AIDS Reference Laboratory, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium
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Abstract |
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Keywords: reservoirs of resistance , mechanisms of resistance , mutations
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Introduction |
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Long-term latent reservoir |
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The HIV reservoir during HAART treatment |
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But perhaps the most convincing argument for long-term conservation of viral strains comes from the observation that a cessation of treatment or a switch of antiretroviral drugs in patients treated for more than 2 years with suboptimal drug regimens, resulted in the replacement of the resistant virus in the plasma by wild-type variants.1214 In the majority of the patients studied, the replacement of the mutant by the wild-type virus was abrupt and fast, indicating that it was the result of the reappearance of archived wild-type virus and not of the reversal of mutations in the resistant variants. This finding was remarkable since drug-resistant virus predominated in the plasma of these patients for several years and at least an important reduction in the population of wild-type virus through a natural process of cell death could be presumed. If wild-type virus persists in the latent reservoir for such a long time, then it could be postulated that drug-resistant strains too will be conserved.
Ruff et al.15 were the first to demonstrate that drug-resistant viruses, selected by non-suppressive regimens in infected children, entered the reservoir and persisted during HAART. Subsequently, Lambotte et al.16 compared a polymorphic region of the env gene and part of the reverse transcriptase gene in pre-HAART plasma and in the reservoir lymphocytes, in nine treated patients with long-term undetectable plasma viral load. They observed archiving of pre-HAART plasma clones in six patients and confirmed the co-existence of wild-type and drug-resistant virus in reservoir T cells in two. We studied the variability of the RT and protease gene in the provirus of 11 patients on successful HAART for years, but with a period of suboptimal regimens before.17 Not only could we confirm the co-existence of wild-type and drug-resistant virus in the proviral reservoir after 5 years or more of HAART, but we were also able to show that, with a few exceptions, all mutant virus variants that were detected in the plasma before HAART initiation, during the process of gradually building up resistance, were still present in the latent reservoir. Moreover, we observed a correlation between the time period on suboptimal therapy before HAART and the proportion of mutant, drug-resistant, proviral sequences in the cells, indicating that the quantity that a certain variant occupies within the reservoir depends in part on the period that this variant has been able to replicate. These data prove that the reservoir of latently HIV-1-infected cells is dynamic, and that newly infected cells continuously turn into latency to enter the reservoir. These data also indicate the extreme long-term conservation of all variants that have ever entered the reservoir. The latent reservoir can be considered as the life-long archive of whatever viral strain that ever evolved and replicated.
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Clinical implications of the persistence of drug resistance |
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However, the observation that the viral reservoir contains a heterogeneous mix of wild-type variants and mutant variants with different degrees of drug resistance, also indicates that even drugs to which resistance has developed may still add to the activity of a combination therapy by preventing the replication of the drug-sensitive virus pool in the reservoir. Since the wild-type virus is believed to be the fittest variant, suppressing the replication of these wild-type strains can be important, especially in patients with limited treatment options, and might contribute to the reduced viral-load set-point as is observed in many treated patients with drug-resistant viraemia.18,19 On the other hand, continuation of a failing regimen risks the further accumulation of drug-resistance mutations and an expansion of the reservoir of cells infected with drug-resistant variants, and is not advisable. Whether the proportion of cells infected with drug-resistant strains in the latent reservoir has any impact on the success or failure of subsequent salvage regimens still remains to be examined.
Currently, plasma is the only compartment used routinely for drug resistance testing. However, the observation that the proviral compartment contains an archive of the different strains, wild-type and drug-resistant, that have evolved during the infection, makes this proviral reservoir the ideal substrate for analysis of the resistance-potential in a patient. This can be of special importance in those patients from whom no samples have been conserved and no historical data are available.
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Conclusion |
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Our knowledge of the latent HIV-1 latent reservoir is rapidly increasing. Only a thorough understanding of the development and maintenance of the latent reservoir will allow the development of new therapeutic strategies, aimed at a combined effect of arresting viral replication and eliminating the latent reservoir.
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Acknowledgements |
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References |
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2 . Chun, T. W., Carruth, L., Finzi, D. et al. (1997). Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387, 1838.[CrossRef][ISI][Medline]
3
.
Pierson, T., Hoffman, T. L., Blankson, J. et al. (2000). Characterization of chemokine receptor utilization of viruses in the latent reservoir for human immunodeficiency virus type 1. Journal of Virology 74, 782433.
4 . Blankson, J. N., Persaud, D. & Siliciano, R. F. (2002). The challenge of viral reservoirs in HIV-1 infection. Annual Review of Medicine 53, 55793.[CrossRef][ISI][Medline]
5
.
Persaud, D., Zhou, Y., Siliciano, J. M. et al. (2003). Latency in human immunodeficiency virus type 1 infection: no easy answers. Journal of Virology 77, 165965.
6 . Frost, S. D. W., Leigh-Brown, A. J., Ignacio, C. C. et al. (1999). Evolution of envelope sequences of Human Immunodeficiency Virus type 1 in cellular reservoirs in the setting of potent antiviral therapy. Journal of Virology 73, 940412.
7
.
Chun, T. W., Stuyver, L., Mizell, S. B. et al. (1997). Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proceedings of the National Academy of Sciences, USA 94, 131937.
8 . Finzi, D., Blankson, J., Siliciano, J. D. et al. (1999). Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Medicine 5, 5127.[CrossRef][ISI][Medline]
9
.
Persaud, D., Pierson, T., Ruff, C. et al. (2000). A stable latent reservoir for HIV-1 in resting CD4+ T lymphocytes in infected children. Journal of Clinical Investigation 105, 9951003.
10 . Ruiz, L., Martinez-Picado, J., Romeu, J. et al. (2000). Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression. AIDS 14, 397403.[CrossRef][ISI][Medline]
11 . Chen, R. Y., Westfall, A. O., Raper, J. L. et al. (2002). Immunologic and virologic consequences of temporary antiretroviral treatment interruption in clinical practice. AIDS Research and Human Retroviruses 18, 90916.[CrossRef][ISI][Medline]
12 . Devereux, H. L., Youle, M., Johnson, M. A. et al. (1999). Rapid decline in detectability of HIV-1 drug resistance mutations after stopping therapy. AIDS 13, F1237.[CrossRef][ISI][Medline]
13 . Verhofstede, C., Van Wanzeele, F. V., Van Der Gucht, B. et al. (1999). Interruption of reverse transcriptase inhibitors or a switch from reverse transcriptase to protease inhibitors results in a fast reappearance of virus strains with a reverse transcriptase inhibitor-sensitive genotype. AIDS 13, 25416.[CrossRef][ISI][Medline]
14
.
Deeks, S. G., Wrin, T., Liegler, T. et al. (2001). Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. New England Journal of Medicine 344, 47280.
15
.
Ruff, C. T., Ray, S. C., Kwon, P. et al. (2002). Persistence of wild-type virus and lack of temporal structure in the latent reservoir for human immunodeficiency virus type 1 in pediatric patients with extensive antiretroviral exposure. Journal of Virology 76, 948192.
16 . Lambotte, O., Chaix, M. L., Gubler, B. et al. (2004). The lymphocyte HIV reservoir in patients on long-term HAART is a memory of virus evolution. AIDS 18, 114758.[CrossRef][ISI][Medline]
17 . Verhofstede, C., Noë, A., Demecheleer, E. et al. (2004). Drug-resistant variants that evolve during nonsuppressive therapy persist in HIV-1-infected peripheral blood mononuclear cells after long-term highly active antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes 35, 47383.[Medline]
18 . Bates, M., Wrin, T., Huang, W. et al. (2003). Practical applications of viral fitness in clinical practice. Current Opinion in Infectious Diseases 16, 1118.[ISI][Medline]
19 . Deeks, S. G., Barbour, J. D., Martin, J. N. et al. (2000). Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. Journal of Infectious Diseases 181, 94653.[CrossRef][ISI][Medline]
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