Genotypic HIV‐coreceptor tropism prediction with geno2pheno [coreceptor]: differences depending on HIV‐1‐subtype

Abstract

Purpose of the study: Determination of HIV-1 coreceptor tropism is a major prerequisite before starting treatment with a CCR5-antagonist. While most of the patients currently under treatment with maraviroc are probably infected with HIV-1 subtype B viruses, recently published data show differences in the distribution of coreceptor tropism in different HIV-1 subtypes. Methods: In a Germany-wide project within the HIV-GRADE society, V3-loop sequences of 2466 isolates were analysed with geno2pheno for coreceptor tropism using a FPR cut-off of 10%. HIV-1 subtype was determined by using the COMET HIV subtyping tool. Sequences consisted of at least the V3 loop fragment. The ratio of CCR5 vs CXCR4 tropic viruses was calculated for each subtype. A normalized mean for all analyzed subtypes was calculated to extrapolate the overall ratio of coreceptor usage distribution. From this the expected distribution in the particular subtype was calculated and compared to the observed one. Statistical analysis was performed using the chi2 test. Summary of Results: Most samples were classified as HIV-1 subtype B (79%, n=1952). Other subtypes present in at least 23 samples were A1 (9.5%, n=234), C (4.8%, n=118), CRF01_AE (2.2%, n=55), G (1.6%, n=39), D (1.1%, n=27), F (0.9%, n=23). The calculated normalized mean distribution over all subtypes was 71% CCR5- vs. 29% CXCR4-tropic viruses. No significant difference compared to the mean distribution could be observed for HIV-1 subtypes B (71/29%), C (76/24%) and F (70/30%). Higher rates of CXCR4 tropic virus were detected in subtypes D (52/48%, p=0.01) and CRF01_AE (49/51%, p=0.001), while in HIV-1 subtypes A1 (22/78%, p=0.02) and G (13/87%, p=0.02), a higher rate of CCR5-tropic virus was observed. Conclusions: Our analysis shows a different distribution of CCR5 and CXCR4 tropic virus in some subtypes. In contrast to other publications, we could not observe a statistically significant difference in subtype C compared to the overall mean distribution, while we could confirm a higher rate of CXCR4-tropic virus in subtype D, as previously described. Without further data on treatment success of patients with non-B subtypes under treatment with maraviroc, it remains unclear if subtype-specific differences in the distribution of tropism are biased by differences in clinical variables before test or if there is a bias in the tropism interpretation system. In the latter case, individual interpretation cut-offs for different subtypes may be necessary

Novel Computerized Approaches to Investigating Pharmacological Activities

“…As shown in Figure 7, this program does not recommend HBX2 treatment with the CCR5 antagonist. These results are consistent with clinical findings [26].…”

“…The results of the abrogation of inhibitory effect of the Plasmodial Host Protein nDARC by its mutant (nDARC Y41F) [19] are also presented. Finally, the outcomes of the geno2-pheno CORECEPTOR-based analyses [26] of two HIV-1 strains, HXB2 and Yu-2 are also shown. These are used to show how pharmacological activities can be obtained using computerized procedures.…”

“…They also developed a computerized procedure, geno2pheno CORECEPTOR, which determines susceptibilities and/or resistances of HIV isolates to CCR5 antagonists using their Hyper-variable V3 domain sequences [26]. The program is available at [http://coreceptor.bioinf.mpi-inf.mpg.de/].…”

“…Obermeier et al have devised a computerized procedure and a program [26] that determines susceptibility of HIV strains to a class of antiretroviral agents (CCR5 antagonists) prior to treatment using the V3 sequence information of the strains. This computer-based pharmacological assessment is demonstrated in this study using two isolates, HXB2 (HIV-1 T cell lymphocyte-loving virus) and Yu-2 (HIV-1 Macrophage-loving virus).…”

“…Others computer-based assessments of pharmacological activities have been reported [23][24][25][26]. For example, HCV protein sequences associated with the Interferon/Rabavarin combination therapy have been determined using ISM [23].…”