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HIV-1 X4/R5 co-receptor in viral reservoir during suppressive HAART
[Research Letters]
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AIDS:Volume 21(16)October 2007p 2243-2245
Soulie, Cathiaa; Marcelin, Anne-Genevievea; Ghosn, Jadeb; Amellal, Bahiaa; Assoumou, Lambertc; Lambert, Sidoniea; Duvivier, Claudineb; Costagliola, Dominiquec; Katlama, Christineb; Calvez, Vincenta
aDepartment of Virology-EA2387, Pitie Salpetriere Hospital, University Pierre et Marie Curie, Paris, France
bDepartment of Infectious Diseases, Pitie Salpetriere Hospital, University Pierre et Marie Curie, Paris, France
cINSERM UMR720, Paris 6 University, Paris, France.
Abstract
As immune recovery during HAART is mainly caused by the expansion of X4-naive cells, we studied the evolution of HIV tropism in the reservoir of 34 patients receiving 48 weeks of HAART. No change in virus tropism was observed over time, but patients with X4 viruses had higher HIV-1 proviral DNA levels than patients with R5 viruses. This suggests that CCR5 antagonist activity should not be compromised in patients harbouring R5 viruses before starting HAART.
The restoration of CD4 T cells in response to HAART depends on a slow increase in naive CD4 T cells [1]. Naive CD4 T cells could be a significant HIV reservoir in patients harbouring X4 variants perhaps because these cells almost exclusively bear the X4 co-receptor [2,3].
A relationship between co-receptor use and HIV disease progression has been established [4], but the impact of an effective HAART regimen on HIV-1 tropism is not completely understood. The potential influence of HAART on the selection of X4 viruses has been underlined in a study on 28 HIV-1 subtype C-infected patients describing the emergence of X4 viruses associated with the use of HAART [5]. A switch from R5 to X4 variants was found in a longitudinal follow-up of patients under 5 years HAART, but other studies suggested that HAART might delay the selection of X4 viruses [6-8]. Moreover, the X4 viruses could play a role in the pathogenesis of poor immune reconstitution on HAART [9]. Those previous studies raised the question of the risk of improving the reservoir with X4 viruses in patients under HAART and harbouring an immune reconstitution, because there is still a debate about the existence of persistent low viral replication under HAART [10]. This could have an impact on the use of CCR5 antagonists, such as maraviroc and vicriviroc, which block HIV entry into the cell and are particularly active against HIV-1 R5 strains. In maraviroc clinical trials, the emergence of X4 viruses has been described in some patients [4,11,12]. Phylogenic analysis indicated that the X4-using variants probably emerge from a pre-existing X4-using reservoir, rather than via co-receptor switch of R5 tropic clones under maraviroc selection pressure. It is thus important to determine HIV tropism in the reservoir during HAART to know whether CCR5 antagonists can still be effective after months of HAART. The objectives of this study were to investigate the tropism of viruses present in the cellular reservoir in a group of patients under suppressive HAART and to determine the potential impact of the evolution of tropism.
Thirty-four naive patients, all HIV-1 subtype B infected, enrolled in the Hippocampe-ANRS 121 trial comparing regimens including protease inhibitors or non-nucleoside reverse transcriptase inhibitors, were studied [13]. These patients harboured HIV-1 plasma viral loads less than 50 copies/ml after 48 weeks of HAART except for three patients (Table 1). V3 env was amplified and sequenced from plasma and peripheral blood mononuclear cells (PBMC) at baseline and in PBMC at week 48. HIV-1 co-receptor usage was determined from the V3 env region sequence by Geno2pheno (http://coreceptor.bioinf.mpi-sb.mpg.de/cgi-bin/coreceptor.pl ) and PSSM algorithms (http://ubik.microbiol.washington.edu/computing/pssm/ ) [14,15]. Viruses were classified into two categories: those with a lack (R5) or presence of X4-tropic viruses (R5X4 or X4). HIV-1 proviral DNA was quantified at baseline and week 48 as previously described [16].
At baseline, 22 out of 34 patients harboured a majority of R5 variants and X4 or R5X4 variants were predominant in 12 out of 34 patients in plasma and PBMC (Table 1). The same tropism was observed in plasma and PBMC for all patients. There was a switch from R5 to R5X4 variants at week 48 in only one of the 22 patients who harboured R5 variants at baseline. Patients harbouring R5X4/X4 variants at baseline had significantly lower CD4 T-cells counts (median 112 ± 106 and 269 ± 104 cells/μl, P = 0.03) and higher HIV-1 proviral DNA (median 3.4 ± 0.3 and 2.9 ± 0.4 log10 copies per 106 cells, P = 0.004) than patients with R5 variants. At week 48, only HIV-1 proviral DNA remained significantly different between patients harbouring R5 and R5X4/X4 viruses (median 2.56 ± 0.3 and 2.72 ± 0.51 log10 copies per 106 cells, respectively, P = 0.004). CD4 T-cell counts tended to be lower in patients harbouring R5X4/X4 variants than in patients harbouring R5 viruses (median 352 ± 163 and 457 ± 197 cells/μl, respectively, P = 0.21).
These results suggest that the tropism of viruses present in the reservoir cells did not change after 48 weeks of suppressive HAART despite the increase in CD4 cells as a result of the expansion of naive cells. The discrepancy with a previous study could be explained by the type of regimen or different time of analysis [8].
In the present study, patients harbouring X4 strains had significantly lower CD4 T-cell counts than patients harbouring R5 strains. After 48 weeks of HAART, this difference did not remain significant, but patients with R5X4/X4 viruses tended to have lower CD4 T-cell counts, even though the CD4 T-cell counts had increased from baseline. These results are in accordance with those of the HOMER cohort, in which the CD4 cell counts in subjects harbouring X4 variants were, on average, three times lower than those in subjects harbouring exclusively R5 variants [17]. In addition, there is a link between the presence of R5X4/X4 strains and the level of HIV-1 proviral DNA: the presence of X4 viruses was associated with higher HIV-1 proviral DNA at baseline and after 48 weeks of HAART, in comparison with R5 variants, and this difference remained significant despite the decrease in HIV-1 proviral DNA induced by HAART. It has been shown that the presence of X4 viruses clearly increases the risk of disease progression and this could be related to a higher rate of HIV-1 proviral DNA [17]. R5 and X4 viruses do not infect all CD4 T cells with equal efficiency, probably because of the differences in co-receptor expression [18,19]. This co-receptor expression pattern may thus be critical to explain the differences in integration of HIV-1 DNA in host cells.
In conclusion, in the group of patients receiving HAART studied here, X4 variants did not emerge in the reservoir over time. This study suggests that the use of CCR5 antagonists should not be compromised in patients harbouring R5 viruses before starting fully suppressive HAART without R5 antagonists. As the emergence of X4 viruses in plasma during treatment with R5 antagonists has been described for a minority of treated patients, it will be interesting also to study the reservoir and its possible evolution in the context of R5 antagonist treatment.
Sponsorship: This work was supported by ANRS (National French Agency for AIDS Research).
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