Human immunodeficiency virus type 1 fitness and tropism: concept, quantification, and clinical relevance.

Two distinct aspects of human immunodeficiency virus type 1 (HIV-1) biopathology with important implications for the management of treated patients have emerged during the last decade: changes in relative viral fitness, and viral tropism. First, it has been observed that HIV-1 accumulates deleterious mutations leading to drug resistance and different degrees of reduction in relative fitness during antiretroviral therapy (ART). Although the latter normally parallel a failure of ART resulting from selection of resistant mutants, the drop in viral replication capacity may be beneficial for the host. Moreover, specific antiviral compounds aimed at reducing viral fitness could be developed. Analysis of the determinants of viral fitness in highly evolving viral populations has shown that viral extinction may also be obtained by forcing highly dynamic viral populations through increased (lethal) mutagenesis that abolishes viral replication (violation of the error threshold). It could be of great interest in the near future to address this point with strategies specifically planned at the molecular level. Furthermore, diagnostic evaluation limited to the master sequence has low predictive value in rapidly evolving viral populations. These observations, together with the evidence that all of the methodologies currently used for fitness analysis have important limitations, strongly suggest that further research is warranted. This should use highly sensitive and flexible technologies to evaluate viral fitness directly in vivo or ex vivo, not only for the dominant mutants, but also for minority variants. Second, discovery of the two main co-receptors for HIV-1, CCR5 and CXCR4, has led to a better understanding of the interaction of the viral envelope with host cells and to the development of novel therapeutic agents that inhibit viral entry. In this perspective, analysis of HIV-1 tropism has acquired a major diagnostic role.