Helping hand for HIV | Nature Reviews Drug Discovery

Major efforts have been made to develop agents that prevent the transmission of HIV, but so far, none has been as successful as hoped. Kirchhoff and colleagues now present data showing that

semen-derived amyloid fibrils greatly enhance HIV infection. Targeting the formation of these amyloid fibrils from their precursor, prostatic acidic phosphatase (PAP), or blocking their

enhancing activity could represent a fresh preventive strategy for HIV. The authors identified the fibril-forming PAP fragments by screening a complex peptide/protein library of human semen

for factors involved in the transmission of HIV. One fraction that enhanced HIV infection in CD4+ T cells _in vitro_ contained fragments of PAP. Driven partly by the knowledge that amyloid

fibrils associated with Alzheimer's disease enhance HIV infection, the authors used structural analyses to confirm that the PAP fragments also formed amyloid fibrils that they termed

semen-derived enhancer of virus infection (SEVI). _In vitro_ experiments indicated that SEVI enhanced HIV virion binding and fusion to target cells. Enhancement of HIV virion fusion was

blocked when cells infected with SEVI-treated HIV were incubated with the fusion inhibitor T20 or a chemokine (C-C motif) receptor 5 (CCR5) antagonist, indicating that SEVI does not bypass

HIV's need for a co-receptor to enter a target cell. Further investigation showed that SEVI amplified HIV infection of CD4+ T cells _in vitro_, with the magnitude of the enhancing

effects being highest when the levels of infectious virus were low. SEVI also amplified infection of macrophages and increased _trans_-HIV infection of CD4+ T cells by an epithelial cell

line and primary dendritic cells _in vitro_. _In vivo_, SEVI significantly enhanced HIV infection of transgenic rats that express human CD4 and CCR5 on T cells and macrophages. _Ex vivo_,

infection of tonsillar tissues with very low doses of HIV occurred only in the presence of SEVI. Finally, the authors showed that seminal fluid and semen also enhance HIV infection, possibly

due to PAP fragments forming amyloid aggregates. Overall, Kirchhoff and colleagues show that semen and SEVI enhance infection by HIV, particularly at low viral titres, resembling the

conditions of sexual HIV transmission. This was most notable when peripheral blood mononuclear cell cultures and _ex vivo_ tonsillar tissues were infected at low viral doses only in the

presence of SEVI. New HIV prevention strategies could be developed by blocking the generation of SEVI, possibly by targeting PAP, or by inhibiting the enhancing ability of SEVI. As SEVI is a

type of amyloid fibril, research into therapeutic strategies against human amyloid diseases might be applied to the design of therapeutic agents against amyloid aggregates. REFERENCES

ORIGINAL RESEARCH PAPER * Münch, J. et al. Semen-derived amyloid fibrils drastically enhance HIV infection. _Cell_ 131, 1059–1071 (2007) Article  Google Scholar  FURTHER READING * Flexner,

C. et al. HIV drug development: the next 25 years. _Nature Rev. Drug Discov._ 6, 959–966 (2007) Article  CAS  Google Scholar  * Sacchettini, J. C. and Kelly, J. W. Therapeutic strategies for

human amyloid diseases. _Nature Rev. Drug Discov._ 1, 267–275 (2002) Article  CAS  Google Scholar  Download references Authors * Bethan Hughes View author publications You can also search

for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hughes, B. Helping hand for HIV. _Nat Rev Drug Discov_ 7, 120

(2008). https://doi.org/10.1038/nrd2523 Download citation * Issue Date: February 2008 * DOI: https://doi.org/10.1038/nrd2523 SHARE THIS ARTICLE Anyone you share the following link with will

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