Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection

To understand the high variability of the asymptomatic interval between pri mary human immunodeficiency virus type 1 (HIV-1) infection and the developm ent of AIDS, we studied the evolution of the C2-V5 region of the HIV-1 env gene and of T-cell subsets in nine men with a moderate or slow rate of dise ase progression. They were monitored from the time of seroconversion for a period of 6 to 12 years until the development of advanced disease in seven men. Based on the analysis of viral divergence from the founder strain, vir al population diversity within sequential time points, and the outgrowth of viruses capable of utilizing the CXCR-1 receptor (X4 viruses), the existen ce of three distinct phases within the asymptomatic interval is suggested: an early phase of variable duration during which linear increases (similar to 1% per year) in both divergence and diversity were observed; an intermed iate phase lasting an average of 1.8 years, characterized by a continued in crease in divergence but with stabilization or decline in diversity; and a late phase characterized by a slowdown or stabilization of divergence and c ontinued stability or decline in diversity. X4 variants emerged around the time of the early- to intermediate-phase transition and then achieved peak representation and began a decline around the transition between the interm ediate and late phases, The late-phase transition was also associated with failure of T-cell homeostasis (defined by a downward inflection in CD3(+) T cells) and decline of CD4(+) T cells to less than or equal to 200 cells/mu l. The strength of these temporal associations between viral divergence an d diversity, viral coreceptor specificity, and T-cell homeostasis and subse t composition supports the concept that the phases described represent a co nsistent pattern of viral evolution during the course of HIV-1 infection in moderate progressors, Recognition of this pattern may help explain previou s conflicting data on the relationship between viral evolution and disease progression and may provide a useful framework for evaluating immune damage and recovery in untreated and treated HIV-1 infections.