HIV-1 GENETIC VARIATION IN INFECTED HEMOPHILIACS OVER TIME

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The large majority of human immunodeficiency virus (HIV)-1-infected people develop acquired immune deficiency syndrome (AIDS) and die; however, there is considerable variation in the duration of the latency period and in the rate of CD4 decline. Cofactors such as other viruses, host genetic differences, and variants within the virus quasi-species have all been implicated in the observed heterogeneity of disease progression. This project is analyzing the extent and pattern of HIV-1 sequence divergence within a selected group of patients from the Hemophilia Growth and Development Study (HGDS). The study is comparing the quantitative and qualitative differences in viral sequences between fast and slow progressors using decline of CD4 and T-lymphocyte counts as a surrogate marker for progression to AIDS. Slow progressors are defined as subjects whose CD4 counts remain stable or increase over the 2-year period between baseline and second annual visit. Nested primer polymerase chain reaction is being used to amplify selected regions of env, gag, pol, and nef from cDNA from RNA extracted from virions in the plasma and from provirus. Amplified gene segments will be cloned and sequence analysis will be done to detect and examine the accumulation of mutations under the selective pressure of the host immune system. At least 20 clones will be sequenced from each patient from sequential time points. Progress to date has been limited to working out technical methods, selecting primers, and retrieving plasma and cell specimens from the HGDS. Fifteen sequences from the env gene obtained from plasma particles have been cloned and sequenced.