DOI: 10.1097/01.qai.0000351065.51590.44
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Issn Print: 1525-4135
Publication Date: 2009/06/01
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Excerpt
Methods: Recently, we developed a mathematical model of viral sequence evolution in acute HIV-1 infection and an empirical dataset of 3449 complete HIV-1 subtype B env sequences derived by single genome amplication (SGA)-direct amplicon sequencing that allowed us to infer the exact nucleotide sequences of full-length env genes of transmitted and early founder viruses in 98 of 102 consecutively studied patients (Keele et al., PNAS 2008). Here, we applied the same experimental strategy to the identification of full-length HIV-1 genomes in 12 subjects with acute or early subtype B or C infection and characterized their early evolution.
Results: Prior to antibody seroconversion, viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to inferred transmitted/early founder consensus sequences at or near the estimated time of virus transmission. 11 of 12 subjects were productively infected by a single virus (or virally-infected cell) and one was infected by two viruses. In four subjects, we performed sequential SGA analyses of complete viral genomes over the first year of infection and mapped each autologous CTL epitope recognized and escaped. We also mapped neutralizing antibody (Nab) recognition and escape in Env. Immune recognition and escape occurred substantially earlier for CTLs (∼4 wks post-infection) than for Nabs (∼12 wks post-infection). Within a two week period beginning at peak viremia, virtually the entire body's population of productively infected cells was replaced by cells infected with viruses containing CTL escape mutations that were confirmed phenotypically. Complete replacement of transmitted wildtype virus by Nab escape virus occurred between 8 and 12 weeks post-infection.
Conclusions: Identification of transmitted/founder full-length genomes allows for a comprehensive and dynamic assessment of immune recognition and escape in HIV-1 infected humans, including individuals immunized with candidate HIV-1 vaccines who experience breakthrough infections. We are currently conducting similar studies in monkeys infected intrarectally by SIVmac251 or SIVsmE660 to better define this animal model system and its relationship to humans infected mucosally by HIV-1.
