A common component of semen appears to enhance the ability of HIV to infect cells, researchers here said.
Amyloid fibrils, dubbed semen-derived enhancer of virus infection (SEVI), capture HIV viral particles and promote their attachment to target cells, according to Frank Kirchhoff, Ph.D., of the University of Ulm, and colleagues.
Depending on the cell type, the interaction increases the infectivity of HIV by many orders of magnitude, Dr. Kirchhoff and colleagues reported in the Dec. 14 issue of Cell.
SEVI probably plays a role in sexual transmission of HIV and may offer a target for preventive strategies, perhaps in novel microbicides, the researchers said.
The researchers were looking for natural factors that inhibit HIV, but instead found that fragments of a semen marker called prostatic acid phosphatase (PAP) enhance the infectivity of the virus.
“We were not expecting to find an enhancer, and were even more surprised about the strength,” Dr. Kirchhoff said. “Most enhancers have maybe a two- or threefold effect, but here the effect was amazing - more than 50-fold and, under certain conditions, more than 100,000-fold.”
“At first, I didn’t believe it,” Dr. Kirchhoff said, “but we ran the experiment over and over, always with the same result.”
PAP itself has no effect on HIV infectivity, but it breaks down into relatively small fragments of about 4.0 to 4.5 kiloDalton. These fragments form amyloid fibrils that do enhance infectivity, the researchers said.
Interestingly, the effect is not confined to the natural products. Synthesized peptides with the same sequence also enhanced infectivity, although peptides with the same amino acids but a scrambled sequence had no effect.
In cell culture experiments, SEVI increased HIV infectivity by a factor of four in a lymphoid cell line (CEMx M7 cells) and by a factor of 400,000 in peripheral blood mononuclear cells, the researchers said.
“Just one to three virions are usually sufficient for productive HIV-1 infection of PBMC in the presence of SEVI,” Dr. Kirchhoff and colleagues said.
A similar effect was seen in transgenic rats whose T cells and macrophages express human CD4 and CCR5, the researchers reported.
Four days after the animals were given tail vein injections of HIV, between three and 12 copies of HIV cDNA per nanogram of total DNA were detected in splenocyte extracts, they found.
But when similar animals were injected with HIV treated with SEVI, the HIV load four days later was sharply higher - ranging from 21 to 49 copies of HIV cDNA.
The data from a series of experiments suggest that SEVI may “help HIV to pass the early ‘bottleneck’ in infection by assisting the virus to attach to genital surfaces, to establish a self-propagating infection at the point of entry, and to cross the mucosal barrier with migrating (dendritic cells),” Dr. Kirchhoff and colleagues said.
The authors noted several potential applications of the findings. “The high potency of SEVI in promoting viral infection together with its relatively low cytotoxicity suggests that it may not only play a relevant role in sexual HIV transmission but could also help to improve vaccine approaches and gene delivery by lentiviral vectors,” they wrote,
In addition, “agents blocking the generation or enhancing activity of SEVI and potential related virus attachment factors may offer new prospects for preventive strategies
The study was supported by the NIH, the NICHD, the European TRIoH Consortium, the government of Lower Saxony, the VW Foundation, the German Research Foundation, and the Wilhelm-Sander Foundation. The researchers reported no conflicts.
Additional source: Cell
Münch J, et al “Semen-derived amyloid fibrils drastically enhance HIV infection” Cell 2007; 131: 1059-71.