Different hypotheses have been postulated to explain the naturally long but variable progression of HIV-1 infection. An understanding of the reasons for this variable pattern of disease progression is of fundamental importance in AIDS research. Based on the most recent evidence, a new fundamental theory is considered prevalent. This theory proposes that the proven shift in tropism HIV-1 infection soon becomes deadly because T-lymphocyte tropic viruses (T-tropic, X4) replicate at a much higher rate and kill more cells than the macrophage-tropic viruses (M-tropic, RS) consistently seen in initial infection. This theory, although popular and prevalent, is not yet a proven hypothesis of how HIV becomes increasingly cytotoxic and thereby influences disease progression. We hypothesize that the early appearance of T-tropic virus in patient plasma will precede or directly relate to fast progression. We also believe that the CD-4 T-lymphocyte sub-population depletion patterns will relate to or even predict the appearance of T-tropic viral variants. Therefore, we propose to document and better characterize the viral variants, genomic and tropic involved in different rates of progression in Puerto Rican patients and their T-lymphocyte sub-population depletion patterns. We will compare approximately twenty fast progressors with twenty normal/slow progressors. We propose to do a study, sub-cloning and sequencing the C2V3 region of the envelope gene, at multiple time points, from all patients in both cohorts. We will track viral evolution and diversity by studying the tendency to form clusters associated with sampling time in the phylogenetic re-constructions. A consensus motif in the V3 domain that predicts CCR5 usage (M-tropic/R5) has been delineated. Based on this consensus, we propose to identify the tropism of the viral forms present at these sampling time points by genomic sequence analyses of the V3 envelope region, in order to better understand tropism and disease progression. We also propose to conduct a flow-cytometry study of both cohorts at these sampling time points to evaluate if the recent discovery (1999) of the "ex-vivo" depletion of a CD4-CCR5 T-lymphocyte sub-population caused by M-tropic virus relates to or precedes the eventual appearance in plasma of T-tropic viruses. This may provide an early, efficient and cost effective marker of disease progression.
NIH ExPorter
NIH ExPorter