Most HIV-1 Infections Result From Single Virus
NEW YORK (Reuters Health) May 30 - Most primary HIV-1 infections result from transmission of single virus lineages that are able to avoid the immune system, according to a report in the May 19th issue of PNAS Early Edition.
“The results of this study provide one more important piece to the puzzle of understanding the molecular and cellular basis of HIV-1 transmission and eventually, hopefully, means to prevent transmission,” Dr. George M. Shaw from the University of Alabama at Birmingham told Reuters Health.
Dr. Shaw and associates developed and implemented an experimental strategy to enable them to identify unambiguously the transmitted or early founder env genes of viruses responsible for establishing productive HIV-1 infection; to track their evolution between transmission, peak viremia, and seroconversion; and to evaluate their phenotypic properties.
Using neighbor-joining phylogenetic tree methods and the Highlighter novel sequence visualization tool, the authors concluded that 78 of 102 subjects were productively infected by a single virus or virus-infected cell and 24 others were infected by at least 2 to 5 infectious units.
Sixteen of the 24 patients with multiple viruses had clear evidence of recombination, the report indicates.
In all 10 subjects examined longitudinally, the proportion of identical env sequences declined abruptly at the time of selection for cytotoxic T lymphocyte (CTL) escape mutants. However, no transmitted viral lineage was lost during acute infection, before peak viremia, and no predominant viral lineage appeared de novo.
All 55 Env glycoproteins corresponding to transmitted or early founder viruses were biologically functional in mediating CD4-dependent virus entry (54 were CCR5 tropic, 1 was CCR5/X4 dual-tropic), the investigators say, “indicating that the R5 phenotype is a property of the transmitted virus per se and not one that evolves during acute or early infection.”
Compared with chronic Envs, the transmitted or early founder Envs also showed masking of coreceptor binding regions and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and to broadly neutralizing antibodies, the researchers note.
“We interpret the findings of low multiplicity infection and limited viral evolution preceding peak viremia to suggest a crucial but finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses,” the authors conclude.
The findings provide an experimental strategy for analyzing patients (and animals) immunized with candidate vaccines but who nonetheless become infected, Dr. Shaw explained. By identifying the transmitted virus, “one can determine in molecular detail how mechanistically the virus escaped elimination. That should assist and hasten vaccine development.”
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