Natural Enhancers and Inhibitors of HIV Infection
J Munch1, L Standker2,3, W G Forssmann2,3, and Frank Kirchhoff*1
1Univ Clin of Ulm, Germany; 2VIRO Pharma GmbH & Co, Hannover, Germany; and 3Hannover Med Sch, Ctr of Pharma, Hannover, Germany
Background: Natural compounds in human body fluids or
tissues may affect HIV infection and hence play a role in virus transmission or
pathogenesis. However, it has frequently proven difficult to purify and
characterize these agents because of the limited quantities of available human
material and the lack of reliable methods.
Methods: To overcome these limitations we have developed standardized
methods to generate peptide libraries from body fluids or tissues.
Screening of a comprehensive peptide library generated from human
hemofiltrate led to the identification of a 20-residue peptide, designated
VIRus-Inhibitory Peptide (VIRIP), which corresponds to a C-proximal region of
α1-antitrypsin and inhibits HIV-1 by blocking the function of the gp41
fusion peptide. Interestingly, a few amino acid changes increased its
antiretroviral potency by 2 orders of magnitude, making it interesting for
clinical development. More recently, we screened a peptide library derived from
seminal fluid to identify natural agents that might play a role in sexual
transmission of HIV/AIDS.
Results: We found that naturally occurring fragments of the abundant
semen marker prostatic acidic phosphatase (PAP) drastically enhance HIV infection.
Further analyses showed that these peptides form amyloid-like fibrils, termed
semen-derived enhancer of virus Infection (SEVI), that capture HIV virions and
promote their attachment to target cells, thereby enhancing the infectious
virus titer by several orders of magnitude. Physiological concentrations of
SEVI amplified HIV infection of T cells, macrophages, ex vivo human
tonsillar tissues and transgenic rats in vivo, as well as trans-HIV
infection of T cells by dendritic or epithelial cells. In agreement with a
relevant role in vivo we found that semen and seminal fluid also enhance
HIV infection and provide evidence that fibril-forming PAP fragments contribute
to this effect.
Conclusions: Our ongoing experiments aim to further elucidate the
enhancing mechanism and to identify agents that suppress this effect. Moreover,
we are investigating the effect of seminal fluid and different fibrils on
infection by other viruses to clarify whether amyloid-like aggregates may play
a more general role in the spread of sexually transmitted diseases.