Implications of X4 tropic virus detection before HAART and disease progression (2008)

Although combination antiretroviral chemotherapy (cART) has clearly made an enormous impact on decreased morbidity and delayed progression of human HIV-1 infection, the questions as to the criteria to be utilized for the initiation of such chemotherapy and the choice of drugs has been and continues to be a subject of debate. The availability of an ever increasing number of antiretroviral agents and the increasingly rapid evolution of knowledge on the effects of these drugs has thus contributed a great deal to the complexity in the selection and timing of treatment regimens. The reason for concern for such issues is based on the fact that although cART is clearly effective in a majority of HIV-1-infected patients and our ability to treat such patients is clearly improving [1], a significant number of patients experience virological failure [2]. Virological failure is defined as incomplete or lack of HIV-1-RNA response to the chemotherapy. The cost of cART, the associated toxicity with the use of such drugs, and the potential to increase the number of patients who do not respond to cART and who may have or may develop drug-resistant viral infections has prompted concern and a need for the identification of biomarkers that can aid either in optimal timing for the institution of therapy or in identifying the optimum drug regimes. In addition, the mechanisms for such unreponsiveness to chemotherapy is clearly of importance. A study was recently performed [3] utilizing a highly sensitive assay for the quantitation of CXCR4 (X4) and CCR5 (R5) co-receptors using viruses in plasma samples from a select group of HIV-1-infected patients before cART who not only had a diminished CD4 cell response but also showed an increased risk of disease progression or death under therapy (n = 96). Controls analysed in parallel consisted of plasma samples from age, sex and clinical stage matched HIV-1-infected patients from the same cohort who had been initiated on cART at the same time. The results of this study showed a high degree of correlation between the presence of the X4 co-receptor using viruses in plasma samples at baseline and disease progression, with the conclusion that the detection of such X4 tropic HIV-1 is an important biomarker that maybe utilized for the clinical management of such patients. There is a general consensus that X4 co-receptor utilizing isolates of HIV-1 have a different impact on CD4 T cells than isolates utilizing the R5 co-receptor. The X4 co-receptor utilizing HIV-1 isolates has thus been shown to possess increased cytotoxicity, which is manifested not only within the infected CD4 T-cell pool but is also associated with the increased killing of innocent bystander CD4 T cells by mechanisms that are still not clear [4]. The fact that the nearly complete depletion of CD4 T cells that occurs during the late stage of the disease is associated with the appearance of such n X4 co-receptor utilizing HIV-1 supports the concept that disease progression and rapid disease course are probably caused by the emergence of such X4 tropic HIV-1 and a likely advanced level of immune dysfunction allowing for the emergence of such X4 tropic viral isolates. These observations basically support the conclusions put forward by the authors. Clearly, larger and other multicenter studies are needed to validate these important findings. There are, however, a number of issues that should be considered in the interpretation of these data. Central to the claim by the authors is the criteria being utilized for initiating these rapidly progressing patients on cART within this cohort. There are thus a number of parameters other than age, sex, CD4 cell counts, clinical stage and the other variables the authors utilized that could play a role in the decision-making process for the initiation of cART in this particular group of patients. Therefore, as reported earlier, the quality of the general immune status and the virus-specific immune response is likely to be markedly lower in this group, which could allow for X4 tropic viruses to emerge in these patients. In addition, it has been shown that a significant number of HIV-1-infected patients use a variety of drugs of abuse, including alcohol and medicinal herbs, which not only interfere with cART metabolism but can also influence immune potential before the institution of cART and thus promote X4 variants. Other issues such as the presence of other underlying diseases that are not readily apparent and recognizable could also play a role in inducing immune compromise, leading to the selective propagation of X4 tropic viruses. It is thus possible that patients in this group were more immune compromised even before the initiation of cART than the control group, which could be the basis of the results obtained. Although the finding that patients with X4 tropic HIV-1 at baseline progress more rapidly in their disease course does provide a valuable parameter, a study of what influences this phenotype is important, and careful thought needs to be given to identifying these parameters. In addition, the poor subsequent response of these patients to cART could be secondary to multifactorial causes. These include differences in pharmacokinetics as a result of genetically based polymorphisms in genes involved in drug metabolism, drug transport, drug compliance issues, and a host of other genetic factors, including co-receptor polymorphisms, the inheritance of major histocompatibility complex alleles that could individually or in concert influence the outcome of the therapy. Finally, it should be noted that variations in the HIV env sequences in the plasma of select drug failure patients have also been identified as a biomarker, and as such it is possible that multiple biomarkers may provide a more refined understanding of virological failure. In summary, in the light of the findings by the authors that detection of the X4 co-receptor utilizing HIV-1 may be an important new biomarker that can be utilized for clinical management of these patients and clinical decision making, it is very important to identify the basic mechanisms that allow for the replication of X4 co-receptor utilizing viruses in such patients.