Background:  HIV that uses the CXCR4 coreceptor for T-cell entry (X4), or that induces syncytia on indicator cells (SI), has been associated with accelerated progression of HIV disease. Concordance between SI and X4 states is high, but not perfect. Anecdotal evidence suggests that unusually early outgrowth of, or infection with, X4/SI viruses can lead to rapid disease progression (AIDS/death <5 yrs post-seroconversion (SC)). We explored the converse question, whether rapid progressors (RP) are characterized by early acquisition of X4/SI virus. We hypothesized that RP are more likely to harbor viruses with the genotypic characteristics of X4/SI viruses within ~1.5 yr of infection than are typical progressors (TP, AIDS/death >5yr post-SC).

Methods:  Thirty-two seroconverters from the Multicenter AIDS Cohort Study were analyzed: 21 were RP, 11 were TP; 3 of the RP were dually infected ("duals") (Gottlieb et al., Lancet, in press). For each, a median of 30 V3 loop sequences (range 10 to 77) were obtained at 6 mo intervals within 1.5 yr of SC. We used position-specific scoring matrices (PSSM, Jensen et al., J. Virol., in press) to assess V3 sequences for both X4 and SI potential. PSSM scores reflect a continuum of amino acid changes leading from non-X4/SI virus to X4/SI during intrapatient viral evolution, in which higher scoring V3 sequences are more likely to be X4 or SI. Score distributions between RP and TP, and between singly infected and dual RP, were compared using Kruskal-Wallis tests (KWT) and ANOVA.

Results:  Mean and maximum SI scores were higher in RP (p <0.016, KWT), and remained so after duals were excluded (p <0.044). X4 scores were not significantly different between RP and TP. Within RP, duals had higher X4 and SI mean and max scores (p <0.017, KWT). ANOVA suggested that SI mean score influenced progression independently of dual infection (p = 0.027).

Conclusions:  Our results suggest that early acquisition of, or infection with virus in intermediate stages of X4 or SI evolution may promote or predict rapid disease, even though the virus may not use CXCR4 or be SI at that point. Clinical genotypic assessment of V3 loops may therefore have prognostic value earlier in infection than phenotypic testing. SI score may be more informative in this regard than X4 score. The dual infections may be associated with rapid progression in part because of increased X4/SI potential of one or both infecting strains.

Keywords: Coreceptor; Progression; Evolution