Intra-host HIV-1 evolution and the co-receptor switch

The course of an infection with the human immunodeficiency virus type 1 (HIV-1) is characterised by three phases: primary infection, chronic infection and acquired immunodeficiency syndrome (AIDS). These stages are defined based on levels of the number of CD4-positive T-helper cells (CD4+). This characteristic three-staged classification is also reflected in the course of the viral divergence and in the emergence of viral diversity. It is known that the V3 loop, a region encoded in the HIV envelope gene, is important for T cell infection. The CD4 receptor of the cells is used as primary receptor for viral cell entry, and the CCR5 or CXCR4 are the most important co-receptors that are necessary for cell entry. In about half of all patients, HIV switches from CCR5 towards CXCR4 usage during the late stage of infection, which hints at the onset of AIDS. Since the co-receptor tropism is determined by the V3 loop sequence, an understanding of the mechanisms of its evolution and of the circumstances leading to the co-receptor switch is of high interest. In the first part of the present work, we analysed longitudinal patient data, comprising information on CD4+ cell count, viral load, medication, coinfections and V3 loop sequences. We examined the correlations among the clinical and evolutionary data as well as the co-receptor usage over time, guided by different questions: Is the course of disease one-directional? Can successful drug therapy influence co-receptor usage? What are the genetic differences between CCR5- and CXCR4-tropic viruses? Due to the weak statistical support of our data, we only found few indications that successful HAART therapy influences the course of disease and the direction of the coreceptor switch. We hypothesise that successful therapy can pause or roll back the course of infection, enabling the CD4+ cells to recover to high levels of immune pressure. A suppression of the viral load further can displace X4-tropic viral variants in the viral population in favour of R5-tropic variants. In the ...