIV-1-Tat protein activates phosphatidylinositol 3-kinase/AKT-dependent survival pathways in Kaposis sarcoma cells. Journal of Biological Chemistry 277, 25195202.
21 . Ensoli, B., Barillari, G., Salahuddin, S. Z., Gallo, R. C. & Wong-Staal, F. (1990). Tat protein of HIV-1 stimulates growth of cells derived from Kaposis sarcoma lesions of AIDS patients. Nature 345, 846.[CrossRef][ISI][Medline]
22 . Albini, A., Benelli, R., Presta, M., Rusnati, M., Ziche, M., Rubartelli, A. et al. (1996). HIV-tat protein is a heparin-binding angiogenic growth factor. Oncogene 12, 28997.[ISI][Medline]
23 . Barnett, S. W., Murthy, K. K., Herndier, B. G. & Levy, J. A. (1994). An AIDS-like condition induced in baboons by HIV-2. Science 266, 6426.[ISI][Medline]
24 . Varthakavi, V., Smith, R. M., Deng, H., Sun, R. & Spearman, P. (2002). Human immunodeficiency virus type-1 activates lytic cycle replication of Kaposis sarcoma-associated herpesvirus through induction of KSHV Rta. Virology 297, 27080.[CrossRef][ISI][Medline]
25 . Harrington, W., Jr, Sieczkowski, L., Sosa, C., Chan-a-Sue, S., Cai, J. P., Cabral, L. et al. (1997). Activation of HHV-8 by HIV-1 tat. Lancet 349, 7745.[CrossRef][ISI][Medline]
26 . Sgadari, C., Barillari, G., Toschi, E., Carlei, D., Bacigalupo, I., Baccarini, S. et al. (2002). HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nature Medicine 8, 22532.[CrossRef][ISI][Medline]
27
.
Albini, A., Morini, M., DAgostini, F., Ferrari, N., Campelli, F., Arena, G. et al. (2001). Inhibition of angiogenesis-driven Kaposis sarcoma tumor growth in nude mice by oral N-acetylcysteine. Cancer Research 61, 81718.
28 . Bower, M., Nelson, M., Portsmouth, S., Mandalia, S. & Gazzard, B. G. (2002). Falling incidence of AIDS related Kaposis sarcoma on HAART: the protective effect of NNRTIs. In Abstracts of the fourteenth International AIDS Conference, Barcelona, Spain, 2002. Abstract ThPeC7485.
29 . Murdaca, G., Campelli, A., Setti, M., Indiveri, F. & Puppo, F. (2002). Complete remission of AIDS/Kaposis sarcoma after treatment with a combination of two nucleoside reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor. AIDS 16, 3045.[CrossRef][ISI][Medline]
30
.
Fiorelli, V., Gendelman, R., Sirianni, M. C., Chang, H. K., Colombini, S., Markham, P. D. et al. (1998). -Interferon produced by CD8+ T cells infiltrating Kaposis sarcoma induces spindle cells with angiogenic phenotype and synergy with human immunodeficiency virus-1 Tat protein: an immune response to human herpesvirus-8 infection? Blood 91, 95667.
31
.
Kedes, D. H. & Ganem, D. (1997). Sensitivity of Kaposis sarcoma-associated herpesvirus replication to antiviral drugs. Implications for potential therapy. Journal of Clinical Investigation 99, 20826.
32 . Mazzi, R., Parisi, S. G., Sarmati, L., Uccella, I., Nicastri, E., Carolo, G. et al. (2001). Efficacy of cidofovir on human herpesvirus 8 viraemia and Kaposis sarcoma progression in two patients with AIDS. AIDS 15, 20612.[CrossRef][ISI][Medline]
33
.
Beadle, J. R., Hartline, C., Aldern, K. A., Rodriguez, N., Harden, E., Kern, E. R. et al. (2002). Alkoxyalkyl esters of cidofovir and cyclic cidofovir exhibit multiple-log enhancement of antiviral activity against cytomegalovirus and herpesvirus replication in vitro. Antimicrobial Agents and Chemotherapy 46, 23816.