Semen enhances HIV infectivity and impairs the antiviral efficacy of microbicides.
Topically applied microbicides potently inhibit HIV in vitro but have largely failed to exert protective effects in clinical trials. One possible reason for this discrepancy is that the preclinical testing of microbicides does not faithfully reflect the conditions of HIV sexual transmission. We report that candidate microbicides that target HIV components show greatly reduced antiviral efficacy in the presence of semen, the main vector for HIV transmission. This diminished antiviral activity was dependent on the ability of amyloid fibrils in semen to enhance the infectivity of HIV. Thus, the anti-HIV efficacy of microbicides determined in the absence of semen greatly underestimated the drug concentrations needed to block semen-exposed virus. One notable exception was maraviroc. This HIV entry inhibitor targets the host cell CCR5 co-receptor and was highly active against both untreated and semen-exposed HIV. These data help to explain why microbicides have failed to protect against HIV in clinical trials and suggest that antiviral compounds targeting host factors hold promise for further development. These findings also suggest that the in vitro efficacy of candidate microbicides should be determined in the presence of semen to identify the best candidates for the prevention of HIV sexual transmission.
Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Onofrio
O
Zirafi
Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Kyeong-Ae
KA
Kim
Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA. Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA.
Nadia R
NR
Roan
Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Silvia F
SF
Kluge
Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Janis A
JA
Müller
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
Shibo
S
Jiang
Institute of Epidemiology and Medical Biometry, Ulm University, 89081 Ulm, Germany.
Benjamin
B
Mayer
Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA. Departments of Medicine and Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
Warner C
WC
Greene
Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Frank
F
Kirchhoff
Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany. jan.muench@uni-ulm.de.
Jan
J
Münch
D019380:Anti-HIV Agents / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D050091:Dendrimers / Q000494:pharmacology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control*; D015497:HIV-1 / Q000472:pathogenicity; D006801:Humans; D020128:Inhibitory Concentration 50; D011107:Polylysine / Q000494:pharmacology; D012661:Semen / Q000737:chemistry* / Q000821:virology*
D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D050091:Dendrimers; D011107:Polylysine; C480351:astodrimer