Drug resistance mutations: yes but where?
From the Laboratory of Virology, Geneva University Hospital, Geneva, Switzerland.
Correspondence to Professor Luc Perrin, Laboratory of Virology, Geneva University Hospital, 1211 Geneva 14, Switzerland.
Tel: +41 22 37 249 91; fax +41 22 37 24 9 90; e-mail: firstname.lastname@example.org
Received: 17 September 2003; accepted: 8 October 2003.
HIV-1 turns over with around 200 cycles of replication per year . This high turnover, in combination with the error prone reverse transcriptase activity, results in the generation of multiple quasi-species. The main consequence in terms of treatment efficacy is that all single mutations associated with drug resistance are present at low level very early in the course of the infection . This however does not mean that combination of mutations are present on the same gene, as illustrated by the success of highly active antiretroviral therapy (HAART) for the control of viral replication.
One of the key steps in our understanding of the pathogenesis of HIV-1 infection was the identification of a reservoir/pool of latently infected cells . This pool of long-lived CD4 infected cells (half life of more than 6 months) constitutes the biological viral archives [4,5]. Cells from this pool can be reactivated following immune activation. Alternatively reseeding of drug-resistant mutant variants originating from the reservoir can occur once drug pressure decreases, with treatment changes or following selection of additional mutations because of low drug concentrations. Phenotypic and genotypic resistance testing, usually performed on virus in plasma, may therefore not capture the full range of mutant variants present in the reservoir of latently infected cells or in sanctuaries such as the central nervous system or the genitalia. In these latter compartments, decreased drug concentrations as compared to blood  or infection of peculiar cell types can lead to the selection of variants different from those detected in the blood .
There is nowadays a renewed interest to better assess and compare the viral characteristics of plasma virus in comparison with archived viruses and/or viruses present in sanctuaries. Behind these investigations there is the recurrent issue of the clinical relevance for treatment of the differences detected in these viral populations. In this issue of AIDS, two contributions address this problem indirectly [8,9]. Olivier Lambotte and colleagues compare, in pre-HAART patients, the polymorphic region of env and the reverse transcriptase in plasma virus with virus of the blood lymphocytes using phylogenetic analysis of cloned sequences . The patients selected were infected for years, and five of nine had received suboptimal therapy before long-term successful HAART. Archived clones corresponding to pre-HAART plasma viruses were detected in the lymphocytes from six of nine patients. For the five patients on suboptimal therapy before HAART initiation, zidovudine drug-resistant variants were detected in two and in two additional patients archived virus corresponding to pre-HAART plasma viruses were detected on the basis of C2V4 phylogenetic analysis. As in previous studies, following treatment interruption, the sequences of rebounding virus revealed that blood lymphocyte virus only partially accounted for the rebounding plasma viruses . The failure to detect pre-HAART plasma viruses in the blood lymphocytes of two patients and the emergence of rebounding viruses differing from those of the blood lymphocytes can be interpreted as a sensitivity issue, a progressive clearance of stored ancestral virus or poor seeding of the earliest viruses in the blood lymphocytes. An alternative explanation is that viral genetic diversity varies in different body's compartments. For instance the sequences from the rebounding virus from one of the patients were quite divergent from those in lymphocytes which in addition presented a low genetic diversity. Altogether these data confirm that during the course of HIV-1 infection, the various emerging viral strains are archived in latently infected cells. They also suggest that determination of sequences in lymphocytes can complement data derived from sequences of plasma viruses and help in therapeutic decisions.
The diversity of archived virus in various body compartments was evidenced in autopsy cases. In the second contribution, Jade Ghosn and collaborators assessed the diversity of archived virus and cell free virus in the blood and the semen in a population of 20 heavily pre-treated viremic males. This is of major interest since sexual transmission is the main route of infection worldwide and since, in western countries, where antiviral drugs are largely available, transmission of drug-resistant variants accounts for approximately 10% of new infections. The authors confirm the compartmentalization of viral strains with reference to the blood and the male genital tract using phylogenetic analysis of protease gene clones. The blood and genital compartments exhibited different genotypic resistance patterns in 30% of the patients and mutations not detected in the blood were found in the semen of four patients. Accordingly, viral strains in the seminal plasma originated not only from diffusion from the plasma but also from local production in semen.
Altogether these results suggest that the risk of transmission of resistant variants can only partly be predicted by determination of sequences in plasma virus. In addition, as in the first contribution, there were marked differences in drug resistance patterns between cell free virus and cell-associated virus but with more mutations in cell free virus. These patients were heavily pre-treated, most of them on HAART with virological failure, there was thus an ongoing selection of drug-resistant variants and an apparent delay for their storage in the reservoirs pointing to the dynamics of the exchanges between different compartments.
I am grateful to Professor Bernard Hirschel for helpful discussions.
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© 2004 Lippincott Williams & Wilkins, Inc.